Retinoblastoma (RB) management often involves the combination of chemotherapeutic agents (e.g., carboplatin and etoposide) and techniques (e.g., chemotherapy and thermotherapy). Chemoresistance and relapse, as well as systemic and ocular toxicities of current retinoblastoma chemotherapeutics necessitate the implementation of alternative drugs. Fewer resources and concern for pediatric cancer hinder drug discovery and development in an effective way. To overcome the obstacle, a drug repurposing strategy without intuition was adopted to identify promising drug candidates that are both cytotoxic and selective towards human RB Y79 cells in vitro and an orthotopic xenograft mice model in vivo. By using high-throughput screening, gemcitabine demonstrated high cytotoxicity in Y79 cells, also potentially synergizing with thermotherapy, with minimal impact on a human retinal pigment epithelial RPE-1 cells. Furthermore, the synergistic effect of gemcitabine with carboplatin is superior to the clinically used combination of etoposide with carboplatin. Efficacy studies in orthotopic xenografts showed significant eye survival advantages after intravitreal gemcitabine administration or the combination of intravitreal gemcitabine with systemic carboplatin compared to relevant controls. Importantly, the combination resulted in lower tumor invasion in the optic nerves of the xenografts. Since gemcitabine is an FDA-approved chemotherapeutic agent, already used to treat other pediatric cancers, it could be repurposed to RB treatment alone or in combination with carboplatin, and potentially combined with thermotherapy, providing the basis for an alternative and improved treatment option for RB patients.

Purpose To report and describe transient spectral-domain OCT (SD-OCT) changes following high-dose intravitreal topotecan (HD-IvitTopo) in retinoblastoma patients. Design Retrospective case series. Subjects Three eyes of three children with retinoblastoma treated with HD-IvitTopo (100 μg/0.20 cc), administered either as monotherapy during first-line treatment for macular (Case 1) or optic nerve-threatening tumors (Case 2), or combined with intracameral topotecan for vitreous and aqueous humor relapse (Case 3). Methods Clinical examination, fundus photography, and SD-OCT were performed before and after each intravitreal injection. Full-field electroretinography (ERG) was assessed in one case Main Outcome Measures Structural retinal changes on SD-OCT, reversibility of retinal alterations and functional outcomes. Results All cases received 1 to 2 HD-IvitTopo injections. Case 1 developed early signs of loss of the ellipsoid zone and diffuse microcystic macular edema after the first HD-IvitTopo, which worsened after the second, without ERG alterations. Case 2 developed isolated foveolar cystic edema after the second HD-IvitTopo. Case 3 developed transient papillary and diffuse microcystic macular edema after the first combined intravitreal and intracameral topotecan injection. In all cases, all structural changes resolved completely within 10-16 weeks, with no permanent visual loss at date last seen. Conclusions High-dose IvitTopo (100 μg/0.20 cc) may induce transient, subclinical intraocular alterations detectable by SD-OCT. Further studies are warranted to elucidate the exact cause, incidence and functional impact of such events.

The increasing number of cancer cases and the prevalence of failed treatments underscore the need for alternative therapeutics and more predictive screening methods. In this context, the field of 3D cultures (termed spheroid, organoid, or tumoroid models) has seen rapid growth in recent years, leading to a range of more physiologically relevant models compared to standard 2D culture methods. However, many of these models face limitations in scalability due to their complex setup, maintenance requirements, and high costs, which restrict their use in drug discovery. In response, we present a simple but robust spheroid model for two distinct types of solid tumors, colorectal cancer and retinoblastoma, specifically designed for high-throughput drug screening. This model is reproducible and cost-effective, utilizing commercially available components and automation. We applied this model to screen chemotherapeutics and used high-content image-based analysis to identify prospective drug candidates. This spheroid model has the potential to advance drug discovery, particularly in challenging areas of cancer research.

Intraocular seeds in retinoblastoma are formed from dispersion of the tumor into the adjacent liquid or semiliquid compartments. They are highly resistant to traditional treatment modalities and remain the most important cause of treatment failure. Intraocular seeds can be focal or diffuse in the vitreous, retrohyaloid, subretinal or aqueous compartments. Intravitreal and intracameral chemotherapy with melphalan and/or topotecan have allowed targeted drug delivery in desired concentration to achieve improved outcomes of seed regression and globe salvage. Group E disease, diffuse and recurrent seeds, as well as anterior chamber seeds continue to have suboptimal prognosis. We review the published literature on intraocular seeds, the evolution of their management, and the outcomes and complications of established treatment modalities.

Background/Aaims Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression.Methods This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated.Results 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively.Conclusions Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.

Pathogenic variants in ADAMTSL4 are an important cause of isolated ectopia lentis with an increasing number of genetically confirmed cases internationally. We sought to better describe ocular features seen with pathogenic variants in ADAMTSL4. We performed a retrospective, multicenter study examining the phenotypic and genotypic spectrum of ADAMTSL4-associated ocular disease. We identified 41 individuals from 32 families with genetically confirmed ADAMTSL4-related disease across six tertiary referral centers across Europe. Identified participants had a young age of diagnosis (median 1.3 years) and a highly myopic refractive error (mean SE -10.27 D). A diagnosis of ectopia lentis et pupillae was made in a third of cases, with a younger age at diagnosis (median 0.5 years). Subluxation tended to be in the inferior direction (~33%). Zonules were noted to be missing or absent in the majority of cases. Sixteen different pathogenic variants in ADAMTSL4 were reported. A previously reported 20-bp deletion (c.767_786del) was highly prevalent in this cohort (23/32), and all ectopia lentis et pupillae cases carried this variant. ADAMTSL4-related disease tends to present at a younger age and be associated with higher myopia than other forms of ectopia lentis (such as FBN1). Early identification of typical phenotypic features alongside genetic testing can aid early, precise diagnosis and prevent unnecessary investigations.

Aims/Purpose: Early access programs enable patients with Leber hereditary optic neuropathy (LHON) due to the m.11778G>A MT‐ND4 mutation to receive lenadogene nolparvovec, a gene therapy that has not yet received marketing authorization. Methods: Lenadogene nolparvovec was provided based on unsolicited requests and its use was authorized by local regulations. Patients received lenadogene nolparvovec in 4 countries (France, Italy, the United Kingdom [UK], and the United States of America [USA]) as a unilateral or bilateral intravitreal injection at 9x10 10 viral genomes/eye. Results: Lenadogene nolparvovec was administered to 63 patients with MT‐ND4 LHON, mainly in France (56%) and the USA (29%); 42 (67%) patients received bilateral injections. At the time of the first injection, mean age (standard deviation [SD]) was 33.7 (16.6) years and mean (SD) duration of disease was 11.4 (9.6) months. Most (84%) patients were treated with idebenone at the same time as or after gene therapy injection. At one year, mean change in best‐corrected visual acuity (BCVA) from nadir was ‐0.42 (0.54) LogMAR (+21 ETDRS letters equivalent) ( n = 53 patients). An improvement of at least 0.3 LogMAR from nadir was observed in 61% of patients. Lenadogene nolparvovec safety was favorable and comparable to that of phase 3 clinical trials. Conclusions: Injection of lenadogene nolparvovec in the real‐life setting was associated with a clinically meaningful improvement in BCVA from nadir and a favorable safety profile similar to that observed in phase 3 clinical trials.

Purpose:To report the retinal phenotype in 2 patients simulating type 2 macular telangiectasis with new variants in CYP2U1 implicated in hereditary spastic paraplegia type 56 (HSP 56). Design:Cross sectional case series study. Participants:Five members of a non-consanguineous family (parents and 3 male children) were investigated. Methods:All family members underwent a full ophthalmic evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography, and electro-oculography. Whole-exome sequencing was performed in all 5 family members. Main Outcome Measures:To characterize the retinal phenotype in affected patients with variants in CYP2U1, using multimodal imaging: dual-wavelength autofluorescence, fluorescence lifetime, OCT angiography. Results:The 2 siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) in CYP2U1 demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of macular pigment to the parafoveal edge, photoreceptor loss, and fluorescence lifetime imaging ophthalmoscopy anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for 1 variant and were neurologically and ophthalmically normal. Conclusions:These CYP2U1 variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the etiology and pathogenesis of these diseases. Financial Disclosures:The author(s) have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE:Coats disease is a rare, retinal vascular disorder characterized by telangiectasias, aneurysmal dilations, and progressive exudative retinal detachment. Limited understanding of the disease warranted the need to identify controversial issues through an extensive literature search and a debate and discussion among international panels of experts. METHODS:Extensive literature search was done on multiple aspects of the disease-classification patterns, disease, Coats-plus, and Coats-like response. Other key factors included the etiology, possible genetic patterns, relationship with other vascular disorders, the role of inflammatory factors and vascular endothelial growth factor (VEGF) in the pathogenesis, diagnostic features, and complications. Considering the varying treatment patterns followed, imaging modalities, clinical findings, differential diagnosis, treatment options, prognostic factors, and emerging concepts in management were all covered in the search. Eighteen experts were included to opine on questions spanning classification, pathogenesis, diagnostic and treatment methods, prognostic controversies, and newer concepts in disease management. RESULTS:Of the 52 questions in 7 sections, the experts arrived at a consensus for 48 (92.3%) statements (with 75% voted as strong agreement or agreement). Most experts agreed on the suggested classification, diagnosis, and prognosis. The controversy, however, remained in questions regarding association with other vascular disorders, treatment of stages 3 and 4, possible benefits of newer anti-VEGF agents, and the role of artificial intelligence. CONCLUSIONS:These debates reflect the rarity of the condition, complex pathophysiology, and the challenges of treating a progressive blinding disease primarily affecting children. Hence, further studies are warranted, especially in areas that have not reached a consensus.

Evaluating the Predictability of Postoperative Target Refraction Using the Prototype of a New Intraoperative Aberrometer

Hallermann-Streiff syndrome (HSS), also known as oculo-mandibulo-facial syndrome or François dyscephalic syndrome, is an extremely rare congenital developmental disorder, first described by Aubry in 1893 and later further delineated as a distinct entity by Hallermann (1948) and Streiff (1950) [1]. Its prevalence is estimated to be around 0.96 – 1.28 per 10 million in Japan, which can be converted to a presumptive incidence of 1 in 3 – 4 millions live births per year according to the relevant Japanese demographic statistics and a putative average HSS mortality of 30% [2]. Boys and girls are equally affected and usually diagnosed during the first months of life based on the presence of 7 cardinal signs described by François, namely, dyscephalia with birdlike facies, dental abnormalities, proportionate short stature, atrophy of skin (especially on the nose), alopecia and hypotrichosis (including eyebrows and eye lashes), bilateral microphthalmia, and bilateral congenital cataract [1]. Mental development is usually normal [1], [3].

Aims To report long-term results of intracameral chemotherapy (ICC) for aqueous seeding (AS) in retinoblastoma. Methods Retrospective study including 20 patients with primary (n=4) or secondary non-iatrogenic (n=16) AS treated with ICC according to a previously described technique between 2011 and 2020 with at least 1-year follow-up. Results AS control was initially achieved in all cases with a mean 5 injections of melphalan (n=13) or topotecan (n=7). Three eyes had an isolated AS relapse at a mean interval of 8 months after the first ICC course, which regressed with a second course of intracameral melphalan. Concomitant interciliary process seed implantation was treated with additional brachytherapy if sectorial (n=3) or proton therapy if annular (n=1). Other therapies including systemic, intra-arterial chemotherapy and/or focal treatments were given in 15 eyes to treat concomitant tumour sites. Eye preservation was achieved in 85% of the eyes (n=17/20) at a mean event-free follow-up of 45 months for aqueous disease, and 40 months for any other intraocular tumour activity. Three cases were enucleated due to refractory non-aqueous disease. All patients are alive without metastasis (mean follow-up of 48 months after first ICC). ICC-related intraocular toxicity included iris atrophy (n=5), cataract (n=4), posterior synechiae (n=2) and iris heterochromia (n=1). No patient suffered irreversible vision loss. Useful to normal vision was found in 82% of the cases (n=14/17). Conclusion ICC appears to be safe and efficient for AS without irreversible vision-threatening adverse effects. More data are needed to determine any superiority in efficiency/toxicity of topotecan versus melphalan.

PURPOSE:The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current information on phenotype, histopathology, and genetic analysis. This update is the third edition of the IC3D nomenclature.METHODS:Peer-reviewed publications from 2014 to 2023 were evaluated. The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy [from category 1 (most evidence) to category 4 (least evidence)].RESULTS:Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10). Signs and symptoms are similar to Franceschetti corneal dystrophy, dystrophia Smolandiensis, and dystrophia Helsinglandica, category 4. Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19). Classic lattice corneal dystrophy (LCD) results from TGFBI R124C mutation. The LCD variant group has over 80 dystrophies with non-R124C TGFBI mutations, amyloid deposition, and often similar phenotypes to classic LCD. We propose a new nomenclature for specific LCD pathogenic variants by appending the mutation using 1-letter amino acid abbreviations to LCD. Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10). Typically asymptomatic, it can be distinguished phenotypically from pre-Descemet corneal dystrophy, category 4. We include a corneal dystrophy management table.CONCLUSIONS:The IC3D third edition provides a current summary of corneal dystrophy information. The article is available online at https://corneasociety.org/publications/ic3d .

Of the different modalities used to treat retinoblastoma, a chemothermotherapeutic regimen combining carboplatin and thermotherapy (also termed focal therapy), and the application of melphalan as a monotherapy, are particularly successful. Some studies indicate that melphalan shows potential when applied in combination with focal therapy, and yet is not applied in this combination. Here we describe a series of synthetically modified melphalan derivatives that display enhanced cytotoxicity relative to melphalan itself, with some displaying further enhancements in cytotoxicity when applied in combination with heat (used as a model for thermotherapy). The synthetic approach, which involves modifying melphalan with perfluorous chains of varying lengths via an ester linker, could lead to a more effective treatment option for retinoblastoma with reduced side-effects, which is a key limitation of melphalan. Melphalan, a drug in retinoblastoma treatment, was not designed for combination with focal therapy, but is more active when combined with heat. Incorporating perfluorous chains to the drug rsulted in thermoresponsive and increased cytotoxicity.

BACKGROUND:In intra-arterial chemotherapy for retinoblastoma, a backflow from unreachable external carotid artery branches in the ophthalmic artery can be challenging.OBJECTIVE:To describe a new endovascular technique using Gelfoam pledgets to temporarily occlude distal branches of the external carotid artery to reverse the competitive backflow into the ophthalmic artery in order to perform intra-arterial chemotherapy via the ostium of the ophthalmic artery in selected cases.METHODS:We queried our prospectively collected database of 327 consecutive patients treated for retinoblastoma by intra-arterial chemotherapy and identified those employing Gelfoam pledgets. We describe this new technique with emphasis on feasibility and safety.RESULTS:We treated 11 eyes with 14 infusions of intra-arterial chemotherapy using Gelfoam pledgets to occlude the distal branches of the external carotid artery. We report no perioperative complications due to this occlusion technique. At the ophthalmologic follow-up 1 month after the injection of Gelfoam pledgets, all cases showed tumor regression or stable disease. Two injections into the same eye as the rescue intra-arterial chemotherapy infusion resulted in a transient exudative retinal detachment, and one injection in a heavily pretreated case was followed by iris neovascularization and retinal ischemia. None of the pledget injections led to irreversible vision-threatening intraocular complications.CONCLUSIONS:Intra-arterial chemotherapy in retinoblastoma using Gelfoam to transiently occlude the distal branches of the external carotid artery and reverse the backflow into the ophthalmic artery seems feasible and safe. Larges series will help to confirm the effectiveness of this new technique.

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.

BACKGROUND:We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes. METHODS:Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis. RESULTS:The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in COL4A3, COL4A4, and COL4A5. Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype. CONCLUSION:A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy."