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Julia Canestraro,1 Jerome Sherman2 1SUNY College of Optometry, New York, NY, USA; 2Department of Clinical Education, SUNY College of Optometry, New York, NY, USA Introduction: The classic presentation of pigmentary dispersion syndrome (PDS) often consists of midperipheral iris transillumination defects, Krukenberg’s spindle, and dense homogeneous trabecular pigmentation. Other subtle, sometimes overlooked features include pigment on the lens zonules, pigment on the anterior lens capsule and pigment along the equator of the posterior lens capsule. Case: This unique presentation of PDS presented with bilateral, dense, oblique, and symmetrical pigment deposition along the posterior lens capsule that changed in shape, density, and extent over the span of 3 years. Discussion: There have been few reports in the literature that describe a central accumulation of pigment along the posterior lens capsule associated with PDS. There are reported cases of pigment deposition along the central aspect of the posterior lens capsule, some changing over time, although none were bilateral and symmetrical. There are suggestions that perhaps this central pigment deposition is related to a break in the ligament of Weiger, allowing communication between the posterior chamber and posterior lens capsule. This is a case in which curvilinear, symmetrical, and changing pigment deposition on the posterior lens capsule is suggestive of perhaps another key features of PDS. Keywords: pigment deposition, ligament of Weiger, space of Berger, zonules, pigmentary glaucoma

Purpose: To evaluate choroidal findings in patients with histiocytosis including subfoveal choroidal thickness (SFCT), and multimodal imaging in eyes with choroidal infiltrates visible by ophthalmoscopy; and to determine if abnormalities change with histiocytosis-directed (kinase inhibitor) therapy., Participants: 91 patients with histiocytosis and 41 age- and gender-matched controls., Design: Retrospective comparative study at single tertiary cancer referral center., Methods: Clinical exam, fundus photography and OCT were used to assess choroidal findings. Clinically evident choroidal infiltrates by ophthalmoscopy were recorded and choroidal vascular architecture was qualitatively examined. SFCT and was measured using enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT) from the outer portion of Bruch's membrane to the choroidal scleral interface., Main Outcome Measure: SFCT compared to matched controls; secondary outcome was change in SFCT on histiocytosis-directed (kinase inhibitor) therapy. Multimodal imaging of choroidal infiltrates visible by ophthalmoscopy., Results: One hundred and eighty two eyes of 91 patients (46 males, 45 females) with histiocytiosis (Erdheim-Chester 35, Rosai-Dorfman 21, Xanthogranuloma 7, Mixed histiocytosis 11, Langerhans cell histiocytosis 15 and other 2) were examined. In histiocytosis patients, the mean SFCT was 336.2 +/- 94.9 μm compared with 250.3 +/- 60.7μm in the control group (p<0.0001). 69% of histiocystosis patients had SFCT > 275μm compared to 27% in controls (p< 0.0001). Subtype of histiocytosis, sites of bone or central nervous disease, posterior segment/other sites of ophthalmic disease, or mutational profile did not correlate with SFCT. In a subgroup analysis of 35 patients naïve to prior treatment, with > 6 mos follow-up, the proportion of SFCT > 275 μm significantly decreased (p-value = 0.0016) on histiocytosis-directed (kinase inhibitor) therapy. 19.8% of patients had clinically evident choroidal infiltration: majority were yellow creamy, geographic, located posteriorly and hyperautofluorescent; with enlarged Haller's vein bordering the infiltrate, choriocapillaris compression and loss of choroidal architecture by OCT., Conclusions: In this cohort, 19.8% of histiocytosis patients had clinically evident infiltration of their choroid. Furthermore, the majority of patients with histiocytosis had increased subfoveal choroidal thickness compared with age- and gender-matched controls. The thickened choroid decreases on histiocytosis-directed (kinase inhibitor) therapy and may be a marker of response to systemic treatment., (Copyright © 2024. Published by Elsevier Inc.)

Background/aims: Ocular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and sites of disease., Methods: Prospective registry-based study of predominantly adult histiocytosis patients at a single-institution tertiary referral centre. 180 eyes of 90 patients (46 males, 44 females) with histiocytosis (Erdheim-Chester disease 34, Rosai-Dorfman 20, xanthogranuloma 7, mixed histiocytosis 13, Langerhans cell histiocytosis (LCH) 15, ALK-positive histiocytosis 1). Ocular findings were categorised by the structure involved. Histiocytosis subtype, sites of disease and genetic status were correlated to ocular findings., Results: Ocular disease was present in more than half the histiocytosis patient cohort and occurred with other disease sites. Ocular findings were statistically significantly different across histiocytic subtypes with LCH subtypes having the lowest proportion of ocular findings (7%) and all other subtypes having rates of ocular findings which were five times that of patients with LCH (p=0.0009). Of patients with ocular findings, 41% of patients reported ocular symptoms and were significantly more in the group with ocular disease present versus those patients without ocular involvement. The presence of ocular findings was not statistically different by BRAF V600E, MAP2K1 or RAS isoform mutational status., Conclusions: Ocular disease is a common feature of histiocytosis with significant visual symptomatology and occurrence in tandem with multisystem sites. Ocular findings vary by histiocytic subtype. The mutational profile of the cohort reflects known mutations in this clinical population, with no specific driver mutation associated with ocular disease., Competing Interests: Competing interests: JHF-none, ASR-none, JC-none, RKR-consulting fees from Incyte, Celgene/MS, Blueprint, AbbVie, Promedior, CTI, Stemline, Galecto, Pharmaessentia, Protagonist, Constellation/Morphosys, Novartis, Sierra Oncology/GSK and Servier Research funding from Constellation Pharmaceuticals, Incyte, Zentalis and Stemline Therapeutics, DHA-none, ELD-unpaid editorial support from Pfizer and serves on an advisory board for Day One Biotherapeutics, Springworks Therapeutics and Opna Bio, all outside the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: RFS: none, DHA: none, JC: none, CG: Consultation for: Roche, BTG, Curis, Ono, JHF: none., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The treatment landscape of gynecologic cancers has expanded in recent years to include targeted and immune-based therapies. These therapies often have ocular side effects not seen with conventional chemotherapies, some of which can cause significant visual impairment if not recognized in a timely fashion. Clinicians must know how to appropriately identify, mitigate, and treat these ocular adverse events. Management often involves working with an interdisciplinary team of eye specialists, and it is important to know when to refer patients for specialized care. Proactive identification of eye specialists, especially in rural and community settings where access to care can be limited, may be necessary. Here, we discuss the management of common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers., Competing Interests: Conflicts of interest REO reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health. The other authors do not have potential conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension., Case Presentations: In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients' IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy., Discussion/conclusion: This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors., Competing Interests: All the authors report grants from the National Institute of Health, during the conduct of the study in addition to D.A.C.: none; J.C.: none; G.K.A.-A. discloses research support from Arcus, Agios, AstraZeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva, as well as consulting support from Adicet, Alnylam, AstraZeneca, Autem, Bayer, BeiGene, Berry Genomics, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Surface Oncology, Therabionic, Vector, and Yiviva (PCT/US2014/031545 filed on March 24, 2014, and priority application serial no. 61/804,907 filed March 25, 2013); E.L.D. discloses editorial support from Pfizer Inc., outside the submitted work and paid advisory membership with Day One Biopharmaceuticals and Springworks Therapeutics; D.H.A.: none; J.H.F.: none., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Management of suspected choroidal metastases requires diagnostic imaging and an invasive, sometimes intraocular, biopsy to determine the primary malignancy. This multistep process takes time which may impact morbidity and mortality., Methods: Retrospective review of one case., Results: A 56-year-old woman presented with bilateral amelanotic choroidal masses suspicious for metastases of unknown origin. Plasma circulating tumor DNA revealed EGFR, PTEN, SMAD4, a profile consistent with non-small cell lung cancer. Subsequent radiographic imaging and scapular biopsy revealed lung adenocarcinoma and genetic profile concordant with the liquid biopsy. Patient was started on EGFR-inhibitor, Osimertinib1, with measurable systemic and ocular response., Conclusion: Plasma circulating tumor DNA revealed the genetic profile of the primary malignancy underlying choroidal metastases of unknown origin; aiding in the prompt diagnosis and detecting the driver mutation which guided management with targeted therapy.

Introduction: Many cancers have derangement of the mitogen-activated pathway kinase (MAPK), making this pathway blockade a therapeutic target. However, inhibitors of MAPK can result in adverse effects including retinopathy. This study compares clinical and morphological characteristics of serous retinal disturbances in patients taking agents with variable inhibition of MAPK: either direct interference of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) inhibitors or with indirect inhibition via interference with FGFR signaling., Methods: This retrospective observational study of prospectively collected pooled data is from a single tertiary oncology referral center. Of 339 patients receiving MAPK inhibitors (171, 107, and 61 on FGFR, MEK, and ERK inhibitors, respectively) for treatment of metastatic cancer, this study included 128 eyes of 65 patients with evidence of retinopathy confirmed by optical coherence tomography (OCT). The main outcome was characteristics of treatment-emergent choroid/retinal OCT abnormalities as compared to baseline OCT., Results: In all patients on one of three drug classes (FGFRi, MEKi, ERKi), the retinopathy manifested as subretinal fluid foci that were bilateral, fovea involving, and reversible without intervention. There were notable differences between the three classes of drugs: the proportion of patients with retinopathy, number of fluid foci per eye, proportion of eyes with intraretinal edema, and the proportion of symptomatic patients was least for the upstream target (FGFR inhibitors) and greatest for the downstream targets (MEK or ERK inhibitors)., Conclusion: This study shows MAPK pathway inhibitors may cause subretinal fluid foci with unique clinical and morphological characteristics depending on the target (FGFR, MEK, or ERK) implicated. Retinopathy is more common, more symptomatic, and more severe (more fluid foci, more expansive fluid configurations) the further downstream the MAPK pathway is inhibited., Competing Interests: Jasmine H. Francis, William Foulsham, Julia Canestraro, and David H. Abramson have no conflicts of interest to declare. James J. Harding has received research support from Bristol Myers Squibb and consulting fees from Bristol Myers Squibb, Eli Lilly, Exelixis, Eisai, QED, CytomX, Adaptimmune, Zymeworks, Imvax, and Merck. Eli L. Diamond discloses unpaid editorial support from Pfizer Inc. and paid consultative work with Day One Biopharmaceuticals and SpringWorks Therapeutics, outside the submitted work. Alexander Drilon reports grants from National Institutes of Health/National Cancer Institute, during the conduct of the study; personal fees from Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Repare RX, Pfizer, Liberum, outside the submitted work; associated research paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research from Foundation Medicine; royalties from Wolters Kluwer; other support from Merck, Puma, Merus, and Boehringer Ingelheim; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, and Clinical Care Options. None of the authors have any other relationships or activities that readers could perceive to have influenced or that give the appearance of potentially influencing what is written in the submitted work., (© 2023 S. Karger AG, Basel.)

Purpose: To investigate the presence of plasma circulating tumor DNA (ctDNA) in patients with uveal melanoma during and after primary tumor treatment., Methods: Detectability and variant allele frequency of ctDNA were assessed using a 129-oncogene panel using next-generation deep sequencing and hybridization capture in 69 patients with uveal melanoma undergoing primary treatment with enucleation (n = 8, during surgery) or plaque brachytherapy (n = 61; postoperative day 0, 1, 2, or 3). Follow-up assessments were performed in 39 patients over a median of 21 months (range, 3.2-31.9 months) of follow-up. Correlations between genomic data and disease parameters were performed., Results: Overall, ctDNA was detectable in 20 of 69 patients with uveal melanoma (28.9%) during the perioperative period. On the day of enucleation, ctDNA was detected in two of eight patients (25%). In patients undergoing brachytherapy, ctDNA was significantly more detectable on postoperative days 2 or 3 compared with postoperative day 0 or 1 (32.4% vs 0.0%; P = 0.0015). Patients with follow-up ctDNA that became detectable or had an increased variant allele frequency were significantly more likely to develop metastasis compared with patients with follow-up ctDNA that became undetectable or decreased variant allele frequency (P = 0.04). In patients with detectable vs. undetectable ctDNA, there was no significant difference in tumor size, stage or location., Conclusions: ctDNA is significantly more detectable at 48 to 72 hours after plaque brachytherapy compared with less than 48 hours. ctDNA can be detected during enucleation. Relative increases in ctDNA levels may herald the development of clinically apparent metastases.

Purpose: Antibody-drug conjugates (ADCs) are a class of cancer drug wherein some are associated with corneal abnormalities, but there is a dearth of published information on refractive shifts in patients receiving ADCs. Here, we evaluated the dynamics of refractive error and keratometry readings in patients with ADC-related keratopathy and microcyst-like epithelial changes (MECs)., Methods: This study is a retrospective case series including 58 eyes of 29 patients with ADC-related keratopathy from a single tertiary care cancer referral center (MSKCC). One eye (29 total) was randomly assigned for statistical analysis. In addition, a subset analysis of MEC location-refractive error correlation was performed on 20 eyes. Clinical records including slitlamp examination, indirect ophthalmoscopy, calculated spherical equivalence (SE), keratometry, and visual acuity were recorded at baseline, during, and off treatment., Results: A subset analysis of MEC location-refractive error correlation of 20 eyes revealed the following: Peripheral MECs were significantly associated with hyperopic shifts (P value < 0.001) and paracentral/central associated with myopic shifts (P value < 0.001). In the full cohort and on drug, the greatest change in SE from baseline was myopic (68%, as high as -4.75 D) and hyperopic (32%, as much as +3.75 D). Eighty-nine percent had a change in vision from baseline while on drug, but at the 3-month follow-up off drug, SE and vision returned to baseline in 33% and 82% of eyes., Conclusions: Peripheral MECs were significantly associated with hyperopic shifts, and paracentral/central MECs were associated with myopic shifts. While on drug, most eyes had a myopic refractive shift, which corresponded with corneal steepening., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate clinical and morphologic characteristics of serous retinal disturbances in patients taking extracellular signal-regulated kinase (ERK) inhibitors., Design: Single-center retrospective study of prospectively collected data., Participants: Of 61 patients receiving ERK inhibitors for treatment of metastatic cancer, this study included 40 eyes of 20 patients with evidence of retinopathy confirmed by OCT., Methods: Clinical examination, fundus photography, and OCT were used to evaluate ERK inhibitor retinopathy. The morphologic features, distribution, and location of fluid foci were evaluated serially. Visual acuity (VA) and choroidal thickness measurements were compared at baseline, fluid accumulation, and resolution., Main Outcome Measures: Characteristics of treatment-emergent choroid and retinal OCT abnormalities as compared with baseline OCT findings and the impact of toxicity on VA., Results: Of 20 patients with retinopathy, most showed fluid foci that were bilateral (100%), multifocal in each eye (75%), and with at least 1 focus involving the fovea (95%). All subretinal fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. No statistical difference was found in choroidal thickness at fluid accumulation and resolution compared with baseline. Forty-five percent of eyes showed evidence of concomitant intraretinal edema localized to the outer nuclear layer. At the time of fluid accumulation, 57.5% eyes showed a decline in VA (mainly by 1-2 lines from baseline). For all eyes with follow-up, the subretinal fluid and intraretinal edema were reversible and resolved without medical intervention, and best-corrected VA at fluid resolution was not statistically different from baseline. Concomitant intraretinal fluid was not associated with worsening of VA. No patient discontinued or decreased drug dose because of retinopathy., Conclusions: This study showed that ERK inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics. The observed foci were similar to mitogen-activated protein kinase kinase (MEK) inhibitor-associated retinopathy and distinct from central serous chorioretinopathy. However, unlike with MEK inhibitors, an increased occurrence of concomitant intraretinal fluid without significant additive visual impact seems to occur with ERK inhibitors. In this series, ERK inhibitors did not cause irreversible loss of vision or serious eye damage; retinopathy was self-limited and did not require medical intervention., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor-associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy., Objective: To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors., Design, Setting, and Participants: In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021., Main Outcomes and Measures: Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution., Results: A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor-associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was -0.1 (-0.2 to -0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (-0.03 to 0). No patient discontinued drug therapy on account of their retinopathy., Conclusions and Relevance: FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.