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PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

PURPOSE About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma., PURPOSEAbout half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking.METHODSIn this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety.RESULTSNinety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P <.0001). The median PFS was 7.4 months versus 3.3 months (P <.0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P <.0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group.CONCLUSIONIHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

Background: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of new primary cancer following the diagnosis of posterior UM. Methods: 2179 patients with posterior UM 1968–2016 and 22,717 matched controls without cancer were included. Incidence and time-dependent hazard ratio (HR) of new primary cancer were described, and the effect of SES was emphasized in a sub-cohort. Results: The incidence of new primary cancer was increased in patients with posterior UM, rate ratio (RR) 1.21 (95% CI: 1.08; 1.35), but the specific cancer types did not differ compared to the controls. The rate of new primary cancer following the diagnosis of posterior UM was significantly increased 2–5 years (HR 1.49 (95% CI: 1.23; 1.80)) and 11–15 years (HR: 1.49 (95% CI: 1.12; 1.99)), and adjusting for SES did not change the rate (HR 1.35 (95% CI:1.20; 1.55)). Conclusions: Patients with posterior UM have an increased risk of new primary cancer independent of SES. No difference in incidence of specific cancer type was observed compared to the control group.

Purpose: To estimate the frequency of first-time ocular events in patients treated with immune checkpoint inhibitors (ICI). Methods: Patients with cancer in 2011–2018 in Denmark were included and followed. The outcomes were first-time ophthalmologist consultation and ocular inflammation. One-year absolute risks of outcomes and hazard ratios were estimated. Results: 112,289 patients with cancer were included, and 2195 were treated with ICI. One year after the first ICI treatment, 6% of the patients with cancer, 5% and 8% of the lung cancer (LC) and malignant cutaneous melanoma (MM) patients, respectively, had a first-time ophthalmologist consultation. The risk of ocular inflammation was 1% (95% confidence interval (CI) 0.4–1.2). Among patients with MM, ICI was associated with ocular inflammation in women (HR 12.6 (95% CI 5.83–27.31) and men (4.87 (95% CI 1.79–13.29)). Comparing patients with and without ICI treatment, the risk of first-time ophthalmologist consultation was increased in patients with LC (HR 1.74 (95% CI 1.29–2.34) and MM (HR 3.21 (95% CI 2.31–4.44). Conclusions: The one-year risks of first-time ophthalmologist consultation and ocular inflammation were 6% and 1%, respectively, in patients treated with ICI. In patients with LC and MM, the risk was increased in patients with ICI compared with patients without ICI.

Purpose: To develop a method to label proliferating corneal endothelial cells (ECs) in rabbits in vivo and track their migration over time. Methods: We compared intraperitoneal (IP) and intracameral (IC) administration of 5-ethynyl-2′-deoxyuridine (EdU) in two experiments: (1) six rabbits received IP or IC EdU. Blood and aqueous humor (AH) samples were incubated with HL-60 cells. Flow cytom-etry detected the EdU incorporation, representing the bioavailability of EdU. (2) In vivo EdU labeling was investigated in pulse-chase study: 48 rabbits received EdU IP or IC. The corneas were flat-mounted after 1, 2, 5, or 40 days and imaged using fluorescence microscopy. EdU+ and Ki67+ ECs were quantified and their distance from the peripheral endothelial edge was measured. Results: EdU was bioavailable in the AH up to 4 hours after IC injection. No EdU was detected in the blood or the AH after IP injection. High quality EdU labeling of EC was obtained only after IC injection, achieving 2047 ± 702 labeled ECs. Proliferating ECs were located exclusively in the periphery within 1458 ± 146 μm from the endothelial edge. After 40 days, 1490 ± 397 label-retaining ECs (LRCs) were detected, reaching 2219 ± 141 μm from the edge, indicating that LRCs migrated centripetally. Conclusions: IC EdU injection enables the labeling and tracking of proliferating ECs. LRCs seem to be involved in endothelial homeostasis, yet it remains to be investigated whether they represent endothelial progenitor cells. Translational Relevance: EdU labeling in animal models can aid the search for progenitor cells and the development of cell therapy for corneal endothelial dysfunction.

Purpose: The aim of this study was to optimize the technique of performing vitrectomy-assisted biopsy of intraocular tumors by comparing the cytohistological findings in specimens obtained with different vitrectomy probes and cut rates. Methods: Vitrectomy-assisted biopsies were taken from a fresh porcine liver. For each sampling, the vacuum level was 300 mm Hg. The following parameters were compared; cut rate (60, 600 and 6,000 cuts per minute [cpm]), probe type (standard and two-dimensional cutting [TDC]), and probe diameter (23-gauge and 25-gauge). The specimens were assessed by automated whole-slide imaging analysis and conventional light microscopy. Results: Seventy-two biopsies were analyzed for the number of hepatocytes, total area of tissue fragments, and total stained area of each microscope slide. For all probe types, these parameters were significantly and positively correlated with the cut rate. TDC probes led to significantly higher scores than those of standard probes, independent of the cut rate. There were no significant differences in results when using 23-gauge or 25-gauge standard probes. Light microscopic examination demonstrated well-preserved cells sufficient for cytohistological analyses in all investigated cases. Conclusions: The higher the cut rate, the larger is the amount of aspirated cellular material. There were no significant differences between 23-gauge and 25-gauge biopsies. Cut rates up to 6,000 cpm did not adversely affect the cytohistological features of the samples.

Purpose: Rhino-orbital-cerebral mucormycosis (ROCM) is a rare opportunistic infection with a high mortality despite relevant treatment. Observations: A 3-year-old girl under treatment for acute lymphoblastic leukemia developed periorbital swelling, ophthalmoplegia and a necrotic palatal lesion during a period of neutropenia. Imaging revealed sinusitis, pre- and postseptal cellulitis. The disease later progressed to cerebral involvement and orbital apex syndrome with complete ophthalmoplegia, ptosis and loss of vision. The patient was treated with systemic antifungal therapy, hyperbaric oxygen and extensive surgery. This included orbital exenteration, skull base resection, cerebral debridement with placement of an Ommaya reservoir for intrathecal administrations of amphotericin B (AmB) and in addition endoscopic sinus surgery with local AmB installation. Chemotherapy was safely continued after resolution of the ROCM and the patient remains in complete remission after 5 years. Conclusion and importance: Patients with ROCM can be cured with aggressive multimodality treatment, including surgical intervention, even if in myelosuppression.

Purpose: While early treatment of posterior uveal melanoma can save the eye, the effect of early treatment on survival remains unknown. Therefore, we aimed to determine whether the tumour size at diagnosis has changed over time, and if this has affected survival rates of patients with posterior uveal melanoma in Denmark. Methods: Nationwide retrospective cohort study linking data from registry-based resources to data from clinical charts and pathology records. Including all Danish patients diagnosed with posterior uveal melanoma from 1943 to 2017. Incidence rates were estimated as annual percentage change (APC) overall and by American Joint Committee on Cancer (AJCC) tumour sizes. The age-period-cohort model was applied to estimate the relative risk of calendar period. The cox proportional hazards model, relative survival Kaplan–Meier curves and cumulative incidence curves were applied to estimate the effect of calendar period on survival. Results: An overall increase in incidence rate of uveal melanoma was found (APC = 0.25%, 0.08–0.42; 95% CI). This was due to increasing incidence rate of AJCC T1 + T2 tumours (APC = 0.97%, 0.57–1.37; 95% CI), whereas no increase in incidence rates of AJCC T3 + T4 tumours was found (APC = −0.01%, −0.26 to 0.25; 95% CI). The disease-specific survival improved with calendar period for all tumour sizes (HR = 0.988; 0.984–0.993; 95% CI). Conclusion: Increasing incidence rate and improved survival rate for uveal melanoma was found concordantly with a decrease in tumour size during a 70-year period.

Objective: No method exists to measure aniseikonia tolerance in stereoacuity. The brain can compensate for 2%–3% aniseikonia (i.e. 2–3 dioptres of anisometropia) without impairing stereoacuity; however, a substantial proportion of anisometropic patients experience problems caused by disruptions of sensory fusion due to surgically induced aniseikonia. We hypothesized that individual differences in tolerance to aniseikonia exist and sought to develop a method to measure aniseikonia tolerance. Methods: A total of 21 eye-healthy phakic individuals older than 50 years of age and 11 patients awaiting clear lens extraction were included. Patients were tested with best corrected near and distance visual acuity, cover/uncover test, eye dominance test, stereoacuity threshold (TNO test), slit lamp examination and ocular coherence tomography. The stereoacuity threshold was determined with aniseikonia induced by different size lenses ranging from 1% to 9% magnification of both eyes in increments of 1%. The aniseikonia tolerance range (ATR) was defined as the percentage aniseikonia in which the stereoacuity threshold was maintained. Results: We examined 32 patients with a median age of 65 (95% CI: 62–66 years), CDVA better than 6/7.5 (0.1 logMAR), and median near visual acuity better than 6/6 (0.0 logMAR). The median stereoacuity threshold was 60 arcsec (maximum 30, minimum 120). We observed large inter-individual differences in ATR: 6/31 (19%) participants had an ATR of ≤1%, 1/31 (3%) had an ATR of 1-5%, 7/31 (22%) had an ATR of 5-10%, and 17/31 (54%) had an ATR of >10%. Conclusion: We present a reliable method for measuring the amount of aniseikonia that a person can tolerate without impairing stereopsis. We report large inter-individual differences in tolerance of aniseikonia.

PURPOSE: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma. METHODS: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses. RESULTS: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89). CONCLUSION: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

Purpose: This study evaluates current available endpoints for epiretinal membrane (ERM) surgery and examine their correlation to patient reported outcomes (PRO). Methods: Retrospective study including 38 eyes of 38 patients who underwent cataract extraction and subsequent vitrectomy for idiopathic ERM. The fellow eye was phakic with good visual acuity. The registered outcomes were monocular and binocular visual acuity, stereoacuity, M-chart metamorphopsia score, aniseikonia and aniseikonia tolerance range (ATR). Two questionnaires were completed: the convergence insufficiency symptom survey and Visual Function Questionnaire (VFQ-39). Results: Median total aniseikonia was 11% (range 0–35). There was a statistically significant correlation between the mean total M-chart score of the study eye and VFQ-Near (Spearman rho: VFQ-Near: −0.54, p < 0.01). There was no correlation between the best corrected visual acuity (BCVA) of the project eye, binocular BCVA, stereoacuity, ATR or mean total aniseikonia and PRO (Spearman p-values > 0.05). There was no correlation between mean total aniseikonia and mean total M-chart score (Spearman rho: 0.21 p = 0.26). There was a large variation between the mean total M-chart scores and questionnaire results. Conclusion: The mean total M-chart score is currently the best end-points to predict PRO of ERM surgery; however, it is possible to have high M-chart values and have no visual complaints.

Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.

We report the case of a 25-year-old female, who presented with a large, pale tumor of her ciliary body that extended to >180° of the anterior chamber angle. All preoperative examinations including ultrasound biomicroscopy, scleral transillumination, and MRI indicated melanoma. A thorough systemic work-up was negative. A diagnosis of ring melanoma was suspected, and the patient was scheduled for enucleation. However, perioperative frozen section indicated granulomatous inflammation. The enucleation was cancelled, and a subtenon injection of triamcinolone was administered, which resulted in the disappearance of the tumor. Together, the findings meet the criteria for the diagnosis of isolated ocular sarcoidosis. This case demonstrates that a sarcoid granuloma can mimic all clinical features of a ring melanoma. Therefore, a biopsy should be done before destructive surgery is carried out.

PURPOSE: This study examines aniseikonia, Aniseikonia tolerance range (ATR), anisometropia and patient-reported outcomes (PRO) in an anisometropic population compared with a non-anisometropic population. The relationship between anisometropia and aniseikonia is determined, and the correlations between aniseikonia, anisometropia and ATR versus PRO are described.METHODS: One hundred and twenty-three patients with IOL-induced anisometropia ≥1 dioptre (D) (the anisometropic group) and 17 patients who had IOL-induced anisometropia <1 D (the control group) were included. Best corrected visual acuity, aniseikonia, ATR and stereoacuity were examined, and two questionnaires were completed: convergence insufficiency symptom survey (CISS) and Visual Function Questionnaire (VFQ-39).RESULTS: One hundred and thirteen patients had anisometropia >1 and <3 D, and 10 patients had anisometropia >3 D. There was no difference in PRO between the control group and the anisometropic group (Mann-Whitney, p-values VFQ: 0.96, CISS: 0.06). There was no correlation between anisometropia and PRO (Spearman's rank correlation test p-values: VFQ: 0.54, CISS: 0.57). Patients with low ATR were more sensitive towards anisometropia and had lower PRO than patients with high ATR (Mann-Whitney, p-values: VFQ: 0.0008, CISS: 0.11). A large tolerance of aniseikonia was observed.CONCLUSION: No correlation between PRO and anisometropia or aniseikonia was found. Patients with low ATR are at risk of visual complaints if they are exposed to IOL-induced anisometropia. ATR might be a future screening tool in cataract patients.

PURPOSE: Permanent loss of visual function after rhegmatogenous retinal detachment can occur despite successful surgical reattachment in humans. New treatment modalities could be explored in a detachment model with loss of retinal function. In previous porcine models, retinal function has returned after reattachment, regardless of height and duration of detachment. Difference in retinal tension between the models and the disease might explain these different outcomes. This study investigates, for the first time in an in vivo porcine model, another characteristic of rhegmatogenous retinal detachment - the loss of retinal tension.METHODS: Left eyes (n = 12) of 3-month-old domestic pigs were included. Baseline multifocal electroretinogram (mfERG) and a fundus photograph were obtained following anaesthesia (isoflurane). The pigs were vitrectomized, saline was injected subretinally, and the RPE was removed. The eyes were evaluated at 2, 4 and 6 weeks after surgery. Four eyes were enucleated at each evaluation for histologic examinations.RESULTS: A retinal detachment structurally resembling rhegmatogenous retinal detachment was induced in 11 out of 12 pigs. MfERG amplitudes were significantly decreased despite partial reattachment four and 6 weeks after detachment. The retinal thickness decreased with 27%, the inner nuclear layer degenerated, Müller cells hypertrophied, and outer segments were lost. In the ganglion cell layer, cellularity increased and there was cytoplasmic staining with Cyclin D1. Vimentin and GFAP staining for glial cells increased. After 2 weeks of detachment, the ganglion cells had lost their nucleus and nucleolus.CONCLUSIONS: Loss of retinal tension in the detached retina seems to induce permanent damage with loss of retinal function. Death of ganglion cells, observed as soon as 2 weeks after detachment, explains the permanent loss of retinal function. The new model enables investigations of time-relationship between retinal d