The cornea serves as a transparent protective barrier for the eye, with epithelial homeostasis and renewal critically dependent on limbal epithelial stem cells residing in a specialized niche characterized by stromal invaginations that form limbal crypts. Elegant advanced in vitro models of the limbal niche have been described, but most are technologically demanding, requiring multi-step fabrication that limits scalability. We developed a simple and rapid strategy to fabricate 3D scaffolds with undulating topography using a shape-morphing hydrogel concept. A photocrosslinkable bioink composed of methacrylated collagen, hyaluronic acid, and silk fibroin was patterned using grayscale UV projection. Digital Light Processing technology enabled spatially controlled heterogeneous crosslinking densities in a single-step process. The undulating topography was then formed through differential shrinking dynamics of the hydrogel at 37 °C; specifically, the volume of areas exposed to lower UV doses decreased while areas exposed to higher UV doses remained stable. The addition of silk fibroin proved essential for both temperature-dependent shape morphing and sustained corneal epithelial cell adhesion and growth. The undulating scaffolds supported epithelial stratification for at least three weeks in culture. Physiologically relevant corneal mechanotransduction and apicobasal organization was achieved, with nuclear YAP localization in soft areas, P63-positive progenitor cells enriched in basal layers and PAX6-positive differentiated cells in apical layers. Additionally, progressive epithelial maturation was demonstrated by increased CK3 expression, establishment of tight junctions, and the deposition of a basement membrane. STATEMENT OF SIGNIFICANCE: Paschalidis et al. This work offers dual significance. First, we introduce an innovative, simple and single-step bioprinting approach to create 3D scaffolds with complex topography. Using Digital Light Processing technology, a silk fibroin-containing photocurable bioink is exposed to spatially heterogeneous UV doses. This enables differential crosslinking densities in the printed scaffold, which undergoes programmable shape-morphing. Second, we applied this methodology to engineer advanced corneal models that recapitulate the structural features of the epithelial stem cell niche, an undulating topography. This addresses critical needs in human disease modeling and preclinical testing while reducing animal use. The resulting model sustains three-week cultures and faithfully mimics physiological epithelial organization, with progenitor markers expressed in basal layers and differentiation markers indicating barrier function in apical layers.

PURPOSE:This study aimed to assess the long-term management and 5-year evolution of patients with neuropathic ocular pain (NOP) associated with chronic dry eye disease (DED). METHODS:Fourteen patients with NOP underwent a 5-year follow-up. Baseline and 5-year assessments included questionnaires on dry eye (Dry Eye Questionnaire 5 [DEQ-5] and Ocular Surface Disease Index), pain (Brief Pain Inventory [BPI]), anxiety/depression disorders (Hospital Anxiety and Depression Scale), and a dedicated questionnaire on NOP characteristics (Neuropathic Ocular Pain Questionnaire), which was developed for this study. Treatment tolerance and effectiveness were rated on a 0-5 scale. Clinical examination, meibography, tear film analysis, corneal nerve density, and inflammation assessment using in vivo confocal microscopy (IVCM) were performed at both time points. RESULTS:Patients were predominantly women (93%) with a mean age of 41 ± 17 years. High rates of comorbid anxiety/depressive disorders (85.7%) and diffuse chronic pain (35.7%) were observed, supporting the need for multimodal care. Over 5 years, significant improvements occurred in mean neuropathic pain scores (P = 0.005), BPI scores (P = 0.003), and DEQ-5 scores (P = 0.041). Clinical parameters remained unchanged, except for a significant decrease in IVCM inflammation score (P = 0.004). All patients received topical ophthalmic treatments; 78.6% were treated with systemic neuropathic pain relievers, and 64.3% received psychological care. The most effective treatments included artificial tears, cyclosporine eye drops, scleral lenses, oral therapies, and autologous serum eye drops. CONCLUSION:This study provides the first long-term overview of therapeutic strategies for NOP associated with DED. Findings support a multidisciplinary approach using specific questionnaires and personalized, long-term treatments. However, controlled prospective studies are needed to establish the efficacy of specific therapeutic strategies.

It is widely recognized that the glycocalyx has significant implications in regulating the self-renewal and differentiation of adult stem cells; however, its composition remains poorly understood. Here, we show that the fucose-binding Aleuria aurantia lectin (AAL) binds differentially to basal cells in the stratified epithelium of the human limbus, hair follicle epithelium, and meibomian gland duct. Using fluorescence-activated cell sorting in combination with single-cell transcriptomics, we find that most epithelial progenitor cells and melanocytes in the limbus display low AAL staining (AALlow) on their cell surface, an attribute that is gradually lost in epithelial cells as they differentiate into mature corneal cells. AALlow epithelial cells were enriched in putative limbal stem cell markers and displayed high clonogenic capacity. Further analyses revealed that AALlow epithelial cells had reduced expression of GDP-mannose-4,6-dehydratase, an enzyme catalyzing the first and limiting step in the de novo biosynthesis of GDP-fucose, and that inhibition of fucosylation using a small-molecule fucose analog stimulated the proliferative potential of limbal epithelial cells ex vivo. These results provide crucial insights into the distinctive composition of the glycocalyx in adult stem cells and underscore the significance of fucose modulation in the therapeutic regeneration of the human limbal stem cell niche.

PURPOSE:To determine the maximum extent of corneal thinning induced solely by dehydration and to establish the threshold at which corneal lysis begins, thereby refining therapeutic indications, with the aim of improving clinical management. METHODS:Dehydration was induced in 28 corneas, after 4 ex vivo experimental models. Corneal thickness was regularly measured using swept-source optical coherence tomography (OCT). Histological analysis was performed on 14 of the corneas, with computer-based counting of collagen lamellae. The remaining 14 corneas were rehydrated and remeasured using OCT. RESULTS:Regardless of the model, all corneas exhibited sectoral thinning, clinically resembling corneal dellen. With the most efficient dehydration model, the average minimum pachymetry was 102 ± 30 μm, with minimal values down as low as 49 μm. Computerized histological analysis confirmed that this thinning reflected a greater density of collagen lamellae and not a real loss of collagen. After rehydration, OCT showed a resolution of corneal thinning in all cases. CONCLUSIONS:Corneal dellen thinning reflects the compaction of collagen fibers secondary to localized dehydration. Dehydration alone thinned the cornea to an average of 102 μm, and in some cases, it became as low as 49 μm. Above this threshold, corneal rehydration is sufficient to achieve full recovery.

PURPOSE:The aim of this study was to assess the immediate and delayed effects of tear punctal occlusion with punctal plugs on tear meniscus height (TMH) in severe aqueous-deficient dry eye (ADDE) disease. METHODS:Consecutive patients with severe ADDE related to Sjögren syndrome or ocular graft-versus-host disease underwent inferior and superior occlusion with punctal plugs. TMH was measured using the LacryDiag ocular surface analyzer platform before, 10 minutes, and at least 1 month after punctal occlusion. The corneal fluorescein staining (CFS) score was graded with the Oxford scale (from 0 to 5). Ocular symptoms were graded with a visual analog scale (from 1 to 10). RESULTS:We included 24 eyes of 24 patients (mean age 61 ± 9 years; mean follow-up 7 ± 5 months). The mean TMH was 0.19 ± 0.06 mm at baseline and increased significantly to 0.41 ± 0.13 mm ( P < 0.001) and 0.46 ± 0.17 mm ( P < 0.001) at 10 minutes after punctal plug insertion and at the end of follow-up, respectively. The median CFS score decreased from 3 ± 1 before plug insertion to 1 ± 2 at the end of follow-up ( P < 0.001). Many patients (67%; n = 16) reported subjective improvement of symptoms. TMH was negatively correlated with the CFS score and visual analog scale score assessing symptoms. CONCLUSIONS:Upper and lower punctal occlusion increased TMH in patients with severe ADDE as soon as 10 minutes after plug insertion. TMH remained stable over time, which led to the relief of symptoms and reduced corneal staining.

Antibody-drug conjugates (ADCs) are designed to maximize cancer cell death with lower cytotoxicity toward noncancerous cells and are an increasingly valuable option for targeted cancer therapies. However, anticancer treatment with ADCs may be associated with ocular adverse events (AEs) such as dry eye, conjunctivitis, photophobia, blurred vision, and corneal abnormalities. While the pathophysiology of ADC-related ocular AEs has not been fully elucidated, most ocular AEs are attributed to off-target effects. Product labelling for approved ADCs includes drug-specific guidance for dose modification and management of ocular AEs; however, limited data are available regarding effective strategies to minimize and mitigate ocular AEs. Overall, the majority of ocular AEs are reversible through dose modification or supportive care. Eye care providers play key roles in monitoring patients receiving ADC therapy for ocular signs and symptoms to allow for the early detection of ADC-related ocular AEs and to ensure the timely administration of appropriate treatment. Therefore, awareness is needed to help ophthalmologists to identify treatment-related ocular AEs and provide effective management in collaboration with oncologists as part of the patient’s cancer care team. This review provides an overview of ocular AEs that may occur with approved and investigational ADC anticancer treatments, including potential underlying mechanisms for ADC-related ocular AEs. It also discusses clinical management practices relevant to ophthalmologists for prevention, monitoring, and management of ADC-related ocular AEs. In collaboration with oncologists, ophthalmologists play a vital role in caring for patients with cancer by assisting with the prompt recognition, mitigation, and management of treatment-related ocular AEs.

BACKGROUND: Minor Ophthalmic Procedures (MOP), especially cataract or glaucoma surgery, are considered low risk. However, in France, anesthesia must be monitored continuously and carried out by an anesthetist or a nurse anesthetist (NA). The aim was to assess whether an externalized monitored anesthesia care (MAC) would be non-inferior to an individual MAC inside the OR regarding the incidence of severe hypertension, bradycardia, hypoxemia, and surgeon satisfaction. METHODS: We performed a monocentric randomized, non-inferiority trial. Adults undergoing MOP with topical or locoregional anesthesia were randomly assigned to externalized MAC (the NA monitored simultaneously up to 3 patients with a screen monitor repeating the inside monitor) or inside MAC. The primary endpoint was a composite of per-operative complications defined as a blood pressure >200 mmHg, pulse rate <45/min, pulse oximetry <85%, or surgeon satisfaction regarding patient security <3/10. Secondary endpoints included patient and surgeons' overall satisfaction, re-operation within 24 hours, and nurses' overall satisfaction. RESULTS: A total of 900 patients were enrolled (450 in both groups). The externalized MAC was non-inferior to inside MAC as event occurred in 29 patients (6.4%) and 26 patients (5.8%), respectively (adjusted difference - 0.7%). Patient agitation assessed by the surgeon was lower with the inside MAC (adjusted mean difference -0.33; 95%CI -0.61 to -0.04). CONCLUSIONS: Among patients undergoing MOP with topical or locoregional anesthesia, an externalized MAC strategy with a 1:3 NA-to-patient ratio were non-inferior to an inside monitoring on the incidence of severe hypertension, bradycardia, hypoxemia and surgeon satisfaction regarding patient safety.

A 11-year-old male without visual complaint was referred for diffuse dot-like gray corneal opacities within the stroma of both eyes (Fig. 1A). The lesions were not visible on optical coherence tomography (Fig. 1B), but hyperreflectivity was noted at the level of the Bowman layer in the periphery of the cornea (arrow). Confocal microscopy showed a strong hyperreflectivity of the cytoplasm of keratocytes (Fig. 1C) and dendritic cells (Fig. 1D). This occurrence in a child of consanguineous union was suspicious for a lysosomal storage disorder. Reduced glucocerebrosidase activity and homozygous D409H mutation led to the diagnosis of type III Gaucher disease.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and rare diseases, most often drug-induced, and their incidence has been estimated at 6 cases/million/year in France. SJS and TEN belong to the same spectrum of disease known as epidermal necrolysis (EN). They are characterized by more or less extensive epidermal detachment, associated with mucous membrane involvement, and may be complicated during the acute phase by fatal multiorgan failure. SJS and TEN can lead to severe ophthalmologic sequelae. There are no recommendations for ocular management during the chronic phase. We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. Ophthalmologists and dermatologists from the French reference center for epidermal necrolysis were asked to complete a questionnaire on management practices in the chronic phase of SJS/TEN. The survey focused on the presence of a referent ophthalmologist at the center, the use of local treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers responded to the questionnaire. Based on questionnaire results, 10/11 ophthalmologists systematically prescribed preservative-free artificial tears, and 11/11 administered VA. Antiseptic or antibiotic eye drops or antibiotic-corticosteroid eye drops were recommended as needed by 8/11 and 7/11 ophthalmologists, respectively. In case of chronic inflammation, topical cyclosporine was consistently proposed by 11/11 ophthalmologists. The removal of trichiatic eyelashes was mainly performed by 10/11 ophthalmologists. Patients were referred to a reference center for fitting of scleral lenses (10/10,100%). Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN and we also propose an algorithm for the ophthalmologic management of ocular sequelae.

IntroductionThe purpose of this study is to compare the "real-life" effectiveness of amniotic membrane graft (AMG) and conjunctival (CAT) or limbal conjunctival (LCA) autograft in the management of primary pterygium.MethodsHuman-based studies on primary pterygium surgery that were published between 1993 and 2022 with at least 3 months of follow-up were identified, and only those that were retrospective were included. The global recurrence rate of pterygium was assessed for each surgical technique separately. Specific recurrence rates taking into consideration the fixation technique (glue versus sutures) were also measured.Results35 real-life retrospective subgroups comprising a total of 3747 eyes were included in the final review. The mean global recurrence rates for CAT, LCA and AMG were 7.61%, 5.50% and 9.0%, respectively. Recurrences were less common for patients who received fibrin glue (5.92%, 2.56% and 3.60%) than for those who received sutures (8.99%, 6.03% and 23.0%) for the three groups, respectively. Surgical techniques combining CAT or LCA with AMG yielded an even lower global recurrence rate (1.83%).ConclusionAMG seems like a reasonable option that could be considered in primary pterygium surgery, especially when glued to the underlying sclera. Combining AMG with other treatment modalities such as CAT or LCA seems to offer an interesting alternative in terms of recurrence.

e15003 Background: Tusamitamab ravtansine (tusa rav) is a novel antibody-drug conjugate (ADC) targeted to carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivering DM4, a cytotoxic maytansinoid. CEACAM5 is highly expressed in several tumor types, including nonsquamous non-small cell lung cancer (NSQ NSCLC). An open-label, Phase 1/2, dose-escalation/expansion study (NCT02187848) in patients with advanced solid tumors found the maximum tolerated dose of tusa rav to be 100 mg/m 2 every 2 weeks (Q2W) with a dose-limiting toxicity of microcystic keratopathy. Tusa rav had a favorable safety profile and, in patients with NSQ NSCLC with high CEACAM5 expression, promising antitumor activity. Methods: Here we evaluate pooled corneal safety results in patients (n = 186) who received tusa rav 100 mg/m 2 Q2W, including cohorts of patients with NSQ NSCLC, colorectal, gastric, or small cell lung cancers. Patients who had history of corneal disorders, contraindications to ocular prophylactic drops, or were unable to stop contact lens use for the study were ineligible. Artificial tear use was encouraged during the study. Results: In patients treated with tusa rav 100 mg/m² (median treatment duration 8.7 weeks [range 2–154]), corneal treatment-emergent adverse events (TEAEs) were reported in 56/186 (30.1%), with the worst grade being Grade 1 as asymptomatic (n = 7), Grade 2 (n = 33), and Grade 3 (n = 16). No patients had Grade 4 (perforation or blindness) or serious corneal adverse events. The most frequent corneal TEAEs were keratitis and keratopathy in 22% and 11.8% (Grade 3 in 6.5% and 2.7%) of 186 patients, respectively. Occurrence of Grade ≥2 corneal events was significantly associated with tusa rav exposure in Q2W dosing (including dose-escalation ≤150 mg/m 2 ). Most patients with corneal TEAEs had first occurrence within the first 4 cycles (45/56), including 16 in Cycle 2 and none in Cycle 1. At analysis cut-off, corneal TEAEs had resolved in 40/56 (71.4%) patients. The median recovery time was 20.5 days (range, 8–264). Of the 186 patients, corneal TEAEs led to cycle delay in 15.6%, cycle delay with dose reduction in 7.0%, and no treatment discontinuations. Corneal TEAEs recurred in 19/56 (33.9%) patients with a median time to recurrence of 16 days. Primary prophylaxis (ophthalmic vasoconstrictor, corticosteroid gel, and/or cold masks at infusion) in only the right eye in 107 patients did not show benefit (98% of the 55 events were bilateral), supporting use of secondary prophylaxis only as needed in subsequent patients. Conclusions: Corneal TEAEs observed in the study were nonserious and typically reversible; management with dose modification allowed continuation of treatment. These results support the ongoing clinical development of tusa rav. Further investigation of the mechanisms of corneal TEAEs with ADCs and their management is necessary. Clinical trial information: NCT02187848 .

BackgroundLong-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking.ObjectivesWe conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae.MethodsParticipants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method.ResultsFifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded.ConclusionsOur DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Aims To determine the incidence and risk factors of cystoid macular oedema (CMO) following descemet membrane endothelial keratoplasty (DMEK) with or without combined cataract surgery (triple-DMEK). Methods We reviewed the records of patients who underwent DMEK surgery alone or triple-DMEK performed at the Rothschild Foundation Hospital (Paris, France) between January 2019 and March 2020. Patients with pre-existing CMO observed on the preoperative macular optical coherence tomography (OCT) were excluded. Spectral-domain OCT was performed in patients with postoperative visual impairment. Data regarding comorbidities, intraoperative characteristics and postoperative treatments or complications were collected and analysed. Univariate and multivariate analyses were performed. Results Twenty three of 246 eyes (9.36%) developed clinically significant (cs)-CMO after DMEK. Triple-DMEK was not associated with a higher risk to develop CMO (12.2% in DMEK alone and 6.1% in triple-DMEK). Pseudophakic bullous keratopathy (PBK ; 39.1% vs 9%; OR=3.5 (1.0 to 11.8), p=0.045) and epiretinal membrane (ERM; 39.1% vs 7.7%; OR=10.5 (3.4 to 32.3), p<0.001) were more frequently observed in patients who developed CMO. The occurrence of hyphaema during surgery was statistically associated with postoperative CMO (13% vs 1.3%; OR=7.1 (1.0 to 48.8) p=0.045). Peroperative epithelial debridement was statistically associated with postoperative CMO (65.2% vs 33.2%, p=0.005), but only in univariate analysis. Conclusions We identified a clinically significant CMO incidence of 9.35% after DMEK. Patients with a history of ERM, PBK and intraoperative hyphaema may be at risk of developing CMO after DMEK surgery and should be monitored.

This article discusses 2 cases of severe corneal involvement during mpox.

PURPOSE:To determine whether local corneal thickness changes observed with optical coherence tomography (OCT) can detect subclinical corneal edema in Fuchs endothelial corneal dystrophy (FECD).SETTING:Retrospective cohort study.METHODS:A series of patients presenting FECD who underwent cataract surgery alone (45 eyes) or with concomitant Descemet membrane endothelial keratoplasty (triple procedure; 117 eyes). The study reviewed medical records, collected the preoperative corneal thickness map and calculated the differences and ratio of corneal thickness measured at 5, 7, and 9 mm from the central corneal thickness. Area under the receiver operating characteristic curves (AUCs) were calculated and thresholds were selected to obtain a specificity of 90%.RESULTS:The median difference between 5- and 2-mm corneal thickness in the supra-nasal quadrant (∆5-2mmSN) was 38 µm (interquartile range 34-46) in the cataract group and 17 µm (2-38) in the triple procedure group (P < .001). The corneal thickness ratios of supra-nasal 5- to 2-mm (R5/2mmSN) and 7- to 2-mm (R7/2mmSN) were 1.07 (1.06-1.08) and 1.15 (1.13-1.17)] in the cataract group and 1.03 (1.00-1.06) and 1.09 (1.06-1.14) in the triple procedure group (P < .001). The probability of corneal edema was increased 7-fold with ∆5-2mm SN < 27 µm (AUC = 0.76) and 9.4- and 7.4-fold with R5/2mmSN and R7/2mmSN < 1.045 (AUC = 0.77) and 1.118 (AUC = 0.76), respectively.CONCLUSIONS:Local changes in corneal thickness may be useful in detecting preclinical corneal edema, especially in patients with FECD undergoing cataract surgery.