Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy.

PURPOSE: To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors. PARTICIPANTS: A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT). DESIGN: Single-center, retrospective cohort study. METHODS: Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point. MAIN OUTCOME MEASURES: Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation. RESULTS: The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001). CONCLUSION: The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Risk of cataract among subjects with acquired immune deficiency syndrome free of ocular opportunistic infections.

PURPOSE: To evaluate the risk of cataract in the setting of AIDS. DESIGN: Prospective cohort study. PARTICIPANTS: Subjects with AIDS free of ocular opportunistic infections throughout catamnesis. METHODS: From 1998 through 2008, subjects 13 years of age or older were enrolled. Demographic characteristics and clinical characteristics were documented at enrollment and semiannually. MAIN OUTCOME MEASURES: Cataract was defined as high-grade lens opacity observed by biomicroscopy judged to be the cause of a best-corrected visual acuity worse than 20/40. Eyes that underwent cataract surgery during follow-up were considered to have developed cataract before the first visit when pseudophakia or aphakia was observed. RESULTS: Among 1606 participants (3212 eyes) at enrollment, 1.9% (95% confidence interval [CI]: 1.3%-2.7%) were observed to have cataract or prior cataract surgery. Among the 2812 eyes initially free of cataract and followed longitudinally (median follow-up, 4.6 years), the incidence of cataract was 0.37%/eye-year (95% CI: 0.26%-0.53%). In addition to age, significant cataract risk factors included prior cataract in the contralateral eye (adjusted hazard ratio [aHR], 21.6; 95% CI: 10.4-44.8), anterior segment inflammation (aHR, 4.40; 95% CI: 1.64-11.9), prior retinal detachment (aHR, 4.94; 95% CI: 2.21-11.0), and vitreous inflammation (aHR, 7.12; 95% CI: 2.02-25.0), each studied as a time-updated characteristic. Detectable human immunodeficiency virus RNA in peripheral blood was associated with lower risk of cataract at enrollment (adjusted odds ratio, 0.32; 95% CI: 0.12-0.80) but not of incident cataract (aHR, 1.58; 95% CI: 0.90-2.76). After adjustment for other factors, neither the then-current absolute CD4+ T-cell count nor antiretroviral therapy status showed consistent association with cataract risk, nor did an additive diagnosis of other comorbidities. Compared with the available population-based studies that used similar definitions of cataract, the age-specific prevalence of cataract in our cohort was higher than in 1 of 2 such studies, and the age-specific incidence of cataract surgery was higher. CONCLUSIONS: Our results suggest cataract may occur earlier among patients with AIDS free of ocular opportunistic infections than in the general population. Cataract risk was associated most strongly with age and with other ocular morbidity in this population. With improved survival, the burden of cataract likely will increase for persons with the human immunodeficiency virus or AIDS.

Risk of cataract in persons with cytomegalovirus retinitis and the acquired immune deficiency syndrome.

OBJECTIVE: To evaluate cataract risk in eyes of patients with AIDS and cytomegalovirus (CMV) retinitis and to identify risk factors. DESIGN: Prospective cohort study. PARTICIPANTS: Patients with AIDS and CMV retinitis. METHODS: Patients 13 years of age and older were enrolled between 1998 and 2008. Demographic and clinical characteristics, slit-lamp biomicroscopy findings, and dilated ophthalmoscopy results were documented at quarterly visits. Cataract status was determined at the initial visit (prevalence) and at follow-up visits (incidence). MAIN OUTCOME MEASURES: For cataract, a high grade of lens opacity by biomicroscopy to which best-corrected visual acuity worse than 20/40 was attributed. Eyes that had undergone cataract surgery before enrollment or between visits also were counted as having cataract. RESULTS: Seven hundred twenty-nine eyes of 489 patients diagnosed with CMV retinitis were evaluated. Higher prevalence was observed for patients with bilateral versus unilateral CMV retinitis (adjusted odds ratio [aOR], 2.74; 95% confidence interval [CI], 1.76-4.26) and, among unilateral CMV retinitis cases, for eyes with retinitis versus without retinitis (15% vs. 1.4%; P<0.0001). The age-adjusted prevalence of cataract among CMV retinitis cases was higher than that in a population-based sample (P<0.0001). Cataract prevalence increased with age (aOR, 11.77; 95% CI, 2.28-60.65 for age ≥ 60 years vs. younger than 40 years) and longer duration of retinitis (aOR, 1.36; 95% CI, 1.20-1.54 per year). Among eyes with CMV retinitis initially free of cataract, the cataract incidence was 8.1%/eye-year (95% CI, 6.7%-10.0%). Prior retinal detachment was associated with higher cataract risk (if repaired with silicone oil: adjusted hazard ratio [aHR], 10.37; 95% CI, 6.51-16.52; otherwise: aHR, 2.90; 95% CI, 1.73-4.87). Large CMV retinitis lesions also were associated with higher risk of cataract (for involvement of 25-49% retinal area: aHR, 2.30; 95% CI, 1.51-3.50; for ≥ 50% involvement: aHR, 3.63; 95% CI, 2.18-6.04), each with respect to ≤ 24% involvement, as were anterior segment inflammation (aHR, 2.27; 95% CI, 1.59-3.25) and contralateral cataract (aHR, 2.52; 95% CI, 1.74-3.66). CONCLUSIONS: Cytomegalovirus retinitis is associated with a high absolute and relative risk of cataract. Among several risk factors, large retinal lesion size and use of silicone oil in retinal detachment repair are potentially modifiable, albeit not in all cases. Cataract is likely to be an increasingly important cause of visual morbidity in this population.

Refractive Shifts and Changes in Corneal Curvature Associated With Antibody-Drug Conjugates.

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.

Clinical and Morphologic Characteristics of Fibroblast Growth Factor Receptor Inhibitor-Associated Retinopathy.

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.

Practical management of patients with non-small-cell lung cancer treated with gefitinib.

PURPOSE: The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer. METHODS: This article reviews gefitinib's indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response. RESULTS: We present our recommendations for the management of rash and diarrhea caused by this agent. CONCLUSION: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.

Synthetic neurotensin analogues are nontoxic analgesics for the rabbit cornea.

PURPOSE: To characterize the analgesic potency and toxicity of topical synthetic neurotensin analogues, and localize neurotensin receptors in the cornea and trigeminal ganglion. METHODS: Cochet-Bonnet esthesiometry was performed on the rabbit cornea to test the analgesic dose response and duration of effect for two synthetic neurotensin analogues: NT71 and NT72. Receptors for neurotensin were localized in the murine cornea and trigeminal ganglion using quantitative PCR (qPCR), Western blotting, and immunohistochemistry. In vitro toxicity of NT71, NT72, and sodium channel blockers was evaluated using cytotoxicity, single-cell migration, and scratch closure assays performed on rabbit corneal epithelial cells. In vivo toxicity of these agents was assessed using a rabbit laser phototherapeutic keratectomy (PTK) model and histology. RESULTS: NT71 and NT72 induced potent analgesic effects on the rabbit cornea at concentrations between 1.0 and 2.5 mg/mL, lasting up to 180 minutes. A site-specific distribution of neurotensin receptors was observed in the murine cornea and trigeminal ganglion. NT71 and NT72 did not cause any significant in vitro or in vivo toxicity, in contrast to sodium channel blockers. CONCLUSIONS: Synthetic neurotensin analogues are potent analgesics that avoid the toxicities associated with established topical analgesic agents. Receptors for neurotensin are present in both the cornea and trigeminal ganglion.

Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment.

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0.05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.