Purpose Ophthalmic malignancies are well described in DICER1 syndrome and include intraocular malignancies and, rarely, primary orbital tumors (or medulloepitheliomas). Here, we present the case of an aggressive primary orbital malignancy (embryonal tumor with multilayered rosettes [ETMR]) in a child with germline and somatic DICER1 abnormalities. Observations In a 1-month-old boy born at term, a computed tomography scan revealed an orbital mass initially thought to be consistent with a capillary hemangioma. After initial treatment with a 4-week course of oral propranolol (3 mg/kg/day) without response, a magnetic resonance imaging scan revealed an enlarging lobulated large enhancing left intraconal mass. A series of biopsies and DNA methylation array analyses showed the lesion to be an ETMR, atypical subclass. Germline analysis revealed a mutation in the DICER1 gene. The tumor itself had a second, different mutation in the DICER1 gene. ETMR has been rarely identified in the orbit and there are no accepted treatments, but overall survival of ETMR lesions is poor (<20%) with combinations of surgery, radiation, or brachytherapy. The family was offered exenteration but refused, so intraarterial chemotherapy was offered with the understanding that it had never been tried in DICER1-mutated orbital ETMR. After treatment in 4 monthly 2-hour outpatient sessions with intraarterial chemotherapy, we observed prompt regression of clinical findings. Serial imaging following the final cycle of treatment demonstrated no evidence of recurrent or progressive disease. Twenty-three months later, there has been no regrowth. Conclusion and importance A somatic and germline (“two hit”) DICER1-mutated orbital tumor was successfully managed without surgery, radiation, or systemic chemotherapy using the well-established intraarterial approach presently used for retinoblastoma. In the case of our patient, intraarterial chemotherapy proved to be an effective treatment for this tumor.

Background: This review explores the development and legacy of the Reese-Ellsworth classification system for retinoblastoma, a landmark achievement in pediatric oncology. Summary: We first highlight the history of cancer staging in the early 20th century. Then, we discuss the lives of Algernon B. Reese and Robert M. Ellsworth, two pioneering figures in ophthalmic oncology, and their development of the Reese-Ellsworth classification system in 1963. The system served as the international standard for over 3 decades, stratifying patients by prognosis and enabling standardized treatment protocols and collaborative research that contributed to dramatic improvements in retinoblastoma survival rates. However, as the standard of care shifted from radiation to chemotherapy in the latter half of the 20th century, the system became obsolete and was ultimately replaced. Key Messages: The story of Reese and Ellsworth exemplifies how disease staging systems must adapt to changing therapeutic paradigms while demonstrating the importance of standardized classification in advancing cancer research.

Introduction: The aims of the study were to investigate clinical characteristics and spectrum of immune checkpoint inhibitor optic nerve disorders (ICI-OND), including ICI-optic neuritis (ICI-ON), ICI-optic disc edema (ICI-OE), ICI-optic perineuritis, and ICI-panuveitis; to understand the breadth of management options; to investigate long-term outcomes of these patients; and, importantly, to tackle the question of outcomes following rechallenge of these potentially life-preserving drug regimens. Methods: Retrospective analysis, single-center tertiary cancer hospital. Thirty-seven eyes in twenty consecutive patients with ICI-OND treated at Memorial Sloan Kettering Cancer Center between June 16, 2019, and June 5, 2025, were included. Results: In 37 eyes with ICI-OND, the majority of patients had painless loss of vision (85%), bilateral involvement (70%), dyschromatopsia (59%), abnormal testing: visual field (79%), retinal nerve fiber layer optical coherence tomography (80%), and magnetic resonance imaging (56%). Time to diagnosis occurred following a median of 4.5 drug cycles and was shorter with combination ICI (two ICI's) versus monotherapy (one ICI). The 3 patients with pain all had concurrent intraocular inflammation. Following steroid treatment and ICI cessation, vision was improved in 84% of eyes, stable in 11%, and declined in 5%. Snellen lines regained was associated with baseline vision (p = 0.0002). Five patients were rechallenged, and we did not see nor detect recurrence of ICI-OND in 4 patients; 1 patient had recurrence which resolved with steroids and vision returned to baseline. Conclusions: In the majority of cases, ICI-OND occurs bilaterally with painless vision decline and color vision deficits. Cessation of drug along with initiation of systemic steroids can improve vision to 20/40 or better in at least one involved eye, and although we included a smaller subset of patients, we found that ICI can be rechallenged after completion of steroids, without documented recurrence of ICI-OND in most patients.

Retinoblastoma management has changed notably in the past 11 years. Here, four retinoblastoma experts in the USA and Europe report their management recommendations. Retinoblastoma is now the most curable of all pediatric cancers in developed countries, and major clinical trials are scarce; thus, the experience of these centers carries important information for clinicians worldwide. There is increasing use of intra-arterial chemotherapy for unilateral and bilateral disease in naïve and recurrent eyes. Intravitreal chemotherapy is increasingly being used, and high-dose topotecan for vitreous seeds, anterior chamber tumor (combined with intracameral injection), and recurrent retinal and subretinal tumors is becoming the standard approach.

Background Intra-arterial chemotherapy (IAC) is a growing method of therapy for retinoblastoma (Rb). There is an absence of data to support the safety of catheterization with intra-arterial infusion in this pediatric population Objective To focus on the non-ocular catheter/procedural-related complications that our practice has experienced in order to lay a foundation for practices interested in performing these procedures and hopefully, to help prevent them from occurring. Methods This is a retrospective review of the patient population with Rb treated in our center from May 2006 through May 2024. Every procedure performed was reviewed for non-ocular catheterization-related complications. This review included complications of access, the distal vessel (thrombosis, stenosis, and dissection), and non-ocular infarcts. Results There were 2281 vascular access events, and 2681 distal catheterization procedures were performed for IAC infusion on 623 pediatric patients with Rb. Mean age of the population was 18.9 months. There were 31 complications directly related to catheterization: 7 (0.3%) related to femoral artery access and 24 (0.9%) were distal vessel injuries. Two (0.07% of total catheterizations) of the distal vessel injuries were asymptomatic cerebral infarcts diagnosed on follow-up MRI. Conclusion Catheterization with IAC can be performed safely in this young pediatric population. There is a trend for fewer complications when using the smallest catheter system possible for procedures.

The glymphatic system is a glial-based perivascular network that clears metabolic waste from the central nervous system (CNS), and its dysfunction is related to neurodegenerative disease. This review describes a correlate ocular glymphatic system in the eye and describes how this might relate to ophthalmic diseases. This review article summarizes the published literature on the CNS and ophthalmic glymphatic system and how its dysfunction relates to disease. There are associations in the pathogenesis among neurodegeneration, glaucoma, and age-related macular degeneration (AMD), which could be explained through glymphatic dysfunction in the CNS and eye, respectively. The protective effects of exercise and sleep further demonstrate associations among neurodegeneration, glaucoma, and AMD. We provide new insights on the role of the glymphatic system and intraocular tumors, proposing that tumors may hijack the glymphatic system as a bidirectional pathway of communication between the eye and the brain. New therapies for enhancing CNS glymphatic flow are discussed. Dysfunction of the glymphatic system may be a unifying pathogenesis among neurodegeneration, glaucoma, and AMD. Future research should analyze whether CNS-focused therapeutics may improve ocular disease. The role of the glymphatic system in the pathogenesis of intraocular tumors warrants further investigation.

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.

Purpose: To investigate the utility of intravitreous methotrexate and rituximab in the treatment of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP). Methods: The observational cohort study of five eyes of three patients with BDUMP receiving combination injections of intravitreous methotrexate 400 mcg/0.05 mL and rituximab 1 g/0.1 mL as part of multimodal treatment of BDUMP. Change in central foveal thickness and subfoveal fluid was obtained by optical coherence tomography, and change in logMAR/Snellen vision was compared before and after each injection and over the follow-up duration. Results: Five eyes of three male patients with BDUMP received 39 combination injections of intravitreous methotrexate and rituximab. The median follow-up period was 48.2 months; all eyes exhibited a decrease in central foveal thickness and subfoveal fluid and an improvement in vision at some point from baseline. The median/mean vision increase was 5/3.4 Snellen lines, decrease in central foveal thickness was 243/235 μ m, and decrease in subfoveal fluid was 240/273 μ m. Over the follow-up period, one eye had a gradual decline in vision from 20/40 to 20/150 over 48 months Four of the 5 eyes had marked improvement and sustained vision: from vision ranging 20/50 to 20/150 at baseline to all 4 improving to 20/25 or 20/20. Conclusion: Intravitreous methotrexate and rituximab may be a useful, well-tolerated adjunctive treatment for BDUMP. Improvements in central foveal thickness and subfoveal fluid were noted following injections and over the follow-up period. Unlike the often, rapid decline in vision that is expected of this paraneoplastic disease, the eyes in this cohort appeared to have more favorable outcomes.

Introduction: Uveal melanomas are rare and usually detected in adults over 60 years old. We presented herein an unusual intraocular melanocytic tumor that does not fit into any known category in a child with 10-year follow-up data. The clinical findings, course, ultrasound, MRI, and pathology, including immunohistochemistry and gene profiling, of a child with pigmented intraocular masses simulating uveal melanoma are described. The tumor is provisionally called “endopapillary uveal melanocytic tumor of childhood” based on its unusual pathology and molecular biology. Comprehensive molecular testing, including MSK-IMPACT, which interrogates 468 known cancer genetic alterations, and Archer fusion testing (RNA sequence analysis) revealed no abnormalities. Case Presentation: Our patient was a 7-month-old white boy with a suspected mass in the left eye. There was no family history of melanoma. An MRI scan revealed a 1.9 × 1.7-cm well-circumscribed, heterogeneously T1 pre-contrast hyperintense mass, which demonstrated heterogeneous low signal intensity on T2-weighted imaging. A needle biopsy using a 25-gauge needle revealed a pigmented tumor, so we performed an enucleation. Upon histopathologic examination after enucleation, the tumor was densely pigmented, without significant necrosis or internal cavitation. Tumor cells grew around vascular “papillae.” Six years later, the patient is alive and shows no evidence of local or systemic recurrence. Conclusion: Our case exhibited unique features and pathology, without any of the known genetic abnormalities associated with uveal melanoma and does not match the descriptions in the existing literature. Thus, we have named these masses “endopapillary uveal melanocytic tumor of childhood.”

Purpose: We present our experience treating ocular tumors in a standard pencil beam scanning (PBS) gantry room without apertures, which could broaden access to proton therapy for patients with ocular cancer globally. Besides, this study explores the dosimetric benefits of beam-specific apertures. Methods and Materials: We retrospectively evaluated 11 consecutive patients with uveal melanoma treated in a clinic gantry room. The dose deviations between the planned and received by the patient were investigated by assessing the forward calculation of the treatment plan on the synthetic computed tomography of cone beam computed tomography. Each plan was forward calculated with a beam-specific brass aperture (BSA) using a Monte Carlo algorithm to explore dosimetric improvements. We compared the plan quality to the delivered plan (DP) using target coverage (D95%) and mean/maximum doses to the adjacent organs. Results: A close agreement between the planned and delivered dose was achieved, with D95% deviations within 3.6% for all treatments, maintaining dose constraints for critical organs. Similar target coverage was reached, with D95% at 101% ± 1.0% (DP) and 101% ± 3.2% (BSA). BSA was effective (P < .05) in reducing the mean [DMean (DP, BSA)Gy] and maximum [DMax (DP, BSA)Gy] dose to organs: retina DMean (37.7, 29.5), cornea DMean (10.7, 2.4), conjunctiva DMean (13.6, 4.1), lacrimal gland DMean (25.5, 14.1), optic nerve DMean (19.6, 13.1), lens DMax (22.4, 8.5), cornea DMax (24.4, 10.2), eyebrow DMax (15.3, 6.8). BSA lowered the mean dose to surrounding organs and significantly decreased the maximum dose to nonabutting organs (lens, cornea, eyebrow), but had little impact on the maximum dose to the abutting organs (retina, optic nerve). Conclusions: We demonstrate the successful implementation of ocular proton treatment with a standard PBS gantry beamline without apertures. The beam-specific apertures effectively reduced doses to the organs adjacent to the target in the PBS proton treatment while maintaining similar target coverage. This approach offers an opportunity to expand access to ocular proton therapy widely.

Importance:Plasma cell-free DNA (cfDNA) testing is increasingly used for disease diagnosis and monitoring in retinoblastoma, with RB1 allele fraction in cfDNA actively corresponding to disease status and treatment response. However, while RB1 mosaicism has been reported in retinoblastoma, its clinical implications and potential impact on cfDNA testing remain unclear. Objectives:To identify RB1 mosaicism using paired plasma and buffy coat (containing lymphocytes, monocytes, granulocytes, and platelets) DNA testing, and to characterize the implications of RB1 mosaicism on cfDNA testing outcomes. Design, Setting, and Participants:In this cross-sectional study, participants with retinoblastoma underwent testing with MSK-ACCESS (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a clinical assay that combines plasma cfDNA and buffy coat genomic DNA sequencing, enabling the detection and differentiation of somatic, heterozygous, and mosaic variants, between July 2020 and April 2024 at the Memorial Sloan Kettering Cancer Center. Mosaic findings from MSK-ACCESS were correlated with those from a subgroup of patients who concurrently underwent testing using the MSK-IMPACT germline assay. Data analysis was performed from April to September 2024. Exposure:RB1 mosaicism in retinoblastoma. Main Outcomes and Measures:The RB1 variant allele fractions in cfDNA and buffy coat genomic DNA were used to detect RB1 mosaicism. Results:A total of 136 consecutive patients with retinoblastoma (median age at diagnosis, 1.0 year [IQR, 0.4-1.7 years]; 74 [54.4%] female; 67 with bilateral disease and 69 with unilateral disease) who underwent testing with the MSK-ACCESS assay were included. RB1 mosaicism was identified in buffy coat DNA from 20 patients (14.7%), with consistent results detected in all 11 participants tested concurrently by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) germline assay. Four participants with RB1 mosaicism previously tested negative for germline RB1 variants by external laboratories. Compared with heterozygous participants, participants with RB1 mosaicism had a lower risk of developing bilateral disease (91.7% vs 55.0%, respectively; difference, 36.7% [95% CI, 13.8%-59.6%]; P = .002). In cfDNA, the mosaicism variant was detected both before and after treatment, with variant allele fraction initially decreasing after treatment but then stabilizing at levels consistent with mosaicism, despite the absence of clinical disease. Conclusions and Relevance:The accurate detection and quantification of RB1 mosaicism are crucial. RB1 mosaicism should be considered when RB1 variants persist in cfDNA after treatment without evidence of disease; failure to do so may lead to false-positive results and overtreatment in patients with RB1 mosaicism. Identifying RB1 mosaicism may improve patient counseling, inform treatment decisions, and enhance surveillance efforts.

BACKGROUND/AIMS:To determine if patients with vitreoretinal lymphoma (VRL) and concomitant central nervous system lymphoma (CNSL) may present without brain MRI findings, but possess cerebrospinal fluid (CSF) suspicious for lymphoma. METHODS:This was a retrospective, single-centre, observational study evaluating patients with a diagnosis or suspicion of VRL seen at Memorial Sloan Kettering Cancer Center between 2006 and 2024. Patients were included if the final diagnosis was biopsy-proven CNSL and both MRI brain with and without contrast±CSF evaluation (obligatory for inclusion if MRI negative) were performed at the initial diagnostic workup. Patients were excluded if CNS disease treatment (brain, spine or CSF) preceded ocular disease. Patients with prior extra-CNS disease were included. Clinical records and radiographic imaging were retrospectively reviewed and relevant data were recorded for each patient. We evaluated the proportion of patients with MRI negative and CSF suspicious for lymphoma. Subgroup analysis included imaging features, pathology, treatment and disease course. RESULTS:We identified 65 patients. Of the 65 patients at the presentation of VRL, 30 had negative MRI brain and CSF, 16 had positive brain MRI and negative CSF and 8 had both positive MRI brain and CSF. 11 (16.9%) had CSF suspicious for lymphoma without positive findings on MRI of the brain. In this subgroup, the median age was 66 years (range 49-82) and 36% were female. 86% of these patients were asymptomatic neurologically. 73% underwent systemic treatment. At a mean 3 years follow-up, 91% of patients were living. CONCLUSION:In patients with suspected VRL, it is possible to have CSF test positive for lymphoma in the context of negative brain MRI. This suggests, when evaluating VRL patients for concomitant CNS disease, CSF evaluation leads to earlier detection and systemic treatment, even when MRI brain findings are negative. In our cohort, an absence of CSF evaluation in the context of negative brain MRI could have missed 16.9% of patients with CNS lymphoma.

PURPOSE:The more widely known ocular toxicity of Mirvetuximab soravtansine-gynx (MIRV) is keratopathy. Clinical trial data provides little detail on the lesser known toxicity of anterior uveitis from MIRV. We discuss the potential mechanism for this toxicity and provide suggested adjustments to current clinical practice for patients on this drug. METHODS:This retrospective case series, single center study included 42 consecutive patients treated with MIRV at Memorial Sloan Kettering Cancer Center for High-grade serous ovarian cancer and examined in our ophthalmology department between March 1, 2024 - July 15, 2025. RESULTS:Seventeen of forty-two (40%) patients (median age of 69 years) developed keratitis, and three (7.1%) patients, developed grade 1+ bilateral non-granulomatous anterior uveitis on treatment with MIRV. Uveitis was diagnosed after a median of 12 cycles (range 9-14). CONCLUSION:Although a small cohort, our findings suggest that MIRV-induced anterior uveitis is more common than initially thought. Reassuringly, all cases observed have been mild and reversible with topical steroid drops and most patients were able to continue on MIRV (lifesaving) treatment.

Purpose: To assess the stability of concentrated solutions of topotecan and the ocular and systemic safety of administering repeated very high doses of intravitreal (IVi) topotecan in rabbits. Design: Experimental study. Subjects: Twenty four nontumor-bearing New Zealand White rabbits. Main Outcome Measures: In vitro stability of topotecan solutions, hematologic parameters, fundoscopic examination, electroretinography (ERG) response, fundoscopic photography, and histologic assessment. Methods: Three topotecan solutions (1-4 mg/ml) were assessed for stability at 4°C and –20°C for 1 month of drug reconstitution. Five groups of nontumor-bearing rabbits were used to evaluate systemic and ocular toxicity of 3 monthly doses of topotecan (50 μg, 100 μg, and 200 μg), injected in 50 μL or in 100 μL of diluent, or receiving only the vehicle. Ophthalmic, clinical, and electroretinographic evaluations were performed monthly. One month after the last injection, all eyes were enucleated for histological assessment. Electroretinographic parameters were compared among groups using a linear mixed-effects model (P < 0.05). Results: Topotecan solutions remained stable. During the study period, no hair loss, weight changes, or hematologic abnormalities were observed in any of the animal groups. Eyes treated with vehicle or injected with 3 doses of topotecan up to 100 μg per dose, delivered in either 50 μL or 100 μL diluent, showed no morphological, histological, or functional evidence of damage to the retina. However, eyes injected with 200 μg showed localized retinal alterations near the injection site on fundoscopy and histological analysis, and a significant decrease in the a- and b-wave amplitudes on ERG compared with the other groups (P < 0.05). Conclusions: Three monthly IVi injections of topotecan 50 or 100 μg (100 μg and 200 μg human equivalent doses) caused no systemic or ocular toxicity in a nontumor-bearing rabbit model. Repeated 200 μg doses (400 μg human-equivalent dose) resulted in localized retinal morphological alterations and small but detectable changes in electrophysiological parameters. The results of this study may have clinical utility in the assessment of very high-dose topotecan as a salvage treatment of highly compromised eyes with recurrent or relapsed subretinal seeds and retinal tumors. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BackgroundRetinoblastoma is diagnosed and treated without biopsy based solely on appearance (with the indirect ophthalmoscope and imaging). More than 20 benign ophthalmic disorders resemble retinoblastoma and errors in diagnosis continue to be made worldwide. A better noninvasive method for distinguishing retinoblastoma from pseudo retinoblastoma is needed.MethodsRetCam imaging of retinoblastoma and pseudo retinoblastoma from the largest retinoblastoma center in the U.S. (Memorial Sloan Kettering Cancer Center, New York, NY) were used for this study. We used several neural networks (ResNet-18, ResNet-34, ResNet-50, ResNet-101, ResNet-152, and a Vision Image Transformer, or VIT), using 80% of images for training, 10% for validation, and 10% for testing.ResultsTwo thousand eight hundred eighty-two RetCam images from patients with retinoblastoma at diagnosis, 1,970 images from pseudo retinoblastoma at diagnosis, and 804 normal pediatric fundus images were included. The highest sensitivity (98.6%) was obtained with a ResNet-101 model, as were the highest accuracy and F1 scores of 97.3% and 97.7%. The highest specificity (97.0%) and precision (97.0%) was attained with a ResNet-152 model.ConclusionOur machine learning algorithm successfully distinguished retinoblastoma from retinoblastoma with high specificity and sensitivity and if implemented worldwide will prevent hundreds of eyes from incorrectly being surgically removed yearly.

Introduction:The aim of this study was to investigate the impact of injecting Topotecan 90 μg/0.18 cc on intraocular pressure (IOP) in children with retinoblastoma. Methods:This was a retrospective study of 78 eye encounters of 37 patients with retinoblastoma (22 males, 15 females, mean age: 3.5 ± 2.2 years, range 0.50-7.96 years) injected with intravitreal 90 μg topotecan with 0.18 mL volume. IOP was measured with a Schiotz tonometer at baseline prior to injecting, after digital massage, and then at specified time intervals following intravitreal injection of topotecan 90 μg in 0.18 mL volume. Mean arterial pressure (MAP) was either calculated from anesthesia records or recorded during anesthesia. Results:Mean preinjection IOP was 7.6 ± 2.5 mm Hg (range: 2-20 mm Hg). Mean IOP 60 s after intravitreal topotecan was 37.3 ± 17.4 mm Hg (range: 20-82 mm Hg). The IOP of 93.6% of patients was less than the MAP at all observed time points after injection. In patient eye encounters where IOP exceeded MAP, IOP resolved to below MAP in 4 min in all encounters. Additionally, in 4 min, 91% of patient eye encounters had IOP of below 29 mm Hg. Conclusion:Topotecan 90 μg/0.18 cc dose is increasingly important for retinoblastoma treatment. Injection of intravitreal topotecan 90 μg/0.18 cc chemotherapy caused a transient rise in IOP with spontaneous resolution below MAP for all patients after 4 min without further intervention. This is the first study of intravitreal topotecan 90 μg/0.18 cc on IOP and provides reassurance for the safe use of higher dose and volume of topotecan 90 μg/0.18 cc.

This study reports the single-institution clinical experience of multifield pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) and dosimetric comparison to proton arc for uveal melanoma (UM) in a regular PBS gantry room. Eleven consecutive UM patients were treated with IMPT to 50 Gy in 5 fractions. A customized gaze-fixation device attached to the thermoplastic mask was used to reproduce the globe position for each patient. IMPT plans were robustly optimized with perturbations of 3 mm setup and 3.5 ± 1.0 ± 0.4 ± 0.23 vs. 0.88 ± 0.18, p = 0.11). Both modalities met all the clinical goals for organs-at-risk (OARs), while proton arc significantly reduced the maximum dose for the retina from, on average, 54.5 ± 0.7 to 53.2 ± 0.3 Gy (p < 0.01). Treatment evaluation on synthetic CT showed that the doses received by patients were highly consistent with the planned doses, with a relative target coverage (D95