Targeting GPC2 on intraocular and CNS metastatic retinoblastomas with local and systemic delivery of CAR T-cells.

PURPOSE: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T-cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. EXPERIMENTAL DESIGN: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T-cells with different co-stimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T-cells were evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. RESULTS: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2 and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB co-stimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence that led to significant tumor regression compared to either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T-cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T-cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. CONCLUSIONS: GPC2-directed CAR T-cells are effective against intraocular and CNS metastatic retinoblastomas.

Vitreoretinal Lymphoma Masquerading as Central Serous Chorioretinopathy.

The following is a case of vitreoretinal lymphoma masquerading as central serous chorioretinopathy (CSCR). A 74-year-old man presented with blurred vision in the left eye with unilateral subretinal fluid in the setting of exogenous corticosteroid use, which was diagnosed as CSCR and resolved with corticosteroid cessation. He later experienced a similar self-limited episode in the right eye. Subsequently, he developed bilateral vitritis with yellow-white subretinal pigment epithelial infiltrates. Vitreous biopsy confirmed a diagnosis of large B-cell lymphoma. Vitreoretinal lymphoma can masquerade as a number of ocular pathologies, including CSCR. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Spontaneous onset and resolution of optic disk pit maculopathy in a young patient.

We report the case of an 8-year-old boy who presented with an optic disk pit and subsequently developed optic disk pit maculopathy, consisting of cystoid retinal edema in the peripapillary space and in the papillomacular bundle, which slowly and spontaneously resolved without intervention.

Topical 5-fluorouracil 1% for moderate to extensive ocular surface squamous neoplasia in 73 consecutive patients: Primary versus secondary treatment.

IMPORTANCE: Ocular surface squamous neoplasia (OSSN) is a spectrum of malignancies that generally includes conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC). OSSN can be treated with topical therapies including interferon α-2b (IFN), mitomycin C (MMC), or 5-fluorouracil 1% (5FU). Recently, due to unavailability of IFN and toxicity associated with MMC, therapy has shifted towards 5FU. OBJECTIVE: Herein, we compare the use of 5FU 1% as a primary versus (vs) secondary treatment regimen in eyes with moderate to extensive OSSN. DESIGN SETTING AND PARTICIPANTS: Retrospective cohort study of 73 consecutive patients with unilateral moderate to extensive OSSN treated at a single tertiary ocular oncology center from 2016 to 2023. Mean follow up time was 478.2 days overall, with 283.0 days for primary 5FU group and 860.3 days for secondary 5FU group. INTERVENTION: Topical 5FU 1% 4 times daily for 2 weeks with option for 2-weekly extension until tumor control, either as primary treatment or as secondary treatment to surgical resection, topical IFN or topical MMC, or cryotherapy. MAIN OUTCOMES: Outcome measures included tumor response, need for additional surgery, complications, and visual outcomes. RESULTS: A comparison (primary vs secondary treatment) revealed no difference in mean tumor basal dimension (19.6 vs 17.2 mm, P = 0.46), thickness (3.7 vs 3.4 mm, P = 0.64), or tumor extent (4.4 vs 4.5 clock hours, P = 0.92). The primary treatment group showed greater complete tumor control (77% vs 38%, P = 0.04). Multivariable analysis comparison (primary vs secondary treatment) showed primary treatment more likely to achieve complete tumor control (P = 0.01). There was no difference in the complication rate from 5FU treatment between the groups. There was no difference in visual outcome, and no tumor-related metastasis (0%) or death (0%). CONCLUSION AND RELEVANCE: Topical 5FU 1% is efficacious and safe as a primary or secondary treatment for moderate to extensive OSSN. Tumors treated with primary 5FU 1% demonstrated more complete resolution. In patients with moderate to extensive OSSN, primary treatment with topical 5FU 1% may be warranted.

Multifocal Unilateral Orange Fundus Tumors in a Young Man.

A 38-year-old man had an asymptomatic, orange, macular choroidal mass with macular choroidal folds and a retinal pigment epithelial detachment in the right eye and a second orange mass nasal to the optic disc also in the right eye. What would you do next?

Strabismus management in retinoblastoma survivors.

PURPOSE: To report the result of strabismus surgery in eye-salvaged retinoblastoma (Rb) patients. METHODS: A retrospective case series including 18 patients with Rb and strabismus who underwent strabismus surgery after completing tumor treatment by a single pediatric ophthalmologist. RESULTS: A total of 18 patients (10 females and 8 males) were included with a mean age of 13.3 ± 3.0 (range, 2-39) months at the time tumor presentation and 6.0 ± 1.5 (range, 4-9) years at the time of strabismus surgery. Ten (56%) patients had unilateral and 8(44%) had bilateral involvement and the most common worse eye tumor's group was D (n = 11), C (n = 4), B (n = 2) and E (n = 1). Macula was involved by the tumors in 12 (67%) patients. The tumors were managed by intravenous chemotherapy (n = 8, 47%), intra-arterial chemotherapy (n = 7, 41%) and both (n = 3, 17%). After complete treatment, the average time to strabismus surgery was 29.9 ± 20.5 (range, 12-84) months. Except for one, visual acuity was equal or less than 1.0 logMAR (≤ 20/200) in the affected eye. Seven (39%) patients had exotropia, 11(61%) had esotropia (P = 0.346) and vertical deviation was found in 8 (48%) cases. The angle of deviation was 42.0 ± 10.4 (range, 30-60) prism diopter (PD) for esotropic and 35.7 ± 7.9 (range, 25-50) PD for exotropic patients (P = 0.32) that after surgery significantly decreased to 8.5 ± 5.3 PD in esotropic cases and 5.9 ± 6.7 PD in exotropic cases (P < 0.001). The mean follow-up after surgery was 15.2 ± 2.0 (range, 10-24) months, in which, 3 (17%) patients needed a second surgery. CONCLUSION: Strabismus surgery in treated Rb is safe and results of the surgeries are acceptable and close to the general population. There was not associated with tumor recurrence or metastasis.

Impact of iris color on uveal melanoma-related outcomes in 7245 patients at a single ocular oncology center.

PURPOSE: To determine the relationship between iris color and uveal melanoma (UM)-related metastasis and death in a large cohort of patients from a single ocular oncology center. DESIGN: Retrospective case series. SUBJECTS: Patients diagnosed with UM between February 1971 and August 2007. METHODS: Patient information was obtained from chart documentation. MAIN OUTCOME MEASURES: UM-related metastasis and death. RESULTS: Out of 7245 patients, iris color was blue in 3702 (51%), green in 1458 (20%), and brown in 2085 (29%). Mean age was 58 ± 15 years and mean tumor thickness was 5.5 ± 3.3 millimeters. Some clinical features differed between iris color groups, with the blue irides group having a larger proportion of post-equatorial tumors with significantly closer proximity to the foveola and optic disc compared to the brown irides group. At a mean follow-up of 75 months, there was no statistically significant difference in metastasis between the various iris color groups. On univariate analysis, those with blue irides showed a higher incidence of UM-related death compared to the green and brown irides groups (8.3%, 5.9% and 7.5% respectively, p value = 0.02). Kaplan-Meier event free survival from UM-related death significantly differed only between the blue and green irides groups (p value = 0.007) with the green irides group showing the highest survival. However, on multivariate analysis, iris color was not predictive of UM-related death. CONCLUSION: Iris color was not predictive of UM-related metastasis or death. However, Kaplan-Meier survival at 20 years was poorest for blue irides group compared to green.

BRCA-associated protein1 (BAP1) immunohistochemical stain reliability in postbrachytherapy uveal melanoma enucleation specimens.

PURPOSE: The BRCA-associated protein1 (BAP1) immunohistochemical (IHC) stain has emerged as a powerful and inexpensive prognostic tool in uveal melanoma (UM), correlating with UM genetics and outcome. The data on the reliability of BAP1 immunohistochemistry in previously irradiated UM is scant. We aim to assess BAP1 IHC in post-Iodine-125 plaque brachytherapy-treated UM-enucleated eyes. METHODS: In a case-control study, the medical records of all patients who underwent enucleation for UM at a major Ocular Oncology Service from December 1 st , 2007 to December 31 st , 2014 were reviewed. All cases with either chromosome 3 (ch3) status or sufficient follow-up (>5 years or metastasis) were selected. Nuclear BAP1 (nBAP1) immunoreactivity was interpreted as intact (positive in >90% of nuclei), lost (positive in <5% of nuclei), or heterogeneous (positive in 5-90% of nuclei). Retina and intratumoral blood vessels served as internal positive controls. RESULTS: A comparison of 34 postbrachytherapy UM secondary-enucleated eyes with 47 nonbrachytherapy primary enucleated controls revealed no significant difference with respect to nBAP1 IHC (lost in 41% vs 51%, P = 0.19), ch3 status (ch3 monosomy in 59% vs 60%, P = 0.48), and outcome (metastatic disease in 44% vs 47%, P = 0.8). Association of nBAP1 IHC with ch3 status and outcome [intact nBAP1/(ch3 disomy and/or no metastasis) and lost nBAP1 (ch3 monosomy and/or metastasis)] in post-brachytherapy UM was significantly lower when compared with non-brachytherapy tumors [21/30 (70%) vs 41/44 (93%), P = 0.004*]. CONCLUSION: Although nBAP1 IHC stain is a strong prognostic tool in UM, its association with ch3 status, and outcome in postbrachytherapy UM was significantly lower compared with nonbrachytherapy tumors due to pitfalls in the interpretation of nBAP1 immunoreactivity in irradiated UM. This test should be used judiciously in the prognostication of postbrachytherapy-enucleated UM.

Correlation of fitzpatrick skin type and iris color with tumor size in 823 patients with uveal melanoma.

PURPOSE: To determine the correlation of Fitzpatrick Skin Type (FST) and iris color with tumor size (tumor thickness and basal diameter) in patients with uveal melanoma. DESIGN: Retrospective Cohort METHODS: Retrospective cohort from a single ocular oncology center of 823 patients with uveal melanoma and documented FST, iris color, and tumor size. Patients were classified by FST (type I, II, and III-V) and iris color (blue, green, and brown) on the basis of external facial photography. There were no FST type VI patients. Tumor thickness was classified into small [< 3 millimeter (mm)], medium (3.1-8.0 mm), or large (> 8.0 mm), and basal diameter into small (< 10 mm), medium (10.1-15 mm) or large (> 15 mm). The correlation of FST and iris color with tumor thickness and basal diameter was evaluated using the Kruskal-Wallis H test. RESULTS: The FST classification was type I (n = 92, 11%), type II (n = 643, 78%), or III-V (n = 88, 11%), and iris color was blue (n = 472, 57%), green (n = 102, 12%), or brown (n = 249, 30%). A comparison of FST revealed differences in mean tumor thickness (P = 0.04) and basal diameter (P = 0.006). Iris color showed no difference for mean tumor thickness (P = 0.41) or basal diameter (P = 0.48). There was a statistically significant difference with brown iris color relative to FST III-V for mean tumor thickness (P = 0.003) and basal diameter (P = 0.001) but no difference with blue or green iris color (P > 0.05). CONCLUSIONS: Iris color alone showed no difference in tumor size, but those with brown iris color and FST type III-V demonstrated larger tumor thickness and basal diameter.

Familial retinoblastoma: variations in clinical presentation and management based on paternal versus maternal inheritance.

BACKGROUND: Several studies have demonstrated the effect of parent-of-origin on retinoblastoma penetrance. The purpose of the current study was to assess differences in clinical presentation of paternally versus maternally inherited retinoblastoma. METHODS: The clinical records of all children with familial retinoblastoma treated on a tertiary Ocular Oncology Service between December 1975 and May 2020 were reviewed retrospectively. RESULTS: A total of 179 patients with familial retinoblastoma were included. Paternal inheritance (PI) was identified in 109 (61%) patients and maternal inheritance (MI) in 70 patients (39%). A comparison (PI vs MI) revealed PI patients were older at presentation (57.2 vs 24.4 months [P = 0.002]) with no difference in patient sex (53% females vs 57% males [P = 0.606]) or number of family members affected (3.2 vs 3.0 family members [P = 0.255]). PI patients had more advanced classification according to the International Classification of Retinoblastoma (ICRB) (group E: 31% vs 8% [P = 0.012)] and greater largest tumor in basal diameter (9.0 vs 6.2 mm [P = 0.040]) and thickness (5.6 vs 4.0 mm [P = 0.038]); they were also less likely to be located in the macula (40% vs 60% [P = 0.004]). There was no difference in tumor laterality (69% vs 64% bilaterality [P = 0.530]). PI patients required enucleation more frequently (34% vs 14% [P = 0.007]). There was no difference in need for plaque radiotherapy (P = 0.86) or chemotherapy (P = 0.85). One PI patient developed metastatic retinoblastoma, and there were no retinoblastoma-related deaths. CONCLUSIONS: Patients with paternally inherited retinoblastoma presented at an older age, with larger, more peripheral tumors and more advanced ICRB group, and were more likely to require enucleation compared to those with maternally inherited retinoblastoma.

Large Language Models in Ophthalmology: Potential and Pitfalls.

Large language models (LLMs) show great promise in assisting clinicians in general, and ophthalmology in particular, through knowledge synthesis, decision support, accelerating research, enhancing education, and improving patient interactions. Specifically, LLMs can rapidly summarize the latest literature to keep clinicians up-to-date. They can also analyze patient data to highlight crucial insights and recommend appropriate tests or referrals. LLMs can automate tedious research tasks like data cleaning and literature reviews. As AI tutors, LLMs can fill knowledge gaps and assess competency in trainees. As chatbots, they can provide empathetic, personalized responses to patient inquiries and improve satisfaction. The visual capabilities of LLMs like GPT-4 allow assisting the visually impaired by describing environments. However, there are significant ethical, technical, and legal challenges around the use of LLMs that should be addressed regarding privacy, fairness, robustness, attribution, and regulation. Ongoing oversight and refinement of models is critical to realize benefits while minimizing risks and upholding responsible AI principles. If carefully implemented, LLMs hold immense potential to push the boundaries of care, discovery, and quality of life for ophthalmology patients.

Reliability and accuracy of artificial intelligence ChatGPT in providing information on ophthalmic diseases and management to patients.

PURPOSE: To assess the accuracy of ophthalmic information provided by an artificial intelligence chatbot (ChatGPT). METHODS: Five diseases from 8 subspecialties of Ophthalmology were assessed by ChatGPT version 3.5. Three questions were asked to ChatGPT for each disease: what is x?; how is x diagnosed?; how is x treated? (x = name of the disease). Responses were graded by comparing them to the American Academy of Ophthalmology (AAO) guidelines for patients, with scores ranging from -3 (unvalidated and potentially harmful to a patient's health or well-being if they pursue such a suggestion) to 2 (correct and complete). MAIN OUTCOMES: Accuracy of responses from ChatGPT in response to prompts related to ophthalmic health information in the form of scores on a scale from -3 to 2. RESULTS: Of the 120 questions, 93 (77.5%) scored ≥ 1. 27. (22.5%) scored ≤ -1; among these, 9 (7.5%) obtained a score of -3. The overall median score amongst all subspecialties was 2 for the question "What is x", 1.5 for "How is x diagnosed", and 1 for "How is x treated", though this did not achieve significance by Kruskal-Wallis testing. CONCLUSIONS: Despite the positive scores, ChatGPT on its own still provides incomplete, incorrect, and potentially harmful information about common ophthalmic conditions, defined as the recommendation of invasive procedures or other interventions with potential for adverse sequelae which are not supported by the AAO for the disease in question. ChatGPT may be a valuable adjunct to patient education, but currently, it is not sufficient without concomitant human medical supervision.

Posterior scleritis following COVID-19 vaccination or infection simulating uveal melanoma in 8 consecutive patients.

OBJECTIVES: To determine clinical features and outcomes of posterior scleritis masquerading as uveal melanoma following vaccination against COVID-19 and/or COVID-19 infection. SUBJECTS/METHODS: All patients with posterior scleritis referred to our service to rule out intraocular tumour between February 2021 and June 2022, who previously had COVID-19 vaccination and/or infection (n = 8). A retrospective detailed review of patient charts and imaging was carried out. RESULTS: Previous COVID-19 vaccination was documented in 6 patients (75%) and previous COVID-19 infection and vaccination in 2 patients (25%). Demographic features included mean age of 59 years (median 68, range 5-86 years), white race (n = 7, 87%), and male sex (n = 5, 63%). Mean visual acuity at presentation was 0.24 LogMAR (median 0.18, range 0.0-0.70). The main presenting symptom was blurred vision with pain (n = 5, 63%). Features that suggested scleritis and not uveal melanoma included pain (n = 6, 75%), anterior scleritis (n = 3, 38%), disc oedema (n = 1, 13%), choroidal detachment (n = 3, 38%), choroidal folds (n = 3, 38%), diffusely thickened scleral wall on ultrasonography (n = 2, 25%), Tenon's oedema (n = 5, 63%), and scleral nodule with medium/high internal reflectivity on ultrasonography (n = 4, 50%). Follow-up information at mean of 2 months (range 0.25-7 months) revealed visual acuity at date last seen was mean 0.30 LogMAR (median 0.29, range 0.0-0.54). By 2 months, resolution of "tumour" was noted in 5/6 (83%) patients with follow-up. CONCLUSIONS: Posterior scleritis following COVID-19 vaccination and/or infection can masquerade as choroidal melanoma. At 2 months duration, partial or complete resolution of features with minimal visual consequence was noted.