Corneal Toxicity in Patients Treated by BELANTAMAB MAFODOTIN: How to Improve and Facilitate Patients Follow-Up Using Refractive Shift?

Purpose: Multiple myeloma (MM) is the second most common neoplastic blood disease worldwide. Belantamab mafodotin is a new antibody conjugate anti-B-cell maturation antigen effective against refractory myelomas. It induces intracorneal microcysts leading to refractive fluctuations. The aim of this study is to assess the value of monitoring refractive fluctuations based on the location of microcystic-like epithelial changes (MECs) to facilitate patient follow-up. Methods: This observational and multicentric study was conducted using data collected from several French centers contacted through secure email through a standardized data collection table. Results: The fluctuation of objective refraction in spherical equivalent confirms a significant myopic shift from peripheral to central forms. A decrease in the best-corrected visual acuity (BCVA), an increase in keratometry, and an increase in central epithelial pachymetry have also been observed when MECs migrate toward the center. Conclusion: The myopization found in our study in patients with central and paracentral MECs is consistent with current literature. Fluctuations in BCVA, keratometry, and epithelial pachymetry are also consistent. This study is the first real-world study and highlights heterogeneity in follow-up, emphasizing the need to establish multidisciplinary follow-up strategies. The analysis of refractive fluctuations appears to be a reproducible and noninvasive screening method that could facilitate patient follow-up without the need for consultation focused on corneal diseases.

Real-world experience with brolucizumab in neovascular age-related macular degeneration over 2 years: the REBA extension study.

BACKGROUND: To determine long-term efficacy and safety of intravitreal brolucizumab therapy for neovascular age-related macular degeneration (nAMD) in the real-world setting. METHODS: Retrospective, observational, multicentric study and an extension of the REBA study (Real-world Experience with Brolucizumab in nAMD) to 24 months. The study entailed follow-up of 91 consecutive eyes (67 patients) with nAMD who received brolucizumab therapy and completed 24 months of follow-up. Both treatment-naïve and switch therapy patients were included. All relevant data were collected. The primary outcome measure was changed in best-corrected visual acuity (BCVA) over time. Secondary outcome measures included change in central subfield thickness (CST) and complications. RESULTS: The mean (SD) baseline BCVA was 48.4 (3.5) letters and 36.2 (7.1) letters in treatment-naïve group and switch therapy group, respectively. BCVA gain was + 9.2 (3.7) letters (p = 0.01) and + 7.7 (3.4) letters (p = 0.011), respectively. The change in mean (SD) CST has shown a significant decrease in retinal thickness in treatment-naïve group (from 432.5 (68.4) to 283.0 (51.3) µm; p = 0.018) and in switch therapy group (from 452.5 (40.5) to 271.0 (43.4) µm; p = 0.011) group. One switch patient developed vascular occlusion and another a macular hole after the fifth brolucizumab injection as reported in the primary study. Both patients recovered uneventfully. Three patients demonstrated reversible intraocular inflammation between months 10 and 24. CONCLUSION: Patients showed a significant anatomical and functional response to brolucizumab therapy in the real world, regardless of prior treatment status, until the end of the follow-up period. Overall, 5 significant untoward events were noted.

The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis.

Studies about radiation-induced human cataractogenesis are generally limited by (1) the poor number of epithelial lens cell lines available (likely because of the difficulties of cell sampling and amplification) and (2) the lack of reliable biomarkers of the radiation-induced aging process. We have developed a mechanistic model of the individual response to radiation based on the nucleoshuttling of the ATM protein (RIANS). Recently, in the frame of the RIANS model, we have shown that, to respond to permanent endo- and exogenous stress, the ATM protein progressively agglutinates around the nucleus attracted by overexpressed perinuclear ATM-substrate protein. As a result, perinuclear ATM crowns appear to be an interesting biomarker of aging. The radiobiological characterization of the two human epithelial lens cell lines available and the four porcine epithelial lens cell lines that we have established showed delayed RIANS. The BFSP2 protein, found specifically overexpressed around the lens cell nucleus and interacting with ATM, may be a specific ATM-substrate protein facilitating the formation of perinuclear ATM crowns in lens cells. The perinuclear ATM crowns were observed inasmuch as the number of culture passages is high. Interestingly, 2 Gy X-rays lead to the transient disappearance of the perinuclear ATM crowns. Altogether, our findings suggest a strong influence of the ATM protein in radiation-induced cataractogenesis.

Single-Masked Randomized Phase 2 Study Assessing 2 Forms of Hypofractionated Proton Therapy in Patients With Large Choroidal Melanomas.

PURPOSE: Patients with large uveal melanomas are at major risk of liver metastases. Some patients are reluctant to undergo the standard treatment (ie, immediate enucleation). Proton therapy yields 5-year local control rates and eyeball retention of >85% and ≈20% in large uveal melanomas. Patients with T3/T4 uveal melanomas refusing enucleation were randomized between standard 4 to 13 Gy-fraction or moderately hypofractionated 8 to 6.5 Gy-fraction proton therapy. The main endpoint was the 2-year local recurrence-free survival without enucleation. METHODS AND MATERIALS: A single-masked 1:2 randomized phase 2 trial was conducted between 2015 and 2017 with planned endoresection and distance to the posterior pole as strata. Local events were defined as local relapse, or enucleation due to complications or relapse. RESULTS: The 32 patients, with a mean age of 64 years, had T3/4 (N = 17/15), M1 (N = 2) uveal melanomas, of mean tumor diameter and thickness of 16.5 mm and 9.1 mm, and of posterior location in 56.5%. Median follow-up was 56.7 months. The 2-year local recurrence-free survival rate without enucleation was 79% (95% confidence interval, 65%-96%), similar in both arms. There were 9 enucleations, 3 at relapse and 6 for toxicities. Twelve patients had distant metastases. The 2-year-overall survival was 72% (95% confidence interval, 58%-89%). At baseline, visual acuity by average logarithm value of the minimum angle of resolution was 0.68 and 0.70 in the standard and experimental arms, and at last follow-up 2 and 1.7, with mean differences of 1.44 and 1.01, respectively (P = .39). CONCLUSION: An 8-times 6.5 Gy scheme is feasible without deteriorating local control and with similar toxicity rates in patients with large uveal melanomas. Larger studies incorporating adjuvant treatments are warranted.

REAL WORLD STUDY COMPARING PHAKIC VERSUS PSEUDOPHAKIC EYES IN DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE IMPLANT: The PHAKIDEX Study.

PURPOSE: Dexamethasone implant (DEX-implant) is one treatment choice in diabetic macular edema. However, steroid-induced cataract is a common complication when treating a chronic disease and could lead to vision loss. Because of the lack of studies specifically focused on the functional outcomes according to the lens status, the authors therefore aim to analyze the effectiveness and safety of DEX-implant treatment for diabetic macular edema in phakic versus pseudophakic eyes. METHODS: This multicenter, retrospective study conducted in France included eyes of consecutive patients who had received a DEX-implant for diabetic macular edema. RESULTS: A total of 328 eyes were included: 158 eyes (48.2%) were phakic, 167 eyes (50.9%) were pseudophakic and three were unknown. According to the lens status, mean change in best-corrected visual acuity from baseline was never significantly different between phakic and pseudophakic eyes (likelihood ratio test, P = 0.09) nor in the change in central macular thickness (likelihood ratio test, P = 0.79) in multivariate analysis. Cataract surgery was performed in 63 phakic eyes (39.9%) during the study period with a mean delay of 8.1 months (CI95% [6.59-9.69]). The mean change in best-corrected visual acuity between phakic eyes who underwent cataract surgery and those who did not, was not significantly different during the follow-up at each visit. The risk of ocular hypertension was not statistically different between phakic and pseudophakic subsets ( P = 0.9). CONCLUSION: The authors showed here that phakic eyes treated with DEX-implant for diabetic macular edema did not have a significant difference in visual gain in comparison to pseudophakic eyes, with a comparable safety profile.

Visual outcomes of macular melanocytic lesions after early or delayed proton beam therapy.

PURPOSE: During their initial management, some macular melanocytic lesions can be closely monitored to wait for a documented growth before advocating a treatment by irradiation. However, the visual outcomes of this strategy have not yet been assessed. This study compares the visual outcomes of macular melanocytic lesions that underwent delayed proton beam therapy (PBT) after an initial observation to those treated early. METHODS: A total of 162 patients with suspicious melanocytic lesions whose margins were located within 3 mm of the fovea were recruited from two French ocular oncology centers. RESULTS: Overall, 82 patients treated with PBT within 4 months after the initial visit (early PBT group) were compared to 24 patients treated with delayed PBT (delayed PBT group) and 56 patients not treated with PBT (observation group). Visual acuity was not significantly different between baseline and last visit in the observation group (p = 0.325). Between baseline and last visit, the median [IQR] loss in visual acuity was significant in both the early (0.7 [0.2; 1.8], p < 0.001) and the delayed (0.5 [0.2; 1.5], p < 0.001) PBT groups. After irradiation, there was no significant difference between the early and delayed PBT groups for visual loss (p = 0.575), diameter reduction (p = 0.190), and thickness lowering (p = 0.892). In multivariate analysis, history of diabetes mellitus and Bruch's membrane rupture remained significantly associated with greater visual loss (p = 0.036 and p = 0.002, respectively). CONCLUSION: For small lesions in which there is no clear diagnosis of malignant melanoma, an initial close monitoring to document tumor growth does not impact visual prognosis, despite the potential complications associated with the untreated tumor. However, the survival should remain the main outcome of the treatment of these lesions.

The Effects of Treatment Regimen on the Initial Management of Macular Neovascularization Subtypes in Age-Related Macular Degeneration.

INTRODUCTION: The aim of this study was to evaluate the effect of initial treatment regimen individualization (pro re nata or treat-and-extend [TAE]), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective was to compare the treatment burden between each MNV subtype. METHODS: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes. RESULTS: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the first 2 years of treatment for type 1 (p = 0.106) and type 3 MNV (p = 0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p = 0.017) and type 4 MNV (p = 0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p = 0.0007) but not with intraretinal fluid (p = 0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p = 0.0045). CONCLUSION: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.

Efficacy and safety of Aflibercept for the treatment of inflammatory choroidal neovascularization: The ALINEA study.

PURPOSE: To evaluate mean change in best-corrected visual acuity (BCVA) at 52 weeks in patients with inflammatory choroidal neovascularization (CNV) treated with aflibercept. METHODS: We conducted a prospective non-comparative open-label trial. Following one mandatory intravitreal injection of aflibercept, patients were treated under a pro re nata (PRN) dosing regimen with monthly visits. RESULTS: A total of 19 patients were included, but one presented exclusion criteria; 16 patients were followed for the whole 52-week study, and data for the primary endpoint analysis were available for 14. At baseline, mean BCVA and mean central retinal thickness (CRT) were 64.53 (±19.64) letters and 351.79 (±97.77) µm, respectively. At 52 weeks, the mean change in BCVA was +9.50 (±12.90) letters [95%CI = +2.05-+16.95]. One patient had lost more than 15-letters at 24 weeks, and another one at 52 weeks. CRT change was -62.77 (±100.73) µm at 24 weeks and -66.53 (±97.47) µm at 52 weeks. There was a mean number of 3.56 (±3.29) intravitreal injections at 52 weeks (min = 1; max = 12). No serious ocular adverse events related to the treatment were reported. CONCLUSIONS: Our study shows that aflibercept is clinically effective, both anatomically and functionally in the treatment of inflammatory CNV. Following the first injection, the PRN strategy appears sufficient for treating most choroidal neovessels.

XEN® 63 gel stent to treat a refractory uveitic glaucoma: A case report.

PURPOSE: To describe the effectiveness of the XEN® 63 gel stent in a refractory uveitic glaucoma after failure of an Ahmed Glaucoma Valve. CASE DESCRIPTION: We report the case of a 54-year-old man with a history of uveitic glaucoma on his left eye due to Fuchs heterochromic iridocyclitis and neovascular glaucoma after a central retinal vein occlusion. Pre-operative intraocular pressure was 30 mmHg despite a QD (once-daily) dosed bimatoprost 0.3 mg and timolol 5 mg topical medication. At week 1, the eye exam showed an intraocular pressure of 6 mmHg with a well-formed bleb, a very mild hyphema and a localized choroidal detachment. At month 1, intraocular pressure was 14 mmHg with a formed bleb. Both hyphema and choroidal detachments had resolved. After a year, intraocular pressure was 16 mmHg without any medication and the bleb was still well-formed. CONCLUSION: The XEN® 63 gel stent provides a good intraocular pressure reduction and can be an efficient alternative for tube and filtration surgery in refractory glaucoma. Its long-term effectiveness needs to be evaluated.

Postoperative Aspergillus Infection: A Case Series.

PURPOSE: To report the clinical findings, therapy and outcomes of pauci-symptomatic Aspergillus infection in 11 eyes of 11 patients who had recently undergone uneventful cataract surgery and IOL implantation in a single operating room on the same day. METHODS: Retrospective, observational study that looks at 11 patients who demonstrated Aspergillus infection after cataract surgery. All data were collected and intracameral samples sent for microscopic evaluation and culture. Additional swabs were sent from the operating room and operative consumables. RESULTS: A total of 11 eyes of 11 patients were included in the analysis and were followed for at least 12 months. All patients responded completely to local and systemic voriconazole therapy. The source of infection was noted to be air-conditioning vents. Eyes with manual small incision cataract surgery (11/17) had a higher propensity for infection. CONCLUSION: Pauci-symptomatic aspergillosis infection has been reported here following cataract surgery.

Characterisation of macular neovascularisation subtypes in age-related macular degeneration to optimise treatment outcomes.

The aim of this review is to identify the common characteristics and prognoses of different subtypes of neovascular age-related macular degeneration (nAMD). We also propose recommendations on how to tailor treatments to the subtype of neovessels to optimise patient outcomes. The authors, selected members of the Vision Academy, met to discuss treatment outcomes in nAMD according to macular neovascularisation (MNV) subtypes, using evidence from a literature search conducted on the PubMed database (cut-off date: March 2019). This review article summarises the recommendations of the Vision Academy on how the characterisation of MNV subtypes can optimise treatment outcomes in nAMD. The identification of MNV subtypes has been facilitated by the advent of multimodal imaging. Findings from fluorescein angiography, indocyanine green angiography and spectral-domain optical coherence tomography collectively help refine and standardise the determination of the MNV subtype. To date, three subtypes have been described in the literature and have specific characteristics, as identified by imaging. Type 1 MNV is associated with better long-term outcomes but usually requires more intense anti-vascular endothelial growth factor dosing. Type 2 MNV typically responds quickly to treatment but is more prone to the development of fibrotic scars, which may be associated with poorer outcomes. Type 3 MNV tends to be highly sensitive to anti-vascular endothelial growth factor treatment but may be associated with a higher incidence of outer retinal atrophy, compared with other subtypes. Accurately assessing the MNV subtype provides information on prognosis and helps to optimise the management of patients with nAMD.

How to Manage a Patient with Ocular Metastases?

Ocular metastases are the most frequent ocular malignant tumors; their prevalence is estimated around 5-10% and is even higher in patients with breast or lung cancer. They represent various clinical situations, but they share the same hierarchical multidisciplinary therapeutic challenge with respect to the way systemic and local therapies should be selected in combination or sequentially in the personalized medical history of a patient. The challenges include tumor control, eye preservation, and the minimization of iatrogenic damage to sensitive tissues surrounding the tumor in order to preserve vision. These aims should further contribute to maintaining quality of life in patients with metastases. Many patients with choroidal metastases have systemic molecular treatment for their primary tumor. However, secondary resistance to systemic treatment is common and may ultimately be associated with cancer relapse, even after an initial response. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response. The aim of this review is to present current therapeutic strategies in ocular metastases and discuss how to tailor the treatment to a specific patient.

Do new drugs for diabetic macular edema offer a safer option?

INTRODUCTION: The last decade has witnessed important advances in retinal drug discovery, administered intravitreally, allowing high intraocular concentration and low systemic passage. However, local and systemic adverse events have been described and should be discussed before proposing treatment. In diabetes mellitus specifically, the choice of molecule and treatment regimen should limit the therapeutic burden, avoiding the need for frequent ophthalmological appointments, in patients receiving multi-disciplinary care. AREAS COVERED: We aim to review and discuss the risk/benefit ratio of the main intravitreal therapies currently proposed for diabetic macular edema (DME), and how these treatments could be tailored to each individual patient. EXPERT OPINION: Anti-VEGF injections and steroid implants are currently the two therapeutic options proposed in cases of DME. New molecules in these two classes have recently been approved and are currently being studied under phase IV observations to establish their efficacy and tolerance. The preferred therapeutic option is determined based on the ocular condition and the patient profile. As new treatments are developed, new adverse events will also enter into consideration, and retinal physicians must therefore be able to call on a range of therapeutic options and question the risk/benefit ratio of each of them before proposing a treatment.

Evaluation of the time required to complete a cataract training program on EyeSi surgical simulator during the first-year residency.

PURPOSE: To evaluate the time required to complete a cataract training program for first-year ophthalmology residents using the EyeSi simulator. In addition, evaluate whether the simulator improves virtual performance of cataract surgery during the program. METHODS: We prospectively included first-year ophthalmology residents who had no experience of cataract surgery. The EyeSi simulator was used, and residents were able to follow the cataract training program, including course A (the easiest) through to course D (the hardest). In course B and above, a "cataract challenge" is proposed to the trainee every hour of simulation. RESULTS: A total of 24 participants were included in the study. During the study period, the mean (SD) total time spent on the surgical simulator was 815.6 (174.7) minutes. All the participants completed courses A and B within a mean (SD) of 366.7 (108.0) minutes. A total of 22 residents (91.7%) residents completed course C, and 5 (20.8%) course D. The mean (SD) best score on cataract challenge was 445.6/500 (40.2; range: 330-493) and was obtained in a mean (SD) 7.6 (2.6) attempts. All the residents obtained a score ≥ 60%. The best score in cataract challenge was not correlated to the time spent to achieve courses A and B (r = -0.37, p = 0.0726). CONCLUSIONS: The time required to complete a basic cataract training program is possible during the first-year residency. The scores obtained in the cataract challenge also increased during the training program and should lead to better surgery skills in these young ophthalmologists.

Intra-Ocular Pressure Response to Dexamethasone Implant Injections in Patients with a History of Filtering Surgery: The TRABEX Study.

Patients with both macular edemas, of various etiologies such as diabetes and glaucoma, may suffer serious loss of vision if either disease goes untreated. Where no effective alternative therapies are available, dexamethasone implant (DEX-I) injections may be the only choice of treatment, despite the risk of a possible increase in intraocular pressure (IOP) when using steroids. Although many studies have reported on IOP evolution in eyes treated with DEX-I, little is known specifically about eyes with a history of filtering surgery. The aim of this observational series was to evaluate the IOP response following DEX-I injection in eyes presenting conventional filtering surgeries or microinvasive glaucoma surgeries (MIGS). Twenty-five eyes were included in this study. A total of 64% of the eyes did not experience OHT during follow-up. Additional IOP-lowering therapy was needed for 32% of eyes, and 20% of eyes (all showing bleb fibrosis) required further filtering surgery: 50% of eyes in the MIGS group and 10.5% of eyes in the conventional filtering surgery group. A significant positive correlation was found between IOP at baseline and the maximum IOP throughout follow-ups after DEX-I (r = 0.45, p = 0.02). In conclusion, if DEX-I is used when there are no alternative therapies for treating macular edema, IOP in eyes with a history of filtering surgery is generally manageable. Those eyes which previously underwent conventional therapy with effective blebs obtained better IOP control after DEX-I injections and mostly did not require any additional IOP-lowering therapy or surgery.

QUANTITATIVE ANALYSIS OF CHORIOCAPILLARIS ALTERATIONS IN SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY-ANGIOGRAPHY DURING RADIATION RETINOPATHY.

PURPOSE: To evaluate choriocapillaris alterations following proton beam therapy irradiation using swept-source optical coherence tomography-angiography, and to assess their correlation with the grade of radiation retinopathy (RR). METHODS: Eyes with uveal melanoma evaluated before and after irradiation with proton beam therapy were included, as well as the healthy fellow eye. The gradation of RR was based on a previously published classification. Choriocapillaris flow voids area was analyzed using Phansalkar thresholding. Retinal vascularization was described by foveal avascular zone (FAZ) perimeter, FAZ area, FAZ circularity index, and percentage of nonperfusion area (PAN) in the superficial capillary plexus (SCP) or deep capillary plexus. RESULTS: A total of 157 eyes of 83 patients were analyzed. Overall, there was a significant difference between the control group, the uveal melanoma before proton beam therapy group, and the grades of RR in the uveal melanoma after proton beam therapy group for FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P < 0.001), PAN-SCP ( P < 0.001), PAN-deep capillary plexus ( P < 0.001), and choriocapillaris flow voids area ( P < 0.001). Moreover, choriocapillaris flow voids area was significantly increased in the early stages of RR ( P = 0.003) and was further significantly correlated with FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P = 0.010), PAN-SCP ( P < 0.001), and PAN-deep capillary plexus ( P < 0.001). CONCLUSION: Quantitative optical coherence tomography-angiography alterations in the choriocapillaris microvascularization are an early biomarker of RR and are correlated to the severity of the disease.

Identification of Multidimensional Phenotypes Using Cluster Analysis in Sarcoid Uveitis Patients.

PURPOSE: To identify multidimensional phenotypes of sarcoid uveitis patients. DESIGN: Retrospective cohort. METHODS: Consecutive patients with biopsy-proven, presumed, or probable sarcoid uveitis between December 2003 and December 2020 in Lyon were recruited. Data were collected from the clinical notes, and consisted in laboratory and imaging findings, systemic treatments and outcome. Systemic sarcoidosis was diagnosed according to the Abad's modified criteria and uveitis was classified according to the Standardization of Uveitis Nomenclature. A hierarchical cluster analysis was performed. The main outcome measure was identification of different phenotypes of sarcoid uveitis patients. RESULTS: A total of 299 patients were included. Three clusters were identified: (1) younger non-Caucasian patients who presented acute (75.3%), anterior (55.6%) uveitis, and systemic manifestations (87.8%), requiring oral corticosteroids (75.3%) along with immunosuppressive therapy (17.2%) and who were more prone to experience complete visual recovery (84.1%); (2) middle-aged Caucasian patients who presented chronic (91.7%), panuveitis (79.5%), and isolated uveitis at diagnosis (74.8%), requiring systemic treatment with corticosteroids (74.0%) but less frequently immunosuppressive therapy (9.8%) and a worse prognosis (45.3% complete visual recovery); and (3) middle-aged Caucasian patients, without preferential chronic or acute uveitis, isolated uveitis at diagnosis (81.4%), more homogenous in terms of eye involvement repartition, requiring less corticosteroids or immunosuppressive therapy (respectively 54.1% and 13.1%) and having a prognosis close to cluster 2 patients (55.3% complete visual recovery). CONCLUSIONS: This retrospective study suggested the existence of several phenotypes of sarcoid uveitis patients with different progressions and prognoses. Further studies are needed to determine the genetic and environmental factors that could explain these results.