Morphological Biomarkers Related to Visual Acuity in Patients With Radiation Retinopathy Treated With Intravitreal Ranibizumab.

BACKGROUND AND OBJECTIVE: Our objective was to monitor variables via spectral-domain optical coherence tomography (SD-OCT) and identify the most relevant biomarkers related to best-corrected visual acuity (BCVA) in radiation retinopathy (RR). PATIENTS AND METHODS: A post-hoc analysis of the two-year Ranibizumab for Radiation Retinopathy (RRR) trial analyzed vision and OCT parameters including intraretinal fluid, ellipsoid zone (EZ) disruption, retinal pigment epithelium atrophy, hard exudates, retinal hemorrhage, retinal neovascularization, and subfoveal fluid. BCVA and SD-OCT parameters were evaluated by univariate analysis and a mixed-effects model. RESULTS: Forty eyes from the RRR trial were included. Intraretinal cyst vertical size (week 24: P = 0.032; week 48: P = 0.021), neovascularization (week 48: P = 0.028; week 72: P = 0.025), and EZ disruption (week 72: P = 0.029; week 104: P = 0.019) were the clinical parameters most relevant to BCVA by univariate analysis in at least two time points. The mixed-effects model confirmed the relevance of intraretinal cyst vertical size (P = 0.001) and neovascularization (P = 0.001) but not EZ disruption (P = 0.119) over the course of the study. CONCLUSIONS: This study characterizes the course of visual loss in RR by identifying intraretinal cyst vertical size, neovascularization, and EZ disruption as biomarkers of poor BCVA over a span of two years. Larger multicenter studies are needed to confirm these findings. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Prostaglandin-Induced Macular Hole: A Brief Report.

This case series reports on two patients who developed macular holes while on prostaglandin analogs (PGA) therapy. The first case involves a 63-year-old woman with a history of a macular hole of the left eye that had spontaneously closed. After starting PGA therapy for elevated intraocular pressure, cystoid macular edema formed, which resulted in reopening of the macular hole. The second case involves a 64-year-old man with primary open-angle glaucoma, on PGA therapy, with a newly diagnosed small macular hole of the right eye that closed after cessation of the PGA therapy. These cases demonstrate an association between prostaglandin analogs and the formation or reopening of full-thickness macular holes. [Ophthalmic Surg Lasers Imaging Retina 2024;55:112-115.].

Retrospective Analysis of Radiation-Induced Complications of Uveal Melanoma Patients Treated With Brachytherapy in the Era of Anti-VEGF.

PURPOSE: To associate clinical factors and radiation doses delivered by iodine-125 plaque brachytherapy to visual outcomes and development of radiation-induced ocular complications in patients with uveal melanoma in the era of anti-vascular endothelial growth factor (anti-VEGF) injections. DESIGN: Retrospective cohort study. METHODS: A retrospective chart review was performed for 225 patients treated with iodine-125 brachytherapy for uveal melanoma. The effects of radiation doses (focal doses, average dose to the entire eye, and integral dose) on visual outcomes and development of radiation complications (radiation retinopathy, radiation optic neuropathy, vitreous hemorrhage, and neovascular glaucoma) were analyzed using multivariate Cox regression snalysis. RESULTS: Median follow-up was 33.6 months (range, 12-105.6 months). Radiation retinopathy was associated with younger age, tumor distance to optic nerve <6 mm, and maximum radiation dose to fovea. Radiation optic neuropathy was associated with White race, tumor distance to optic nerve <6 mm, and integral radiation dose. Vitreous hemorrhage was associated with White race and integral radiation dose. Incidence of neovascular glaucoma was low in our study, with 2 patients (0.9%) developing the complication. Of the 123 patients who developed radiation retinopathy, 82 patients (66.7% of radiation retinopathy patients, 37.3% of total patients) received anti-VEGF injections. CONCLUSIONS: Our study found multiple associations between radiation doses and complications as well as visual outcomes on multivariate analysis. Given that the majority of our patients who developed radiation retinopathy received anti-VEGF injections, our study helps to illustrate the course and progression of radiation-induced complications in the new era of anti-VEGF.

Angiographic characteristics and treatment approach in patients undergoing intra-arterial chemotherapy for retinoblastoma.

PURPOSE: To identify the specific clinical and angiographic variables that determine the success of intra-arterial chemotherapy (IAC) in a patient with retinoblastoma. METHODS: Medical records from patients undergoing intra-arterial chemotherapy for the treatment of retinoblastoma between January 2015 and June 2020 within a large academic ocular oncology practice were retrospectively reviewed. Demographics were recorded together with clinical, ocular, and angiographic variables such as the diameter of the ophthalmic artery (OA), angle of ophthalmic artery takeoff, and branching pattern of ophthalmic vasculature. RESULTS: Forty-four eyes from 33 patients with retinoblastoma treated with IAC were identified. Over the total 32 mean months of follow-up, these patients received 144 total catheterizations and a mean of 3.2 IAC cycles for each eye. The number of IAC cycles and the chemotherapeutic agent used did not vary significantly with worsening International Classification of Retinoblastoma (ICRB) groups (P > 0.1). Cumulative dose did not vary with the ICRB group for eyes treated with melphalan, topotecan, or carboplatin (P > 0.1). A higher ICRB group was associated with a smaller mean ophthalmic artery diameter across all procedures (P = 0.016), and femoral artery diameter did not vary significantly between ICRB groups (P = 0.906). A higher cumulative dose of IAC was significantly associated with a smaller takeoff angle of the OA (melphalan, P = 0.011; topotecan, P = 0.009; carboplatin, P = 0.031) in patients who underwent successful IAC procedures. Ophthalmic artery diameter and femoral artery diameter did not have a significant association (P > 0.1) with higher IAC doses in successful IACs. Cumulative IAC dose was not significantly associated with ophthalmic vasculature branching pattern, presence of choroidal blush, temporary OA vasospasm reported during the procedure, and OA occlusion upon microcatheter placement. CONCLUSION: In this study, neurosurgical angioanatomy appeared to influence the cumulative dose of chemotherapy needed during IAC for retinoblastoma. In the future, these anatomic variables may be used to guide the frequency of monitoring, dosing, and estimation of recurrence risk.

Incidence and Risk Factors for Neutropenia After Intra-Arterial Chemotherapy for Retinoblastoma.

Importance: Intra-arterial chemotherapy (IAC) has quickly gained popularity as a mainstay of treatment for retinoblastoma. Intra-arterial chemotherapy has been described as having several advantages over systemic chemotherapy, including reducing systemic toxicity and neutropenia; however, studies on the risk of neutropenia after IAC remain limited. Objective: To estimate the incidence of neutropenia after IAC, as well as identify risk factors associated with the development of neutropenia. Design, Setting, and Participants: This case series included pediatric patients with unilateral or bilateral retinoblastoma who were treated with IAC at a single quaternary care center from July 13, 2013, to January 6, 2023. Exposure: All patients were treated with IAC and underwent multiple IAC cycles depending on treatment response. The primary chemotherapy agent used was melphalan, but topotecan or carboplatin could be used along with melphalan. Melphalan doses were kept to 0.4 mg/kg or less per cycle. After each IAC cycle, complete blood cell counts were obtained within 10 to 12 days and repeated until the absolute neutrophil count (ANC) was greater than or equal to 1000/µL. Main Outcomes and Measures: The primary outcome was the minimum ANC after each IAC cycle. The secondary outcome was the development of severe (grade 3 or 4) neutropenia (ANC <1000/µL). Regression analyses were used to identify associations between variables and outcomes. Receiver operating characteristic curves were used to calculate threshold dose for each chemotherapy agent potentially associated with the development of severe neutropenia. Results: A total of 64 eyes of 49 patients (mean [SD] age, 1.7 [1.2] years; 25 females [51.0%]) with retinoblastoma were treated with 171 cycles of IAC. The mean (SD) nadir ANC was 1325.3 (890.7)/µL and occurred a median (IQR) of 10 (10-14) days (range, 6-28 days) after IAC administration. The frequency distribution of post-IAC neutropenia grades 0, 1, 2, 3, 4, and missing was 31 (18.1% of cycles), 25 (14.6%), 40 (23.4%), 37 (21.6%), 26 (15.2%), and 12 (7.0%), respectively. Factors weakly correlated with a lower ANC were higher melphalan dose (ß = -2356 [95% CI, -4120.6 to -611.2]; adjusted R2 = 0.251; P = .01) and higher topotecan dose (ß = -4056 [95% CI, -7003.6 to -1344.5]; adjusted R2 = 0.251; P = .006). Conclusions and Relevance: In this case series of patients with retinoblastoma, the incidence of severe neutropenia after IAC was nearly 40%, which is higher than previously reported. Extended laboratory monitoring may aid in capturing previously overlooked cases of neutropenia. Topotecan may be associated with the development of neutropenia; limiting topotecan doses, especially in the setting of a high melphalan dose, may be beneficial in reducing the risk of neutropenia.

PRIMARY CENTRAL NERVOUS SYSTEM AND VITREORETINAL LYMPHOMA MIMICKING VIRAL RETINITIS IN A YOUNG PATIENT.

BACKGROUND/PURPOSE: The purpose of this study was to report a young immunocompetent patient with primary central nervous system and vitreoretinal lymphoma initially presenting with peripheral retinitis. METHODS: This study is a case report. RESULTS: A 31-year-old woman presented with 20/60 vision in her left eye, vitreous haze, and peripheral retinal whitening. Intravitreal and oral antivirals were initiated for presumed acute retinal necrosis. Anterior chamber paracentesis was negative for viral nucleotide. Subretinal infiltrates developed, and vitreous biopsy was performed and interpreted as "negative except for rare yeast." Antifungal therapy was initiated. She developed multiple unilateral cranial neuropathies with multifocal areas of enhancement on neuroimaging. Lumbar puncture cytology was negative for neoplastic cells. After further worsening, aforementioned specimens were sent to a specialized ophthalmic pathology laboratory and the diagnosis revised to lymphoma of the diffuse B-cell type. Initial disease regression was seen after combined systemic and intraocular chemotherapy; unfortunately, the patient suffered a central nervous system recurrence and died from systemic complications 1 year later. CONCLUSION: There has been an increased incidence of primary central nervous system and vitreoretinal lymphoma in young patients. Although vitreous biopsy is the diagnostic gold standard for vitreoretinal lymphoma, a risk of false negative interpretation exists. A high index of suspicion and expert interpretation of pathology may be necessary to secure the correct diagnosis.

Randomized Trial of Treat-and-Extend Intravitreal Aflibercept for Radiation Retinopathy: 1-Year Outcomes.

Purpose: Radiation retinopathy (RR)-related macular edema commonly causes poor visual acuity outcomes in patients previously treated with ocular radiation therapy. Current treatments are not US Food and Drug Administration (FDA)-approved and prior studies have variable outcomes. We performed a multicenter, prospective, randomized clinical trial to assess the safety and efficacy of 2 mg intravitreal aflibercept injections (IAIs) for the treatment of RR. Methods: Thirty-nine eyes in 39 patients with RR-related macular edema causing vision loss were assigned randomly to cohorts (1:1 ratio) in which patients either did or did not receive a loading dose of 3 IAIs followed by a treat-and-extend regimen. The primary outcome measure was the mean Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA) change from baseline. Results: Of the 39 randomized patients, 30 (76.9%) completed the year 1 follow-up visit. The overall mean BCVA change from baseline was 4.3 letters (P = 0.087), with 1.57 letters and 6.69 letters gained in cohorts 1 and 2, respectively (P = 0.31). There was a significant difference in central retinal thickness (CRT) from baseline to week 52 overall (484.4 µm to 326.5 µm) and within cohorts 1 (441.2 µm to 311.1 µm) and 2 (522.3 µm to 339.9 µm), respectively (P < 0.001). A total of 96.7% of the patients had visual acuity of 20/200 or better, and 30.0% improved 10 or more letters. Conclusions: Aflibercept may improve CRT and may prevent vision loss in patients with RR using a treat-and-extend regimen through 52 weeks of therapy. Larger, multicenter studies are needed to confirm these findings.

Visual outcome and ocular complications in patients with lacrimal gland carcinoma after eye-sparing surgery and adjuvant radiation therapy.

BACKGROUND: We report visual outcomes and ocular complications in patients with lacrimal gland carcinoma who had eye-sparing surgery followed by radiotherapy. METHODS: This review included consecutive patients with lacrimal gland carcinoma who underwent eye-sparing surgery and adjuvant radiotherapy or concurrent chemoradiation therapy between 2007 and 2018. Clinical data, including details of ophthalmological examinations and radiation treatment were reviewed. RESULTS: The study included 23 patients, 15 males and 8 females, with median age 51 years. Twenty patients (87%) received intensity-modulated proton therapy; 3 (13%) received intensity-modulated radiotherapy. Nineteen patients (83%) received concurrent chemotherapy. After a median follow-up time of 37 months (range: 8-83), 13 patients (57%) had best-corrected visual acuity 20/40 or better, 3 (13%) had moderate vision loss (between 20/40 and 20/200) and 7 (30%) had severe vision loss (20/200 or worse). The most common ocular complications were dry eye disease (21 patients; 91%), radiation retinopathy (16; 70%) and cataract progression (11; 49%). Tumour crossing the orbital midline (p=0.014) and Hispanic ethnicity (p=0.014) were associated with increased risk of severe vision loss. The risk of radiation retinopathy was significantly different among the three racial groups; Hispanic patients (n=3) had the highest rate of retinopathy (p<0.001). Tumour size, initial T category and total prescribed radiation dose were not significantly associated with severe vision loss. CONCLUSION: Eye-sparing surgery followed by adjuvant radiotherapy in patients with lacrimal gland carcinoma has a reasonable overall visual prognosis. Patients with tumours crossing the orbital midline and Hispanic patients have a higher risk of severe vision loss.

Association of Ultrasound Features in Uveal Melanoma With Metastatic Risk as Defined by Preferentially Expressed Antigen in Melanoma Status.

BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the association between clinical and ultrasound features of uveal melanoma and preferentially expressed antigen in melanoma (PRAME), given its role as a biomarker for metastatic mortality. MATERIALS AND METHODS: Ultrasonographic characteristics and PRAME expression status of patients with uveal melanoma (2016 to 2021) were retrospectively analyzed using univariate and multivariate regression. RESULTS: Of the 81 eyes included, 49 (60%) were PRAME negative and 32 (40%) were PRAME positive. Univariate analysis showed that only largest basal diameter (LBD) was significantly associated with PRAME positivity (P = .006). There was a borderline association between shape and PRAME positivity (P = .054), whereas height, internal reflectivity, vascularity, and location showed no effect. Multivariate regression identified LBD as the sole significant predictor of PRAME positivity (odds ratio, 1.196; 95% CI, 1.055 to 1.379; P = .008). CONCLUSION: In this cohort, ultrasonographic LBD was significantly associated with PRAME status. No other clinical or ultrasound variables were predictive of molecular testing results. The results of this PRAME analysis are like prior reports, which suggested a strong association between gene expression profiling class 2 and increasing LBD. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:374-378.].

Three-year outcomes of uveal melanoma treated with intra-operative ultrasound-guided iodine-125 brachytherapy using custom-built eye plaques.

Purpose: The aim of this study was to demonstrate that uveal melanoma (UM) treated with eye plaque brachytherapy (EPB) with intra-operative ultrasound (IOUS) guidance results in increased local control. Material and methods: A retrospective study was conducted among 212 patients with 214 UM tumors treated by iodine-125 EPB with IOUS guidance from 2013 to 2019. 85 Gy was prescribed to tumor apical height or 5 mm from inner sclera, whichever was greater. Lesions were treated to 95% of 85 Gy at 2 mm margin from tumor edge. Local failure (LF), distant metastasis (DM), and radiation-related toxicity were recorded. Results: Median tumor apical height was 3.3 mm. COMS stage was 90 small (42.1%), 81 medium (37.9%), and 43 large (20.1%). Most patients had gene expression profile (GEP) class available, with 119 (55.6%), 30 (14.0%), 55 (25.7%) cases classified as 1A, 1B, and 2, respectively. Median dose at apex for tumor height > 5 mm and ≤ 5 mm was 85.0 Gy and 120.6 Gy, respectively. Outcomes data for 180 patients with over 12 months follow-up were reported. Mean follow-up was 37.3 months. Rates of LF and DM were 0.0% and 12.2%, respectively. Actuarial estimates of 5-year DM for class 1A, 1B, and 2 tumors were 2.5%, 0.0%, and 57.8%, respectively. 87 patients (48.3%) developed radiation-related toxicities. Conclusions: The excellent local control rate amongst lesions ranging across all sizes and GEP classes emphasizes the importance of image-guided brachytherapy with IOUS. We report favorable 5-year DM rates compared to established rates. Acceptable rate and severity of radiation-related toxicities were observed.

Contemporary trends in management of uveal melanoma.

Purpose: In the management of uveal melanoma, eye plaque brachytherapy (EPBT) has replaced enucleation as the standard of care for small size tumors that require treatment, and for medium size tumors. In the modern era, EPBT is being utilized more frequently for certain large tumors as well. While there is prospective randomized evidence to support utilization of EPBT for tumors of appropriate dimensions, it is unclear what the actual practice patterns are across the United States. The purpose of this publication was to look at contemporary trends in the management of uveal melanoma across the United States to determine whether practices are appropriately adopting EPBT, and to investigate demographic and socio-economic factors that might be associated with deviations from this standard of care. Material and methods: The National Cancer Database was queried (2004-2015) for patients with uveal melanoma. Data regarding tumor characteristics and treatment were collected. Two-sided Pearson χ2 test was used to compare categorical frequencies between patients who received globe preserving treatments vs. those who received enucleation. Multivariable logistic regression modeling was used to determine characteristics predictive for receiving enucleation. Results: The enucleation rate for small/medium tumors (≤ 10 mm apical height and ≤ 16 mm basal diameter) decreased from 20% in 2004 to 10% in 2015. The EPBT rate for large tumors increased from 30% in 2004 to 45% in 2015. Numerous demographic and socio-economic factors were found to be associated with higher rates of enucleation. Conclusions: The overall trend across the nation is a decreased enucleation rate for small/medium tumors, and an increased EPBT rate for large tumors. A fraction of patients who should be candidates for EPBT are instead receiving enucleation, and in this study, we have shown that certain adverse demographic factors are associated with this.

Two-year results for ranibizumab for radiation retinopathy (RRR): a randomized, prospective trial.

PURPOSE: To assess the efficacy of a treat-and-extend strategy with intravitreal ranibizumab for radiation-related macular edema. METHODS: Forty eyes with radiation-induced macular edema and decreased visual acuity were enrolled in the phase IIb, prospective clinical trial and randomized into 3 cohorts: (A) monthly ranibizumab, (B) monthly ranibizumab with targeted retinal photocoagulation (TRP), or (C) as-needed ranibizumab and TRP. In year 2, all subjects entered a treat-and-extend protocol for ranibizumab. The primary outcome measure was mean change in early treatment diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) from baseline. RESULTS: Through year 1, the mean change in ETDRS BCVA was significantly different between the three cohorts (p < 0.001); cohort A saw the largest gain with + 4.0 letters. Significant anatomic improvements were also seen in all cohorts. Comparatively, through year 2, cohorts A, B, and C had a mean change in ETDRS BCVA of - 1.9, - 3.9, and + 1.3 letters, respectively; additionally, no significant differences were found in absolute ETDRS BCVA across time (ANOVA, p = 0.123). Overall, 90% of eyes maintained VA 20/200 or better and 33.3% of subjects gained at least one line of vision. There were no significant differences in mean central macular thickness for any cohort compared to baseline (p = 0.09). The presence of retinal hemorrhage and intraretinal exudates stayed consistent from year 1 to year 2 for all cohorts. CONCLUSIONS: Among eyes with radiation-related macular edema, a treat-and-extend regimen with ranibizumab may not result in as many visual and anatomic improvements as monthly injections. However, treat-and-extend still may prevent serious visual complications compared to historical controls. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02222610.

Multiple Genetically Distinct Uveal Melanomas Arise in the Same Eye of Two Patients with Melanosis Oculi.

PURPOSE: To determine whether unilateral multifocal uveal melanomas (UM) in the setting of ocular melanosis (melanosis oculi) represent genetically independent tumors. DESIGN: Clinical case series. METHODS: Two patients with unilateral multifocal UM in the setting of melanosis oculi were included. Tumors were evaluated for gene expression profile (GEP) and next generation sequencing (NGS) for uveal melanoma-associated mutations. Histopathologic analysis of enucleated specimens was also performed when available. RESULTS: Patients were both female, ages 73 and 83 years. In Patient #1, the tumors both exhibited Class 2 GEP but each harbored a unique BAP1 mutation. In Patient #2, one tumor was Class 1 and harbored an SF3B1 mutation, whereas the other tumor was Class 2 and harbored a BAP1 mutation. CONCLUSIONS: Unilateral multifocal UM in the setting of melanosis oculi can arise due to the development of genetically independent primary tumors, which is detectable based on the mutation profile of each tumor. This is the first report of genetically-confirmed independent primary tumors in the setting of unilateral multifocal UM.

Peripapillary Neuroendocrine Carcinoma Metastasis: A Novel Approach to Treatment.

Peripapillary and circumpapillary retinal intraocular metastases are rare and present a treatment challenge for ophthalmologists because of the high risk of iatrogenic injury to the optic nerve. There are no clear guidelines on the management of these lesions, and many clinicians will initially observe for improvement of the metastases with systemic chemotherapy before considering local therapy with external beam radiation. Radiation to the optic disc carries a significant risk of injuring the optic nerve, leading to worsening of vision. Alternative treatment approaches are needed. We present a patient with large-cell neuroendocrine carcinoma with metastasis to the peripapillary retina who was treated with intravitreal topotecan and with intravitreal aflibercept. Serial fundus photos, ultrasound, and optical coherence tomography demonstrated a reduction in size of the lesion and a decrease in subretinal fluid with intravitreal topotecan and aflibercept. In addition, visual acuity was stabilized during treatment. Intravitreal chemotherapy for intraocular metastases in vision-sensitive areas such as the peripapillary retina may be a viable alternative for patients who seek to preserve their vision and maintain their quality of life.

Recent advancements in the management of retinoblastoma and uveal melanoma.

Retinoblastoma in children and uveal melanoma in adults can pose a serious threat to both vision and life. For many decades, enucleation was often the only option to treat these intraocular malignancies. For retinoblastoma, intra-arterial chemotherapy is often utilized as the primary treatment at advanced academic centers and has dramatically improved local tumor control and eye salvage rates. For uveal melanoma, both plaque brachytherapy and proton beam irradiation have served as widely utilized therapies with a local failure rate of approximately 1-10%, depending on the series. Major recent advancements have allowed for a better understanding of the genomics of uveal melanoma and the impact of certain mutations on metastatic susceptibility. Gene expression profile stratifies uveal melanomas into two classes: low-risk (class 1) and high-risk (class 2). A loss-of-function mutation of BAP1 is associated with a class 2 gene expression profile and therefore confers worse prognosis due to elevated risk of metastasis. On the other hand, gain-of-function mutations of EIF1AX and SF3B1 correspond to a gene expression profile of class 1A and class 1B and confer a better prognosis. Preferentially expressed antigen in melanoma (PRAME) is an antigen that increases metastatic susceptibility when expressed in uveal melanoma cells. In addition to plaque brachytherapy and proton beam irradiation, both of which have demonstrated superb clinical outcomes, scientists are actively investigating newer therapeutic modalities as either primary therapy or adjuvant treatment, including a novel nanoparticle therapy and immunotherapy.