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Importance: Despite high rates of local tumor control in patients who are treated for uveal melanoma, most patients will eventually die of metastasis. When metastasis develops, the liver is involved in most cases, and hepatic metastases are particularly refractory to treatment. Finding effective treatments has been challenging. A comparison of survival rates in patients who were treated for metastasis over approximately 30 years may offer insights into progress that has been made in prolonging survival., Objective: To compare survival after treatment for metastasis in a cohort of patients who were treated for uveal melanoma at the Massachusetts Eye and Ear Infirmary (MEE) during an approximately 30-year period with an earlier analysis to determine if there was meaningful improvement in survival rates after treatment for metastasis., Design, Setting, and Participants: This review included patients (n = 661) who received a diagnosis of metastasis from uveal melanoma who were identified from a cohort of 3063 patients treated at MEE between January 1982 and December 2009 and followed up through December 2011. They were compared with findings from a previous study of patients treated between 1975 and 1987., Main Outcomes and Measures: Survival rates in patients who received treatment for metastasis were compared with those who did not receive treatment. The differences in survival rates were compared with an earlier analysis that was completed at MEE. A comparison of patients with hepatic metastases and extrahepatic metastases was also completed. Kaplan-Meier analysis was used to calculate survival rates and the log rank test was used to test for statistically significant differences between the groups., Results: Of 620 patients with race information available, 615 (97.3%) were white; the mean (SD) age of patients was 59.71 (13.23) years and 307 (47.3%) were women. The median time from the initial treatment of the tumor to metastasis was 3.45 years (interquartile range [IQR], 2.0-5.57). Overall, the median survival time was poor (3.9 months [IQR, 1.6-10.1]). Patients who received treatment fared better than those who did not receive treatment (median survival after metastasis diagnosis, 6.3 months [IQR, 2.96-14.41] vs 1.7 months [IQR, 0.66-3.5]). This finding was similar to that of our earlier study in which median survival was 5.2 months and 2 months for treated and untreated patients, respectively., Conclusions and Relevance: These findings suggest that advances in treatments that lead to clinically meaningful improvements in survival times have not been realized. Similar survival rates in patients who were treated for metastasis were observed in this recent analysis compared with our earlier study. Adjuvant therapies that are initiated at the time of melanoma diagnosis may be the most effective way to prolong survival.

Importance: Although radiotherapy has been used more frequently in past decades for the management of large melanomas, long-term efficacy of proton beam irradiation (PBI) of large choroidal melanomas has not been reported., Objective: To evaluate long-term outcomes in patients who underwent PBI for the treatment of large choroidal melanomas., Design, Setting, and Participants: Data were obtained at a single Boston, Massachusetts, academic tertiary referral practice for this retrospective cohort study. In total, 336 patients with large tumors treated over a 13-year period from January 1, 1985, to December 31, 1997, and followed up until the end points were reached or until December 31, 2008, were included. Data analyses were initially completed in February 2017 and finalized in July 2017. Large tumors were those with a height 10 mm or greater or a longest linear diameter greater than 16 mm or a height greater than 8 mm when the optic nerve was involved., Intervention: Proton beam irradiation (total 70 Gy) delivered in 5 equal fractions., Main Outcomes and Measures: The primary outcomes of rates of visual acuity retention, eye retention, tumor recurrence, and melanoma-related mortality were calculated using Kaplan-Meier estimates, and Cox proportional hazards regression analyses were completed to evaluate risk factors for tumor recurrence and melanoma-related mortality., Results: In this cohort of 336 patients with large tumors, 150 were women and 329 were white; mean (SD) age was 60.0 (14.0) years. Of 178 patients without optic nerve involvement (tumor >1 disc diameter from optic nerve), the mean (SD) largest basal diameter was 18.1 (1.9) mm and mean height was 8.2 (2.7) mm. Optic nerve involvement and tumors greater than 8 mm were observed in 109 patients (32.4% of the cohort). Baseline visual acuity of 20/200 or better was observed in 244 patients (72.6%), and worse than 20/800 in 52 (15.5%). Ten-year rates of visual acuity retention were 8.7% (95% CI, 4.1%-15.6%) for at least 20/200 and 22.4% (95% CI, 15.4%-30.4%) for at least counting fingers. Ten years after PBI therapy, the eye was retained (70.4%; 95% CI, 61.5%-77.6%) and tumor controlled (87.5%; 95% CI, 76.8%-93.5%) in most patients. The 10-year all-cause mortality rate was 60.7% (95% CI, 55.5%-65.9%). Approximately half of the patients died of metastatic uveal melanoma (10-year rate, 48.5%; 95% CI, 43.0%-54.4%)., Conclusions and Relevance: This study demonstrates that eye conservation is possible in most cases, with ambulatory vision retained in a small proportion of patients 10 years after PBI. Tumor recurrence rates were low and mortality rates were comparable to those observed after enucleation.

Importance: Somatic mutations in BAP1 (BRCA1-associated protein 1 gene) are frequently identified in uveal melanoma. To date, the role of germline BAP1 mutations in uveal melanoma has not been characterized., Objective: To characterize the clinical phenotype of uveal melanoma in patients with germline BAP1 mutations., Design, Setting, and Participants: Retrospective cohort study at an academic ophthalmology referral center among 507 patients with uveal melanoma who consented for collection of blood samples. The study dates were June 22, 1992, to December 14, 2010., Main Outcomes and Measures: Clinical characteristics of uveal melanoma and the development of metastases. BAP1 gene sequencing from blood samples of patients with uveal melanoma was correlated with clinical characteristics., Results: Of 507 blood samples analyzed, 25 patients (4.9%) exhibited 18 BAP1 polymorphisms, of which 9 were novel. Computational analyses predicted that 8 BAP1 mutations in 8 patients (1.6%) were likely to result in damaged BAP1 protein. Five of these 8 mutations were novel. These 8 patients were compared with 482 patients in whom no BAP1 polymorphisms were identified. In univariate analyses, patients with germline BAP1 mutations exhibited larger tumor diameters (mean, 15.9 vs 12.3 mm; P = .004) and higher rates of ciliary body involvement (75.0% vs 21.6%, P = .002) and metastases (71.4% vs 18.0%, P = .003) compared with control subjects. Patients with germline BAP1 mutations exhibited increased frequency of family history of cancer (100% vs 65.9%, P = .06), particularly cutaneous melanoma (62.5% vs 9.9%, P < .001) and ocular melanoma (25.0% vs 1.9%, P = .01). No differences were identified in age at diagnosis, sex, history of other malignant neoplasm, presenting visual acuity, distance of the tumor from the optic nerve or fovea, iris involvement, extrascleral extension, or tumor pigmentation. Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P = .02). Germline BAP1 mutation approached significance as an independent risk factor for metastasis (P = .09)., Conclusions and Relevance: These data suggest that germline BAP1 mutations occur infrequently in uveal melanoma and are associated with larger tumors and higher rates of ciliary body involvement, 2 known risk factors for metastasis.

Importance: Little is known about the long-term risk of dying of uveal melanoma after treatment with radiotherapy., Objective: To determine the long-term risk of dying of this disease, we evaluated melanoma-related mortality rates up to 25 years after proton beam therapy in a large series of patients with uveal melanoma., Design, Setting, and Participants: In this analysis, we included 3088 patients with uveal melanoma, identified from a hospital-based cohort and treated with proton irradiation between January 1975 and December 2005. Vital status and cause of death were ascertained through active follow-up and searches of government databases (the Social Security Death Index and the National Death Index) through December 31, 2008. Cumulative rates of melanoma-related mortality were calculated using the Kaplan-Meier method. Patient and tumor characteristics of known prognostic significance for melanoma-associated death were evaluated, including patient age and tumor dimensions., Main Outcomes and Measures: The primary outcome measure was cumulative rates of melanoma-specific mortality, and secondary measures included annual melanoma-specific mortality hazard rates and cumulative all-cause mortality rates., Results: Of 1490 deceased patients, 620 (41.6%) died of ocular melanoma. In addition, 19 patients were alive, but their melanoma metastasized, by the end of the observation period (mean follow-up after diagnosis of metastasis, 5.3 years). All-cause mortality rates in this cohort were 49.0% (95% CI, 47.0-51.1) at 15 years, 58.6% (95% CI, 56.4%-60.8%) at 20 years, and 66.8% (95% CI, 64.2%-69.4%) at 25 years. Melanoma-related mortality rates were 24.6% (95% CI, 22.8-26.4) at 15 years after treatment, 25.8% (95% CI, 24.0-27.8) at 20 years after treatment, and 26.4% (95% CI, 24.5-28.5) at 25 years after treatment. The 20-year mortality rate was 8.6% (95% CI, 6.2-11.9) for younger patients (≤ 60 years) with small tumors (≤ 11 mm) and 40.1% (95% CI, 36.1-44.3) for older patients (>60 years) with large tumors (>11 mm)., Conclusions and Relevance: In this large series of patients with ocular melanoma treated conservatively with proton beam irradiation, the cumulative melanoma-related mortality rates continued to increase up to 23 years after treatment. Annual rates decreased considerably (to <1%) 14 years after treatment. Information regarding the long-term risk of dying of uveal melanoma may be useful to clinicians when counseling patients.

Objective: To examine ocular outcomes and survival after proton irradiation in patients with peripapillary and parapapillary melanomas ineligible for the Collaborative Ocular Melanoma Study., Methods: A total of 573 patients who received proton irradiation from January 4, 1985, through December 24, 1997, for tumors located within 1 disc diameter of the optic nerve, and therefore ineligible for the Collaborative Ocular Melanoma Study, were evaluated. Cumulative rates of vision loss in the treated eye, eye loss, melanoma-related mortality, and tumor recurrence were estimated using the Kaplan-Meier method., Results: Most (53.4%) tumors abutted the optic disc; median distance from the tumor to the macula was 0.5 disc diameters. By 5 years after proton therapy, radiation papillopathy had developed in 56.8% and maculopathy in 60.4% of patients. Of 450 patients with a baseline visual acuity of 20/200 or better in the treated eye, vision was retained in 54.9% at 2 years after irradiation. This decreased to 20.3% by 5 years after treatment, although 56.2% had visual acuity of counting fingers or better. Five- and 10-year rates of local recurrence were 3.3% and 6.0%, respectively. Enucleation rates were 13.3% at 5 years and 17.1% at 10 years after treatment. Melanoma-related mortality rates were similar to those in our larger cohort of patients (24.0% at 15 years)., Conclusions: Proton irradiation should be considered for treating patients with tumors contiguous to the optic disc. Although visual acuity is compromised, some preservation is possible (counting fingers or better in many patients). Eye conservation is likely, with low rates of tumor recurrence and no increased risk of metastasis.

Objective: To evaluate the risk of dying of metastatic choroidal melanoma in patients with small, indeterminate, pigmented lesions of the uveal tract., Methods: A cohort of 1063 consecutive patients were evaluated in the Ocular Oncology Clinic of the Massachusetts Eye and Ear Infirmary between January 1976 and June 1996 with definite choroidal nevus (n = 256), indeterminate lesions (n = 334), or small melanoma (n = 373). Deaths occurring up to December 1998 were identified through active follow-up or by a search of the National Death Index. Cumulative death rates were compared among diagnostic groups using the Kaplan-Meier method., Results: Mean lesion diameter was 4.6 mm in the nevi, 7.0 mm in the indeterminate lesions, and 8.1 mm in the small melanomas. Patients ranged in age from 3 to 95 years (median, 64 years). A total of 15 deaths due to ocular melanoma were ascertained (median follow-up of survivors, 8.2 years), 13 in the melanoma group and 2 in the indeterminate lesion group; actuarial tumor-specific death rates at 10 years after evaluation were 5% (95% confidence interval, 3%-8%) and 1% (95% confidence interval 0%-3%), respectively. No deaths due to ocular melanoma occurred in the nevus group., Conclusions: These data document the very low malignant potential of most indeterminate melanocytic lesions of the choroid and support the current practice of monitoring these tumors, with treatment provided when growth and other signs of malignant transformation are observed.

Objective: To determine if patients diagnosed as having metastatic uveal melanoma before the onset of symptoms experience more favorable survival outcomes than patients diagnosed after the onset of symptoms., Methods: A retrospective cohort study was performed among 90 patients who were diagnosed as having metastatic uveal melanoma after proton beam irradiation by routine surveillance testing (asymptomatic group) compared with 259 patients who were diagnosed as having metastatic uveal melanoma after development of symptoms (symptomatic group). The median survival times and cumulative rates of melanoma-related death after diagnosis of metastasis were compared between the 2 groups., Results: No differences were noted between groups in known prognostic factors for melanoma-related death, including age and tumor size. Cumulative rates of melanoma-related death were higher for patients in the symptomatic group vs the asymptomatic group (P < .001, log-rank test) owing to differences in mortality observed in the first year after diagnosis of metastasis (87.8% vs 68.5%). By the second year after diagnosis of metastasis, cumulative rates had reached 90% or higher in both groups. The median time to melanoma-related death after primary tumor diagnosis was 40.6 months in the asymptomatic group vs 45.1 months in the symptomatic group (P = .61)., Conclusion: Presymptomatic detection of metastatic uveal melanoma by routine surveillance testing seems to confer a survival advantage only in the first year after diagnosis of metastasis, which is likely because of lead-time bias.

Objective: To study the safety and efficacy of intravitreal injections of anti-vascular endothelial growth factor antibody fragment (ranibizumab [formerly known as rhuFabV2], Lucentis; Genentech, South San Francisco, Calif) in combination with intravenous verteporfin (Visudyne; Novartis, East Hanover, NJ) photodynamic therapy (PDT) on experimental choroidal neovascularization in the monkey eye., Methods: Choroidal neovascularization was induced by laser injury in both eyes of cynomolgus monkeys and followed with weekly fundus photography and fluorescein angiography. Two weeks after induction, weekly treatments were initiated. These treatments included using either an intravitreal injection of ranibizumab (previously known as rhuFabV2) in combination with verteporfin PDT or a ranibizumab vehicle (placebo) in combination with verteporfin PDT (PDT only). Six animals (group 1) initially received intravitreal injections followed 1 week later by PDT. Four animals (group 2) initially received PDT followed 1 week later by intravitreal injection. Two animals (group 3) received injections and PDT on the same day at 2-week intervals. Photodynamic therapy was applied in all 3 groups every 2 weeks for 3 treatments with follow-up through 2 weeks after the last PDT treatment. Fluorescein angiograms were graded using a masked standardized protocol. The data were analyzed using the McNemar chi(2) test for matched pairs., Results: No choroidal neovascularization leakage was observed in the eyes of animals treated with ranibizumab and PDT at day 21 or 42 after the start of the first treatment. Leakage persisted in eyes treated with PDT alone at 21 days (3 of 12 eyes) and 42 days (2 of 12 eyes). At all time points studied, the ranibizumab and PDT-treated eyes experienced better angiographic outcomes than the eyes receiving PDT alone., Conclusion: These preliminary data indicate that an intravitreal ranibizumab injection in combination with verteporfin PDT (ranibizumab and PDT) causes a greater reduction in angiographic leakage than PDT and intravitreal vehicle injection (PDT only) in experimental choroidal neovascularization., Clinical Relevance: This combination therapy can potentially offer a new treatment modality for choroidal neovascularization in patients with macular degeneration and other diseases.

Objective: To evaluate an antisense oligodeoxynucleotide (AS-ODN) targeted against vascular endothelial growth factor for its effects on ocular angiogenesis and its intraocular localization in a nonhuman primate model of iris neovascularization., Methods: Bilateral laser retinal vein occlusion was performed in monkeys, followed by intravitreal injections of a vascular endothelial growth factor-specific AS-ODN or control. Serial fluorescein angiograms were graded in a masked manner to measure iris neovascularization. Localization was determined using a fluorescent-labeled AS-ODN and confocal microscopy on fixed tissue., Results: Intravitreally injected vascular endothelial growth factor-specific AS-ODN localized to the retina, in the ganglion cell layer, inner nuclear layer, outer plexiform layer, photoreceptor outer segments, and retinal pigment epithelium. In 8 animals tested with 3microM ODN, AS-ODN-treated eyes had a significant reduction in iris neovascularization compared with control fellow eyes (P = .006, MIXOR analysis). Overall, in 17 animals tested across a range of ODN concentrations (0.1-50.0microM), AS-ODN-treated eyes were more likely to have lower iris neovascularization grades (P = .006, McNemar test) and the absence of iris neovascularization (P< .001, mixed-effects logistic regression model)., Conclusion: Antisense ODNs that target vascular endothelial growth factor delivered to the retina via intravitreal injection reduced iris neovascularization in this model. Clinical Relevance Antisense ODNs against vascular endothelial growth factor may have therapeutic potential for neovascular eye diseases.

Objective: To evaluate the feasibility, efficacy, and selectivity of photodynamic therapy (PDT) using targeted delivery of verteporfin to choroidal neovascularization (CNV) in the rat laser-injury model of CNV., Methods: We performed PDT in rat eyes on experimental CNV and normal retina and choroid using verteporfin conjugates. A targeted verteporfin conjugate was made by conjugating verteporfin (after isolation from its liposomal formulation) to a modified polyvinyl alcohol (PVA) polymer (verteporfin-PVA) followed by linkage to the peptide ATWLPPR known to bind the receptor for vascular endothelial growth factor, VEGFR2. The verteporfin-PVA conjugate served as a control. We performed fluorescent fundus angiography to determine the optimal timing of light application for PDT using the conjugates. Closure of CNV was assessed angiographically and graded in a masked standardized fashion. We used standardized histological grading to compare the effects on normal retina and choroid., Results: The verteporfin-PVA conjugation ratio was on average 28:1. The conjugate retained typical emission/excitation spectra and photosensitizing activity and was as efficient as an equivalent amount of verteporfin. Peak intensity of targeted verteporfin in CNV was detected angiographically at 1 hour after intravenous injection. Photodynamic therapy using targeted verteporfin (3 or 4.5 mg/m2) with light application 1 hour after drug injection showed angiographic closure of all treated CNV (17/17) 1 day after treatment. Photodynamic therapy using verteporfin-PVA at the same drug dose achieved closure in 18 of 20 CNV. Histological examination after PDT of normal retina and choroid using targeted verteporfin and irradiation at 1 hour showed minimal effect on retinal pigment epithelium and no injury to photoreceptors, whereas PDT using verteporfin-PVA resulted in retinal pigment epithelium necrosis and mild damage to photoreceptors., Conclusions: Verteporfin bound to the targeting peptide, ATWLPPR, retained its spectral and photosensitizing properties. Angiography demonstrated localization of the targeted verteporfin 1 hour after injection. Photodynamic therapy using targeted verteporfin and the control conjugate were more effective in causing CNV closure than standard liposomal verteporfin. The targeted verteporfin resulted in more selective treatment than the control conjugate or standard verteporfin. These results suggest that targeted PDT strategies based on selective expression of receptors on CNV vasculature may improve current therapy., Clinical Relevance: Targeted PDT for CNV is feasible and may offer a qualitative improvement in current treatments for patients with age-related macular degeneration. This study provides the basis for further preclinical studies of targeted PDT strategies and subsequent clinical trials.

Objective: To evaluate the effect of a new infrared laser in the destruction of pigmented choroidal melanomas., Methods: B16F10 melanomas were implanted in the subchoroidal space of 64 rabbits (tumor height, 2.0-4.0 mm). Laser radiation from an Nd:yttrium-lanthanum-fluoride laser (1047 nm) was delivered as a focused (beam waist, 25 micro m; irradiance, 100 kW/cm( 2)) raster-scanned transpupillary beam. To investigate melanin heating, treatment with focused light was compared with collimated light (beam waist, 2 mm; irradiance, 16 W/cm(2)). Fine-wire thermocouples were implanted at the base of 3 tumors for in vivo temperature measurements. Untreated animals were used as controls., Results: Of 64 animals, 27 received a single treatment with focused 1047-nm light. The rate of complete tumor eradication was 91% (10 of 11 animals) at a dosage of 125 J/cm(2) and 75% (9/12) at 63 J/cm(2) to 87 J/cm(2). The eradication rate dropped to 25% (1 of 4) at 38 J/cm(2) or less (P<.001). Continuous tumor growth was observed in all animals treated with collimated radiation and in untreated controls. Temperature measurements indicated that tissue heating at the tumor base was more rapid at 1047 nm than at 805 nm., Conclusions: These data suggest that a single treatment with a focused, raster-scanned beam at 1047 nm may play a role in the destruction of pigmented choroidal melanoma. Focused irradiation at 1047 nm may provide more effective submillisecond heating of melanin than collimated irradiation, resulting in immediate photothermal disruption of tumor cells.

Background: Tumor dimension is an established prognostic factor for metastasis-related death after radiotherapy for uveal melanoma., Objective: To compare various methods of modeling the relationship between tumor dimension and metastatic death., Patients and Methods: The analyses were based on a consecutive series of 1204 patients with primary choroidal melanoma treated with proton beam irradiation (70 cobalt-gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between January 1985 and December 1998. Largest basal diameter and largest perpendicular basal diameter were recorded at the time of surgical placement of tantalum rings used for tumor localization during proton treatment. The height of the tumor and the axial diameter of the eye were measured by ultrasonography prior to treatment. Using proportional hazards regression, we compared the prognostic influence of different indices of tumor size with estimated risk ratios and death rates according to tumor basal area and largest basal diameter. All estimates were adjusted for other established prognostic factors., Results: Patients were followed up annually through June 30, 2000. Of the 1204 patients analyzed, 193 died of melanoma metastasis. The median follow-up among survivors was 7.9 years. The 5- and 10-year metastatic death rates were 12.8% and 20.7%, respectively. Among various approaches for modeling tumor dimension, the logarithm of tumor basal area had the highest log-likelihood and performed better than other approaches in 85% of the simulations. Based on this model, the covariate-adjusted rate ratio for any doubling in tumor basal area was 1.92 (95% confidence interval, 1.62-2.28)., Conclusion: Tumor basal area is a better prognostic indicator than largest tumor diameter and tumor volume in the prediction of metastatic death after proton beam irradiation for uveal melanoma.

Objective: To explore how baseline lesion composition influenced vision outcomes in patients with age-related macular degeneration (AMD) undergoing photodynamic therapy with verteporfin (Visudyne) for subfoveal choroidal neovascularization (CNV) in the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy Investigation., Methods: Patients with subfoveal lesions secondary to AMD with evidence of classic CNV were categorized into 2 subgroups based on baseline color photographs and fluorescein angiograms assessed by graders at the Wilmer Photograph Reading Center (The Johns Hopkins University School of Medicine) before any outcome analyses as follows: (1) predominantly classic CNV (area of classic CNV >/=50% of the area of the entire lesion) or (2) minimally classic CNV (area of classic CNV <50% but >0% of the area of the entire lesion). Additional exploratory analyses were performed in the predominantly classic subgroup to investigate the effects of visual acuity, lesion size, prior laser photocoagulation, phakic status, micronutrient use, and presence of occult CNV on vision outcomes., Main Outcome Measures: Subgroup analyses of vision and fluorescein angiographic outcomes at 1 and 2 years after study enrollment were examined in an intent-to-treat analysis from 2 multicenter, double-masked, placebo-controlled, randomized clinical trials., Results: Compared with patients who had minimally classic CNV, patients with predominantly classic CNV had a worse initial mean visual acuity and smaller lesions and were more likely to have lesions that included blood or blocked fluorescence. When evaluated by treatment assignment and lesion composition, 84% to 88% completed the month 24 examination. In the subgroup with predominantly classic lesions, visual acuity outcomes were consistently better in verteporfin-treated patients. Outcomes for patients with predominantly classic lesions without occult CNV tended to be better than outcomes for patients with predominantly classic lesions with occult CNV, although the former tended to have smaller lesions and lower levels of visual acuity at baseline. Contrast sensitivity and fluorescein angiographic outcomes (total lesion size, progression of classic CNV, and absence of classic CNV) were better in verteporfin-treated patients than in placebo-treated patients in the predominantly classic and the minimally classic CNV subgroups. In patients with predominantly classic CNV, no interaction of the treatment benefit by phakic status, micronutrient use, or prior laser photocoagulation therapy was noted., Conclusions: Verteporfin therapy can safely reduce the risk of moderate and severe vision loss in patients with subfoveal lesions that are predominantly classic CNV secondary to AMD. While this benefit seemed to be even greater in the absence of occult CNV, the effect may be related to the smaller lesions and worse visual acuity associated with predominantly classic lesions without occult CNV and not solely to the lesion composition itself. These analyses support initial reports that verteporfin therapy should be used to treat patients with AMD who have predominantly classic CNV, with or without occult CNV, but suggest that further investigations should be performed to determine if lesions with a minimally classic composition might benefit when they are smaller and have lower levels of visual acuity.

Objective: To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV)., Methods: In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography., Results: rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001)., Conclusions: Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects., Clinical Relevance: This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.

Background: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival., Methods and Design: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors., Results: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively., Conclusion: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

Objective: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications., Design: Randomized, double-masked clinical trial., Participants: A total of 188 patients with small or medium-sized choroidal melanomas (<15 mm in diameter and <5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure)., Methods: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis., Results: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P>.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors >1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss., Conclusions: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. Arch Ophthalmol. 2000;118:773-778

Objective: To evaluate short-term safety and the effects on visual acuity and fluorescein angiography of single or multiple sessions of photodynamic therapy with verteporfin for choroidal neovascularization (CNV) not related to age-related macular degeneration (AMD), including pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes., Design: A nonrandomized, multicenter, open-label, dose-escalation phase 1 and 2 clinical trial., Setting: Four ophthalmic centers in Europe and North America providing retinal care., Participants: Thirteen patients with subfoveal CNV due to pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of photodynamic therapy treatments with verteporfin. Follow-up ranged from 12 weeks for patients who were treated once to 43 weeks for patients who were treated up to 4 times., Results: Verteporfin therapy was well tolerated in patients with CNV not related to AMD. No deterioration in visual acuity was observed; most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1 week after verteporfin therapy, with complete absence of leakage from classic CNV in almost half of the patients. Improvement in visual acuity after verteporfin therapy was greatest (+6, +8, and +9 lines) in 3 patients with relatively poor initial visual acuity (between 20/200 and 20/800). Up to 4 treatments were found to have short-term safety even with retreatment intervals as short as 4 weeks., Conclusions: Treatment of CNV not related to AMD with verteporfin therapy achieves short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Further randomized clinical trials including a larger number of patients are under way to confirm whether verteporfin therapy is beneficial for subfoveal CNV not related to AMD.

Objective: To determine if anti-vascular endothelial growth factor antibody and a range of dextrans with varying diffusion radii and molecular weights are permeable through experimental choroidal neovascularization (CNV)., Methods: Choroidal neovascularization was induced in 10 cynomolgus monkey retinas by means of argon laser injury. Digital fundus fluorescein angiograms were performed with fluorescein sodium, fluoresceinated IgG antibodies (anti-vascular endothelial growth factor and a control antibody), and fluoresceinated dextrans with molecular weights of 4, 20, 40, 70 and 150 kd. The 40- and 70-kd dextrans straddle the effective diffusion radius of IgG. For each reagent, early and late angiograms were performed in a standardized fashion, with follow-up images obtained to monitor residual fluorescence., Results: Perfusion of retinal vessels and choroidal vasculature was seen with all reagents. Fluorescein and 4- and 20-kd dextran leaked rapidly from the CNV within the first minute. Angiography with the use of 40-kd dextran and fluoresceinated antibody, either anti-vascular endothelial growth factor or control IgG, showed fluorescence within the CNV that increased during the first 1 to 5 hours, with mild leakage from the CNV. By 24 hours, fluorescence in the CNV was minimal, although in some cases persistent fluorescence in the surrounding tissue was evident up to 2 weeks. The 70-kd dextran showed fluorescence within the CNV and leakage in 1 of 3 eyes. The 150-kd dextran showed fluorescence within the CNV but did not demonstrate leakage., Conclusions: Fluoresceinated antibodies and dextran with smaller effective diffusion radii showed CNV perfusion and leakage. Dextrans with larger effective diffusion radii (70 kd and 150 kd) perfused into CNV but did not show leakage consistently., Clinical Relevance: Determining the permeablity of antibodies and molecules of similar size through CNV can help ascertain the feasibility of using intravenously administered antibodies against angiogenic growth factors as a future treatment for choroidal neovascularization.

Objectives: To evaluate safety and short-term visual acuity and fluorescein angiographic effects of photodynamic therapy (PDT) after retreatments with verteporfin for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) that demonstrated fluorescein leakage after at least 1 course of PDT., Design: Nonrandomized, multicenter, open-label phase 1 and 2 clinical trial using 2 different retreatment dosage regimens., Setting: Four ophthalmic centers in Europe and North America providing retinal care., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of multiple PDT treatments. Two regimens (regimens 2 and 4) for treatment and retreatment were chosen from 5 used in a single-treatment study. Both regimens used a verteporfin dose of 6 mg/m2 infused for 10 minutes. However, regimen 2 used a light dose of 100 J/cm2 applied 20 minutes after the start of the verteporfin infusion, whereas regimen 4 used a light dose of 50, 75, or 100 J/cm2 applied 15 minutes after infusion commenced. Posttreatment evaluations were planned in 31 participants up to 3 months after up to 2 retreatments given at 2- or 4-week intervals after initial PDT treatment. Similar posttreatment evaluations were planned after retreatments in 5 additional participants who were reenrolled some time more than 12 weeks after an initial PDT treatment., Results: The average visual acuity change for the 31 participants who had retreatment within 2 to 4 weeks after the initial treatment and a follow-up examination 16 to 20 weeks after the initial treatment was 0.2 lines (range, -4 to 4 lines) in regimen 2 and -1.0 line (range, -5 to 3 lines) in regimen 4. Similar outcomes were noted in the 5 reenrolled participants. Cessation of fluorescein leakage from classic CNV for at least 1 to 4 weeks could be achieved without loss of visual acuity after at least 2 treatments in 2 (6.5%) of 31 patients. Similar to single-treatment effects, the disappearance of leakage was documented regularly at 1 week after each retreatment. Fluorescein leakage reappeared by 4 to 12 weeks after a retreatment in almost all cases. However, compared with baseline, leakage activity appeared to be reduced after multiple PDT courses. For the 31 patients who had follow-up for 3 months after the last retreatment and had received retreatment 2 to 4 weeks after the initial treatment, progression of CNV beyond the area identified before the retreatment was noted in 10 (48%) of the 21 eyes with classic CNV in regimen 2 and 9 (90%) of 10 eyes in regimen 4. The rate and severity of ocular or systemic adverse events were not increased by multiple applications., Conclusions: Multiple applications of PDT with verteporfin achieve repetitive, short-term cessation of fluorescein leakage from CNV secondary to AMD, without loss of visual acuity. This strategy can be used in randomized clinical trials investigating the efficacy of verteporfin in PDT for recurrent fluorescein dye leakage from persistent or recurrent CNV, following an initial or subsequent PDT treatment, with maintenance of visual acuity. Retreatments may achieve progressive cessation of leakage and prevent further growth of CNV and subsequent visual loss.

Objective: To evaluate the safety and short-term visual and fluorescein angiographic effects of a single photodynamic therapy treatment with verteporfin with the use of different dosage regimens in patients with choroidal neovascularization (CNV) from age-related macular degeneration., Design: Nonrandomized, multicenter, open-label, clinical trial using 5 dosage regimens., Setting: Four ophthalmic centers in North America and Europe providing retinal care., Participants: Patients with subfoveal CNV caused by age-related macular degeneration., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examination, color photographs, and fluorescein angiograms were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in 97 patients and for less than 3 months in 31 other patients., Results: The mean visual acuity change (and range of change) from baseline at the follow-up examination at week 12 after a single treatment with regimens 1 through 5 was -0.2 (-3 to +2), -0.9 (-9 to +5), -1.6 (-9 to +2), +0.4 (-8 to +7), and +0.1 (-8 to +9) lines, respectively. Only the highest light dose (150 J/cm2) in regimens 2 and 3, which produced angiographic nonperfusion of neurosensory retinal vessels, caused marked vision loss. Some cessation of fluorescein leakage from CNV was achieved without loss of vision when the light dose used was less than 150 J/cm2. Systemic adverse events were rare. Cessation of fluorescein leakage from CNV was noted in all regimens by 1 week after photodynamic therapy. Fluorescein leakage from at least a portion of the CNV reappeared by 4 to 12 weeks after treatment in almost all cases. Progression of classic CNV beyond the area of CNV identified before treatment was noted in 42 (51%) of the 83 eyes with classic CNV followed up for 3 months after a single treatment. Eyes in which the area of any CNV leakage at 12 weeks was less than at baseline had a significantly better visual acuity outcome (+0.8 line) than eyes in which CNV leakage progressed (-0.8 line)., Conclusions: Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age-related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cm2, no other adverse events were of concern. Randomized clinical trials to investigate whether this new modality can preserve vision in patients with CNV secondary to age-related macular degeneration are justified.

Background: Research in cutaneous melanoma suggests that women may experience better tumor-dependent survival than men, and some studies have shown that the advantage is specific to childbearing., Objective: To examine whether childbearing may be a favorable prognostic factor in melanoma of the uveal tract., Design: Prospective follow-up study., Setting: Hospital., Main Outcome Measure: Death from metastatic choroidal melanoma., Methods: We evaluated a consecutive series of 1818 patients with choroidal melanoma, 748 parous and 165 nulliparous women and 905 men, after treatment with proton irradiation. Three hundred fifty-two deaths from metastasis were documented in follow-up., Results: Overall multivariate-adjusted death rates from metastasis were approximately 25% higher in nulliparous women (relative risk [RR], 1.23; 95% confidence interval [CI], 0.83-1.82) and men (RR, 1.25; 95% CI, 1.00-1.56) than in women who had given birth. The protective influence of parity was strongest in the early period following diagnosis and treatment (RR, 1.58; 95% CI, 0.88-2.86, and RR, 1.51; 95% CI, 1.04-2.19, in nulliparous women and men, respectively, during the first 36 months of follow-up). The level of protection increased with the number of live births (P for trend, .04)., Conclusion: These data provide support for the hypothesis that a history of childbearing confers protection from death in choroidal melanoma.

Background: Ocular melanoma may be more prevalent among patients with light irises than those with dark irises., Objective: To examine a large clinical series of patients with intraocular melanoma to determine if light irises are associated with increased risk of death from these tumors., Methods: A total of 1162 patients treated with proton irradiation between 1984 and 1996 were observed through 1997., Results: Iris color in the patients was blue or gray in 48%, green or hazel in 30%, and brown in 23%. Tumors in patients with blue or gray irises were less heavily pigmented (P<.001) and closer to the optic disc and macula (P<.001). Five- and 10-year metastasis-related death rates were 0.14 and 0.21, respectively, for those with blue or gray irises and 0.10 and 0.15, respectively, for those with darker irises (P = .02). In a Cox proportional hazards regression controlling for tumor characteristics, patients with blue or gray irises died of metastatic disease at a rate 1.90 times (95% confidence interval, 1.26-2.85) that of patients with brown irises. The rate of metastatic death was not significantly elevated for those with green or hazel irises (relative risk, 1.43; 95% confidence interval, 0.91-2.23)., Conclusion: Patients with blue or gray irises appear to be at increased risk of metastatic death from choroidal melanoma, independent of other risk factors.

Objective: To describe the clinical course of affected and unaffected eyes in patients with idiopathic macular holes., Patients: Prospective study of patients with macular holes enrolled in the Eye Disease Case-Control Study., Main Outcome Measures: The best-corrected visual acuity at follow-up was compared with that at baseline. Changes in the macular holes, including increases in size or spontaneous regression, were assessed. The rates of development of new macular holes in fellow unaffected eyes were estimated., Results: Of the 198 patients examined at baseline, 28 (14.1%) died before reevaluation. Of those who survived, 122 (71.8%) had a follow-up examination. Approximately 34% (34.4%) of all eyes with macular holes had an increase in the size of the macular hole. Forty-five percent of eyes had a decrease in visual acuity of 2 or more lines and 27.8%, of 3 or more lines; 40.9% remained stable, with a gain or loss of fewer than 2 lines. The rate of development of a new macular hole during follow-up in fellow eyes that were unaffected at baseline was 4.3% for 3 or fewer years of follow-up, 6.5% for 4 to 5 years of follow-up, and 7.1% for 6 or more years of follow-up. Spontaneous regression of the macular hole occurred in 3 (8.6%) of 35 patients with a follow-up interval of 6 or more years, whereas no regression occurred in patients with a shorter follow-up., Conclusions: The visual acuity of 45.0% of eyes with macular holes deteriorated by 2 or more lines during follow-up. The rate of development of macular holes in unaffected fellow eyes was low.

Objective: To evaluate whether the removal of the eye after radiotherapy alters the rates of metastatic death in patients with melanoma of the choroid., Patients and Methods: Using an extension of the Cox model, we based our analysis on a cohort of 1541 consecutive patients with unilateral choroidal or ciliary body melanoma treated with protons (70 cobalt-gray equivalent in 5 to 7 fractions) at the Harvard University (Boston, Mass) cyclotron between July 1, 1975, through December 31, 1993, and who were observed prospectively up to September 30, 1995. Patient survival and the status of the treated eye were updated annually., Results: By September 1995 (median follow-up among survivors, 8 years), 137 patients underwent enucleation after radiotherapy for complications (n=103) or tumor regrowth (n=34). The overall 10-year rate of eye retention was 89% (95% confidence interval, 87%-91%). Of the 1541 patients, 300 died of tumor metastasis, 38 following enucleation of the affected eye (mean interval from enucleation to death, 25 months). The multivariate rate ratio for metastatic death associated with enucleation (modeled as a time-dependent covariate) was 0.9 (95% confidence interval, 0.6-1.4) for enucleation due to complications and 3.8 (95% confidence interval, 2.3-6.3) for enucleation associated with tumor regrowth., Conclusions: In the absence of tumor viability, enucleation after primary irradiation for choroidal melanoma has no deleterious effect on patients' survival. Enucleation concurrent with tumor regrowth is associated with high death rates; growth of the tumor in the eye may presage systemic recurrence and death from metastasis.

Objectives: To determine whether systemic hyperoxia can reverse retinal hypoxia and decrease vascular endothelial growth factor (VEGF) gene expression in ischemic nonhuman primate retina., Methods: Six eyes of 3 cynomolgus monkeys were studied. Retinal ischemia was induced via laser vein occlusion and confirmed with fluorescein angiography. Animals were randomly assigned to treatment with either 21% or 100% inhaled oxygen. Arterial PO2 was monitored while systemic acid-base status was maintained. An oxygen microelectrode on a micromanipulator was used to measure preretinal oxygen concentrations in ischemic and nonischemic retina in situ. RNA was isolated from fresh whole retinas, and VEGF messenger RNA levels were quantified with Northern blotting., Results: The preretinal PO2 in ischemic retina was less than the PO2 in nonischemic retina in animals breathing 21% oxygen (intervascular zone PO2, 14.3+/-0.53 vs 21.8+/-0.55 mm Hg; P=.002). After 8 hours of systemic hyperoxia (arterial PO2, 512+/-18 mm Hg), the preretinal PO2 in ischemic retina increased to 166.2+/-15.6 mm Hg (21.8% oxygen) and retinal VEGF messenger RNA levels were reduced by an average of 55%., Conclusions: These data demonstrate that systemic hyperoxia can lower retinal VEGF gene expression and reoxygenate ischemic adult primate retina.

Objective: To determine whether the angiogenic peptide vascular endothelial growth factor (VEGF) is sufficient to produce iris neovascularization in a nonhuman primate (Macaca fascicularis)., Methods: Eight eyes of 4 animals were studied. The 165-amino acid isoform of human recombinant VEGF (VEGF165) was injected into the vitreous of 5 cynomolgus monkey eyes (doses ranging from 0.25-2.5 micrograms per injection). Equal amounts of inactivated human recombinant VEGF (2 eyes) or vehicle (1 eye) were injected into contralateral control eyes. Eyes were assessed by slitlamp biomicroscopy, tonometry, iris color photography, fluorescein angiography, histopathologic examination, and immunostaining with antibodies against proliferating cell nuclear antigen., Results: All 5 bioactive VEGF-injected eyes developed neovascularization with dilated and tortuous iris vessels that leaked fluorescein. None of the 3 control eyes exhibited any iris vascular changes. Inflammation was absent in both treatment groups. A dose response to VEGF was observed in the single animal that received 2.5 micrograms and 0.25 microgram in the right and left eyes, respectively. Iris vessel endothelial cells were positive for proliferating cell nuclear antigen in the bioactive VEGF-injected eyes only. Injections of 1.25 micrograms of VEGF every 3 days during a 30-day period produced advanced iris neovascularization, ectropion uvea, and neovascular glaucoma., Conclusions: Intravitreal injections of recombinant human VEGF165 in amounts comparable with those measured in eyes with active neovascularization are sufficient to produce noninflammatory iris neovascularization in a nonhuman primate. Prolonged exposure to VEGF165 can produce ectropion uveae and neovascular glaucoma.

Objective: To compare the effectiveness of photodynamic therapy to close experimental choroidal neovascularization using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin) with previous work using a rapid intravenous injection, before initiating clinical trials., Methods: Choroidal neovascularization was induced in cynomolgus monkey eyes using argon laser. Liposomal benzoporphyrin derivative was delivered by an intravenous infusion pump for 10 or 32 minutes at a dose of 0.375 mg/kg. Irradiation was performed with 689- or 692-nm laser light (600-mW/cm2 irradiance and 150-J/cm2 fluence) in 7 normal eyes and 11 eyes with choroidal neovascularization between 30 and 105 minutes after the start of dye infusion. Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy., Results: Irradiation within 32 to 50 minutes of the start of the fast (10 minutes) or slow (32 minutes) dye infusion resulted in closure of choroidal neovascularization. In normal eyes, this technique caused choriocapillaris closure and retinal pigment epithelium damage with minimal damage to surrounding tissues., Conclusion: Photodynamic therapy using intravenous infusion of liposomal benzoporphyrin derivative selectively closed experimental choroidal neovascularization. This may be a suitable modality for clinical use.

Objective: To evaluate the effectiveness of photodynamic therapy of pigmented choroidal melanoma using a liposomal preparation of benzoporphyrin derivative monoacid (BPD), verteporfin., Design: Pigmented choroidal melanomas were established in 25 New Zealand albino rabbit eyes. The animals were treated with daily injections of cyclosporine, and tumor growth was monitored with funduscopic examination and ultrasonography. Fifteen minutes after intravenous injection of BPD (2 mg/kg), the tumors were irradiated at 692 nm through an argon-pumped dye laser with the delivered fluence ranging between 40 and 150 J/cm2. Control animals were treated with light only, photosensitizer only, or observation only. Tumor growth was monitored by indirect ophthalmoscopy, fundus photography, fluorescein angiography, and ultrasonography. Histologic examination was performed., Results: Eighteen tumor-bearing rabbits were treated with light and BPD; 16 were followed up for 1 month, and two were killed immediately for histologic examination. Tumors regressed in all eyes treated with 60 J/cm2 or more. With fluence of 40 J/cm2, tumor regrowth was observed in one animal within 10 days of treatment. In the three control groups, all animals showed continuous tumor growth. Histologic examination of the eyes treated with photosensitizer and light immediately after treatment showed prominent vascular occlusion throughout the full thickness of the tumor. One month after treatment, tumor necrosis and infiltration of mononuclear cells and pigment-laden macrophages were the predominant findings., Conclusions: Photodynamic therapy with BPD may have a role in the treatment of pigmented choroidal melanomas.

Objective: To determine if the angiogenic peptide vascular endothelial growth factor (VEGF) is required for retinal ischemia-associated iris neovascularization in a nonhuman primate., Methods: Laser retinal vein occlusion was used to produce retinal ischemia in 16 eyes of eight animals (Macaca fascicularis). Eyes were randomized to treatment every other day with intravitreal injections of either a neutralizing anti-VEGF monoclonal antibody or a control monoclonal antibody of the same isotype. Serial iris fluorescein angiograms were assessed using a standardized grading system and masked readers. Retinal VEGF and placental growth factor expression were assessed by Northern blotting. The specificity of the antibodies was determined in capillary endothelial cell proliferation assays prior to intravitreal injection., Results: Zero of eight eyes receiving the neutralizing anti-VEGF antibodies developed iris neovascularization. Five of eight control antibody-treated eyes developed iris neovascularization. The difference was statistically significant (P = .03). Intravitreal antibody injection did not impair the ability of the ischemic retina to increase VEGF messenger RNA expression. The anti-VEGF antibodies specifically inhibited VEGF-driven capillary endothelial cell proliferation in vitro., Conclusion: These data demonstrate that VEGF is required for iris neovascularization in an adult nonhuman primate eye. The inhibition of VEGF is a new potential therapeutic strategy for the treatment of ocular neovascularization.

Objective: To investigate photodynamic therapy of experimental choroidal neovascularization using benzoporphyrin derivative monoacid (Verteporfin)., Methods: Photodynamic therapy using benzoporphyrin derivative monoacid was investigated in cynomolgus monkeys. Following intravenous injection of benzoporphyrin derivative monoacid (1 to 2 mg/kg) complexed with low-density lipoprotein, the eyes were irradiated with 692-nm light at a fluence of 50 to 150 J/cm2 and irradiance of 150 to 600 mW/cm2. Choroidal neovascularization was documented before photodynamic therapy and closure was demonstrated by fundus photography, fluorescein angiography, and light and electron microscopic examination., Results: Following photodynamic therapy, vessels within choroidal neovascularization were occluded, and there was damage to the choroidal neovascularization endothelium and the subjacent choriocapillaris. Damage to the retinal pigment epithelium and photoreceptors was also observed., Conclusion: Photodynamic therapy with lipoprotein-delivered benzoporphyrin derivative monoacid was effective in this animal model of choroidal neovascularization and may be a promising, potentially selective, therapy for choroidal neovascularization.

OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods. CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.

Objective: To establish a new model of exudative retinal detachment in the rat., Methods: Photothrombosis was produced in a single retinal vein using direct treatment with a dye laser operating in the yellow wavelength (577 nm). Control eyes received identical laser applications, but treatment was placed alongside the vessel and photothrombosis was not produced. Eyes were examined at intervals during the subsequent week with ophthalmoscopy, photography, fluorescein angiography, and light microscopy., Results: In 13 (41%) of 32 eyes with photothrombosis, bullous retinal detachments developed 1 day after laser treatment, and continued occlusion of the vein was confirmed with fluorescein angiography. Detachments persisted for 2 to 4 days and spontaneously resolved; resolution coincided with restored venous patency at 5 to 7 days. None of the 20 control eyes developed bullous detachments (P < .005)., Conclusions: Laser photothrombosis in the rat offers a simple and accessible model of transient exudative retinal detachment without the need for exogenous chromophores.

The histopathology of eyes with uveal melanoma was compared in a masked fashion in 47 eyes whose primary treatment was enucleation and a matched series of 47 eyes enucleated after proton beam irradiation. Irradiated tumors were more likely to show signs of necrosis (P less than .001) and fibrosis (P = .005) and to have balloon cells present (P = .002). In the irradiated group, mitotic figures were fewer in 40 high-power fields (P = .020), and the prevalence of tumor blood vessel damage (P less than .001) was higher. Changes in the retina were more common in the irradiated series, but damage was usually overlying or in close proximity to the tumor. Based on characteristic changes, the pathologist distinguished irradiated from nonirradiated eyes in 85% of the cases. These findings suggest that irradiation damages tumor cells and blood vessels, and alters the tumor's capacity for cellular reproduction.

We evaluated visual outcome and risk of metastases in patients who underwent cataract extraction after protonbeam irradiation of a uveal melanoma. A total of 84 patients underwent cataract extraction between 2 months and 11 years after irradiation. One year after cataract extraction, approximately half of the patients had visual acuity of 20/100 or better, and approximately one third had an acuity of 20/40 or better. Larger tumor size was highly correlated with poor visual outcome 1 year after extraction. Six patients underwent enucleation after cataract removal, five due to blind, painful eyes and one due to continued growth of a previously undiagnosed ring melanoma. The rate of metastases was not higher among patients who underwent cataract extraction (adjusted rate ratio, 0.83). Results suggest that cataract extraction offers improvement of vision in selected eyes previously irradiated for a uveal melanoma, without adding to the risk of metastases among patients undergoing the procedure.

Five patients presented with vision-threatening retinal tumors and systemic signs of neurofibromatosis, including neurofibromatosis type 1 (four patients) and familial cafe-au-lait spots (one patient). These tumors included large retinal astrocytic hamartomas, multiple retinal capillary hemangiomas, and combined hamartomas of the retina and retinal pigment epithelium, which resulted in rubeotic glaucoma, vitreous hemorrhage, and retinal detachment. Surgical therapy included retinal cryopexy, xenon and argon photocoagulation, scleral buckling, and pars plana vitrectomy with excisional retinal biopsy. Retinal tumors may result in marked visual loss in patients with neurofibromatosis, and vitreoretinal surgery may restore useful vision in some of these patients.

Uveal melanoma threatens life, as well as sight. To evaluate the effect of constitutional factors and UV radiation on the risk of uveal melanoma, 197 cases in New England were compared with 385 matched population controls, identified by random-digit dialing, and 337 cases residing within the United States were compared with 800 sibling controls. In the population-based comparison, estimated relative risks (RRs) of uveal melanoma, after adjustment for other factors, were elevated for the following: ancestry from more northern latitudes with a substantially elevated risk for Northern European ancestry (RR, 6.5; 95% confidence interval [CI], 1.9 to 22.4) and more than a twofold risk for British ancestry (RR, 2.4; 95% CI, 1.1 to 5.1), as compared with Southern European or other Mediterranean heritage; light skin color as compared with dark (RR, 3.8; 95% CI, 1.1 to 12.6); and 10 or more cutaneous nevi as compared with none (RR, 2.7; 95% CI, 1.5 to 4.9). There was a statistically significant trend for increasing risk with more northern heritage and more moles. Southern residence (below latitude 40 degrees N) for more than 5 years also increased risk (RR, 2.8; 95% CI, 1.1 to 6.9), as compared with none. In both comparisons, use of sunlamps was a risk determinant (RR, 3.4; 95% CI, 1.1 to 10.3 with random-digit dialed controls and RR, 2.3; 95% CI, 1.2 to 4.3 with sibling controls, comparing occasional or frequent use to never use), as was intense sun exposure (RR, 1.7; 95% CI, 0.9 to 3.0 and RR, 2.1; 95% CI, 1.4 to 3.2, respectively). However, birthplace below latitude 40 degrees N and outdoor work were associated with a lower risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Proton beam irradiation resulted in clinical and/or histopathological regression of large ciliary body and choroidal melanomas in three eyes. Enucleations were performed 6 1/2 weeks, five months, and 11 months after irradiation for angle-closure glaucoma from total retinal detachment, increase in retinal detachment, and neovascular glaucoma, respectively. A direct relationship was found between the length of the interval from irradiation to enucleation and the degree of histologic changes. Vascular changes in the tumors included endothelial cell swelling and decreased lumen size, basement membrane thickening, collapse of sinusoidal vessels, and thrombosis of vessels. Although apparently unaltered tumor cells remained, degenerative changes occurred in some melanoma cells, including lipid vacuoles in cytoplasm, pyknotic nuclei, and balloon cell formation. Patchy areas of necrosis and proteinaceous exudate were present. Pigment-laden macrophages were found near tumor vessels and all had a substantial chronic inflammatory infiltrate. The effect of proton beam irradiation on tumor vessels probably plays an important role in uveal melanoma regression.

Peripapillary subretinal neovascularization progressively developed in both eyes of a 17-year-old black woman with bilateral chronic granulomatous uveitis. Despite intensive medical therapy, central vision was lost in the left eye due to disciform scarring that extended to the macula. When a similar process was discovered in the right eye, argon laser therapy was started and was successful in eliminating all areas of subretinal neovascularization in the right eye while maintaining good cental vision. Chronic uveitis is probably another cause of peripapillary subretinal neovascularization, which can be treated with photocoagulation in spite of the presence of inflammation.

Congenital anomalous disc changes were associated with acquired macular detachment and peripapillary choroidal neovascularization in two cases. The anomalous disc changes resembled optic nerve pits. In one case, the peripapillary choroidal neovascularization was treated with argon laser photocoagulation, with subsequent reattachment of the macula and considerable improvement in the visual acuity. Although the pathogenesis of macular detachment occurring with optic nerve pits is usually not disclosed by fluorescein angiography, leakage from choroidal neovascularization can occur with this congenital defect and may contribute to the formation of a neurosensory macular detachment. If found, choroidal neovascularization may represent a remedial cause for visual loss in a condition with an otherwise poor prognosis.

Proton beam irradiation was used in the treatment of 76 uveal melanomas from July 1975 to December 1980. Five (7%) were small, 32 (42%) were medium, and 39 (51%) were large melanomas. The follow-up period ranged from two months to 5 1/2 years; 19 patients were followed up for more than two years and 39 were observed for more than a year. Tumor regression has been achieved in all eyes with more than 12 months of follow-up except one, which was enucleated because of secondary complications. Three patients in whom metastatic disease developed died. Our data indicate that proton irradiation can be used for the treatment of relatively large lesions that previously were considered untreatable and reduces the high ocular morbidity experienced with other methods in the treatment of medium and small melanomas.

Clinical evaluation of uveal melanomas by magnetic resonance imaging (MRI) techniques depends on developing an understanding of the appearance of these tumors in magnetic resonance (MR) images. We have determined MR characteristics of uveal melanomas by proton (1H) and sodium 23 MRI of freshly enucleated human eyes at 1.5 tesla. The MR images were obtained using two-turn proton and 23Na surface coils, designed to both transmit and receive the radiofrequency signal. Proton MRI techniques included saturation recovery and spin echo; the gradient-recalled echo technique was used for 23Na MRI. Proton and 23Na MR images provide complementary information; contrast between intraocular tumors and vitreous, lens, or subretinal hemorrhage may be varied by using MR pulse sequences that emphasize tissues based on T1, T2, proton, or sodium density values. A combination of proton and 23Na MRI provides differentiation between normal ocular structures and intraocular tumors, as well as associated complications, such as retinal detachments and subretinal hemorrhages.

A patient with decreased visual acuity had small, glistening white particles that were scattered over both posterior poles. Monochromatic fundus photography revealed ghost vessels and intraluminal particulate matter in small retinal vessels. Fluorescein angiography demonstrated nonperfusion of small arterioles and macular capillaries. The patient admitted to multiple intravenous injections of crushed methylphenidate (Ritalin) hydrochloride tablets, which contain talc 18 months prior to examination. To our knowledge, visual loss and irreversible macular ischemia from talc emboli have not been previously documented.