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BackgroundThe preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited.MethodsA modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread.Results30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135).ConclusionThis technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

Jiaxing Chi,1,* Xiang Zhang,1,* Zetong Nie,1 Yue Pan,1 Wenbo Li,1 Bojie Hu2 1Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China; 2NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bojie Hu, Email bhu07@tmu.edu.cn Wenbo Li, Email wenboli80@163.comBackground: Postoperative vitreous hemorrhage (POVH) after pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) is a common complication that delays visual recovery. While vitreous lavage (VL) mechanically clears hemorrhages, intravitreal ranibizumab (IVR) targets VEGF-mediated neovascularization. We compared the efficacy and safety of IVR and VL for the management of POVH.Objective: To compare the visual outcomes, hemorrhage clearance efficiency, and complications between IVR and VL over a 24-week follow-up period.Methods: In this prospective randomized controlled trial, 26 patients with POVH for PDR were allocated to the VL (n=12) or IVR (n=14) groups. Follow-up evaluations at 1 day, 1 week, 2 weeks, and monthly for up to 6 months included best-corrected visual acuity (BCVA) and complications. Novel metrics that included Visual Acuity Recovery Rate (VARR), Time to 1.0 logMAR-Equivalent Improvement (T1EI), and time to peak BCVA (Tpeak VA) quantified the recovery dynamics.Results: At 24 weeks, BCVA improvement was comparable between groups (VL: 0.30 LogMAR vs IVR: 0.22 LogMAR, p=0.47). VL achieved immediate BCVA gains in one day (1.99 vs 0.91 LogMAR, p< 0.01), whereas IVR demonstrated progressive improvement after 2 weeks. VARR was higher in VL at 1 day (0.76 vs 0.25, p< 0.001) and 2 weeks (0.84 vs 0.61, p=0.06) but converged by 24 weeks (p=0.86). The complication rates (recurrent hemorrhage and neovascular glaucoma) were similar (p> 0.05).Conclusion: VL and IVR were both associated with improved visual outcomes in patients with POVH throughout the 24-week follow-up period. The VL group achieved immediate BCVA improvement, and IVR showed a progressive improvement pattern. The VL group showed superior short-term efficiency. IVR showed a trend towards sustained recovery over the 24-week study period. In our study, IVR showed a trend of higher recovery efficiency within the follow-up timeframe. The advert treatment outcomes after the two treatments did not significantly differ. Thus, treatment selection should balance the urgency of visual rehabilitation and patient-specific factors.Keywords: postoperative vitreous hemorrhage, intravitreal ranibizumab, vitreous lavage

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is increasingly used for the treatment of a wide variety of retinal diseases, including age-related macular degeneration, diabetic retinopathy and retinal vascular occlusions, and retinopathy of prematurity. Despite encouraging results in halting the disease and improving the vision, intravitreal injection of anti-VEGF agents may be associated with systemic adverse events and devastating ocular complications. In this review, we provide an overview of safety data for intravitreal injection of common anti-VEGF agents.

PurposeIntravitreal injection of VEGF inhibitors has become the standard of care for different macular diseases within the last years resulting in improved visual outcomes. Under real-life conditions, however, the necessity for frequent retreatments and reexaminations poses a burden for patients and treatment centers. Non-adherence and non-persistence to intravitreal treatment may lead to inferior clinical outcomes, and knowledge of contributing factors is crucial to improve adherence. This systematic review analyzes current literature for potential factors involved in non-adherence and non-persistence.MethodsA systematic search was conducted in PubMed and Embase including three different aspects of intravitreal injection therapy: (1) diseases with intravitreal injections as treatment, (2) intravitreal injection, and (3) aspects of therapy adherence or therapy persistence. Data from identified quantitative studies were further extracted and grouped according to WHO criteria (condition, socio-economy, therapy, patient, and health system). The methodological quality of identified studies was graded. Identified qualitative studies (i.e., interviews) were descriptively analyzed and their findings narratively reported.ResultsTwenty-four publications were included. In 16 of those publications, a quantitative data analysis was conducted, analyzing factors associated with non-adherence. Worse visual acuity at baseline and unfavorable development of visual acuity, higher age, and greater distance to the treatment center were associated with non-adherence, while there was inconsistent evidence for an association of comorbidity. In qualitative studies, high follow-up/treatment burden, fear and anxiety, disappointed patient expectations, and lack of motivation to continue treatment were reported as reasons for non-persistence.ConclusionsKnowledge of potential barriers in IVT treatment may improve adherence and potentially clinical results. Improvements can be achieved particularly in the healthcare complex (organizational improvements) and the “patient” complex by establishing realistic expectations. Recurrent education of the patient may be necessary.

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Diabetic retinopathy (DR) is associated with retinal neovascularization, hard exudates, inflammation, oxidative stress and cell death, leading to vision loss. Anti-vascular endothelial growth factor (Anti-VEGF) therapy through repeated intravitreal injections is an established treatment for reducing VEGF levels in the retina for inhibiting neovascularization and leakage of hard exudates to prevent vision loss. Although anti-VEGF therapy has several clinical benefits, its monthly injection potentially causes devastating ocular complications, including trauma, intraocular hemorrhage, retinal detachment, endophthalmitis, etc. As mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) demonstrated safety in clinical studies, we have tested the efficacy of MSC-derived small EVs (MSC-sEVs) loaded anti-VEGF drug bevacizumab in a rat model of DR. The study identified a clinically significant finding that sEV loaded with bevacizumab reduces the frequency of intravitreal injection required for treating diabetic retinopathy. The sustained effect is observed from the reduced levels of VEGF, exudates and leukostasis for more than two months following intravitreal injection of sEV loaded with bevacizumab, while bevacizumab alone could maintain reduced levels for about one month. Furthermore, retinal cell death was consistently lower in this period than only bevacizumab. This study provided significant evidence for the prolonged benefits of sEVs as a drug delivery system. Also, EV-mediated drug delivery systems could be considered for clinical application of retinal diseases as they maintain vitreous clarity in the light path due to their composition being similar to cells.

Purpose To report short-term outcomes of treatment switch to faricimab in real-world patients with aflibercept-resistant neovascular age-related macular degeneration (AMD). Methods Single-center, retrospective cohort study with chart-review using electronic injection database, electronic medical records, and optical coherence tomography (OCT) data from May to September 2023. Results A total of 50 eyes of 46 patients were analyzed. Faricimab treatment led to absence of fluid in 32% of the eyes and a reduction of fluid in 84% of the eyes. There was a statistically significant decrease in central retinal thickness (CRT) and pigment epithelial detachment (PED) height in those that responded to the switch (median difference: − 31 μm, IQR: 55, p  < 0.0001 and median difference: − 21 μm, IQR: 36, p  < 0.0001, respectively) and a statistically significant increase in CRT (median difference: + 19 μm, IQR: 20, p  = 0.0143) and no change in PED height (median difference: + 22 μm, IQR: 64, p  = 0.1508) in those that did not. Best-corrected visual acuity (BCVA) showed marginal decrease with low statistical significance. No ocular or systemic safety events were observed. Conclusions Our findings suggest that switching to faricimab is generally safe and effective in patients with neovascular AMD who are otherwise difficult to treat and have residual fluid despite frequent injections with aflibercept. We observed a high rate of morphological response to the treatment switch, improvement of anatomical parameters with about one-third of patients having dry macula following a single injection, and a marginal change in BCVA. Sustainability of these results requires further investigation. Study registration ClinicalTrials.gov registration number: NCT06124677. Date of registration: 09/11/2023, retrospectively registered.

PurposeTo investigate the influence of treatment regularity with intravitreal aflibercept injections (IVT-AFL injections) on visual acuity (VA) outcomes in patients with neovascular age-related macular degeneration (nAMD) enrolled in the PERSEUS trial who received at least 7 IVT-AFL injections during the first year.MethodsThis was a post hoc analysis of the PERSEUS trial, a prospective, non-interventional, multicenter cohort study, and included 370 patients with nAMD who had received ≥ 7 IVT-AFL injections during year 1. In addition to the prespecified subgroups of treatment-naïve and previously treated patients, results were compared between patients with regular (n = 209) and irregular (n = 161) treatment. Regular treatment was defined as initial dosing with monthly IVT-AFL injections for 3 months, then bimonthly IVT-AFL injections until month 12. Irregular treatment was defined as any deviation from regular treatment (provided ≥ 7 injections were received). The outcome of primary interest was the mean change in VA from baseline after 12 months. Further outcomes of interest included VA gain or loss, proportion of patients achieving reading vision, and percentage of patients with fluid.ResultsAt month 12, the mean (± standard deviation, SD) VA improvement from baseline was 6.1 ± 15.6 Early Treatment Diabetic Retinopathy Study letters in the regular cohort and 2.5 ± 16.7 letters in the irregular cohort with ≥ 7 IVT-AFL injections (P = 0.0514). Best results were obtained in the treatment-naïve regular sub-cohort with a mean ± SD VA improvement of 8.0 ± 17.7 letters, whereas treatment-naïve patients with irregular treatment experienced a considerably lower VA gain (2.8 ± 20.0 letters). Irregular treatment consistently correlated with inferior results in treatment-naïve patients. At month 12, the proportion of treatment-naïve patients who had experienced a worsening of ≥ 5 letters was 29.6% in the irregular sub-cohort versus 13.6% in the regular sub-cohort (P = 0.0049). However, among the treatment-naïve patients, the mean number of injections was significantly higher in the irregular than in the regular sub-cohort (8.0 ± 1.2 vs. 7.4 ± 0.6; P = 0.0001). Furthermore, compared with the treatment-naïve, regular sub-cohort, patients in the irregular sub-cohort had more visits (19.1 ± 8.6 vs. 16.1 ± 5.7), VA tests (14.2 ± 6.9 vs. 12.0 ± 4.6), and optical coherence tomography examinations (5.1 ± 3.7 vs. 3.4.0 ± 3.0).ConclusionsAlthough irregularly treated patients received more injections and more monitoring visits during the first year of IVT-AFL treatment, they experienced worse VA outcomes than regularly treated patients.

BackgroundTo investigate the levels of VEGF in the systemic circulation of patients with type 1 ROP who received intravitreal injections of 1 mg (0.025 mL) aflibercept (IVA) or 0.625 mg (0.025 mL) bevacizumab (IVB).MethodsPatients who had type 1 ROP and received either IVA or IVB were enrolled in this prospective study. Serum and plasma samples were collected prior to and up to 12 weeks after IVB or IVA treatment. The serum and plasma VEGF levels were measured using enzyme-linked immunosorbent assays (ELISAs), and the platelet levels in the blood were also quantified. The serum and plasma levels of VEGF, as well as the ratio of VEGF to platelet count (VEGF/PLT) were measured prior to and up to 12 weeks after anti-VEGF treatment.ResultsIn total, 14 patients with type 1 ROP were enrolled in this study; five patients received IVA, and nine patients received IVB. Following either IVA or IVB treatment, all the eyes (100%) showed complete resolution of ROP-induced abnormal neovascularization and presented continued vascularization toward the peripheral retina. Compared to baseline, the serum VEGF levels were significantly reduced in the ROP patients up to 12 weeks after either IVA or IVB treatments (all P < 0.05). At 2, 4, and 8 weeks after intravitreal injection, the serum VEGF levels were more suppressed in the IVB group than in the IVA group (P = 0.039, P = 0.004, and P = 0.003, respectively). The serum VEGF/PLT ratio after IVA or IVB showed similar reductions and trends as the serum VEGF data. Changes in the plasma VEGF levels could not be properly assessed because some of the samples had VEGF levels below the detection limit of the ELISA.ConclusionsSerum VEGF levels and the VEGF/PLT ratio in patients with type 1 ROP were suppressed for 3 months after treatment with either IVA or IVB, but the suppression of systemic VEGF was more pronounced in patients treated with IVB than those treated with IVA.

Purpose This study aimed to compare functional and morphologic changes in the loading phase between patients with treatment-naïve macular neovascularization (MNV) due to neovascular age–related macular degeneration (nAMD) treated with either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting. Methods We retrospectively studied 92 consecutive eyes of 90 patients with neovascular nAMD who were scheduled to receive IVBr (42 eyes of 41 patients) or IVF (50 eyes of 49 patients) injections between October 2021 and December 2022. All patients received three consecutive monthly injections of 6.0 mg/0.05 mL brolucizumab or 6.0 mg/0.05 mL faricimab. The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and central choroidal thickness (CCT) at baseline and 1, 2, and 4 months after the initial treatment were measured and compared between the groups. Results Thirty-seven eyes in IVBr group and forty-seven eyes in IVF group who finished treatments in the loading phase were assessed at the follow-up examination. The BCVA, CFT, and CCT changed significantly after loading phase in both groups ( P < 0.05 for both comparisons). The IVBr group had more rapid improvement of the BCVA ( P = 0.037) at 1 month than the IVF group, but there was no difference at 4 months ( P = 0.367). The CFT and CCT decreases tended to be greater in the IVBr group than in the IVF group throughout the follow-up period. Of the five eyes excluded from the IVBr group, one eye (2.4%) each had intraocular inflammation (IOI) and was a non-responder, and two eyes (4.8%) had retinal pigment epithelial tears after treatment. Of the three eyes excluded from the IVF group, two eyes (4.0%) did not respond to the treatment. Conclusions Both IVBr and IVF injections were well-tolerated and improved the VA in treatment-naïve patients with MNV due to nAMD after a loading phase, although IVBr caused a trend toward faster visual improvements in the BCVA. The IVBr group also had greater reductions of the CFT and CCT than the IVF group. However, the potential for adverse events and no response to treatment with each drug are considerations.