Growth rate of indeterminate choroidal lesions prior to melanoma diagnosis.

PURPOSE: Small choroidal melanocytic lesions have a low rate of metastasis and can be reasonably managed with surveillance until they demonstrate evidence of growth or clinical risk factors for melanoma. However, even choroidal nevi are not stationary, with many exhibiting slow growth over time. We sought to quantify the growth rates of indeterminate choroidal lesions that were initially observed prior to a clinical diagnosis of melanoma. METHODS: A single-center retrospective study was performed of patients diagnosed with choroidal melanoma based upon clinical characteristics who were initially followed for indeterminate lesions over at least 6 months. Subjects were included if they had a minimum of two B-scan ultrasound measurements prior to the visit at which melanoma was diagnosed. Demographic and tumor characteristics were collected from the medical record. Growth rates were calculated as the change in lesion thickness in mm per month and were recorded at 6-month intervals; ultrasound measurements less than 1 month apart were excluded. The characteristics of indeterminate lesions with faster versus slower growth rates prior to melanoma diagnosis were compared. RESULTS: Fifty-four patients met inclusion criteria. The mean age at melanoma diagnosis was 67.4 years, and 53.7% were female. Subjects had a median of four B-scan ultrasound measurements prior to melanoma diagnosis (range 2-19) and were followed for a median of 40.6 months (range 9.9-138.0 months). The mean lesion thickness was 1.4 mm (range 0.5-2.2 mm) at presentation, and increased to 2.3 mm (range 1.5-5.7 mm) at melanoma diagnosis. The mean growth rate did not exceed 0.021 mm/month (95% CI: 0.004-0.039; equivalent to 0.25 mm/year) for indeterminate lesions, but increased to 0.057 mm/month (95% CI: 0.043-0.071 mm/month; equivalent to 0.68 mm/year) at the time of melanoma diagnosis. Rapidly growing lesions had a greater tumor thickness and shorter duration of observation at the time of melanoma diagnosis. CONCLUSION: For most indeterminate choroidal lesions eventually diagnosed as melanoma, the lesion thickness was relatively stable for a period of time, then rose significantly between the penultimate visit and the final visit. These findings confirm the recommendation for continued monitoring of suspicious choroidal lesions, as the growth rate may accelerate just prior to melanoma diagnosis. Lesions with a mean growth rate of up to 0.25 mm/year were observed, whereas lesions clinically determined to have transformed into melanoma demonstrated a mean growth rate of 0.68 mm/year. These values provide a baseline for future studies and potential therapies directed at stabilizing or reducing the growth of indeterminate choroidal lesions or small choroidal melanomas. Limitations of this study include its retrospective nature and reliance on clinical diagnostic criteria.

Conservative management of suspicious melanocytic lesions of the iris.

PURPOSE: The diagnosis of iris melanoma can be difficult, with no established diagnostic criteria currently available. Careful monitoring of patients with suspicious iris lesions is one approach to managing these tumors. We determined the risk of malignant transformation and melanoma-related mortality in patients under observation to evaluate the validity of this management approach. METHODS: This was a retrospective chart review of patients with suspicious iris lesions diagnosed at Massachusetts Eye and Ear Infirmary (MEE) between 1975 and 2014. All patients with an initial diagnosis of suspicious iris lesion followed and/or treated after malignant transformation at the MEE in this 39-year period were included in the cohort. Rates of malignant transformation and melanoma-related mortality were calculated. Treatment outcomes after proton beam irradiation were evaluated in patients who developed iris melanomas during observation. RESULTS: Two hundred thirty-four patients had a diagnosis of suspicious iris lesion (median follow-up, 5.8 years). Malignant transformation occurred in 16 (6.8%) patients with suspicious lesions during the observation period (median follow-up, 9.9 years). All patients diagnosed with iris melanomas were treated with proton beam irradiation (PBI). Complications after treatment included cataract (18.8%), secondary glaucoma (6.3%), and neovascular glaucoma (12.5%). Two of 16 patients (12.5%) who developed iris melanomas died of metastatic melanoma 32.6 months and 10 years after treatment with PBI. Both cases had been followed regularly to monitor for malignant transformation of their suspicious lesions (8.2 years and 3.2 years before melanoma diagnosis, respectively). CONCLUSIONS: These data suggest that suspicious iris lesions have low malignant potential, and a conservative approach to the management of these lesions is appropriate. Survival does not appear to be compromised with an observational approach, and there is potential for preservation of good visual function because vision-threatening treatments can be avoided.

Visual Outcomes after Proton Beam Irradiation for Choroidal Melanomas Involving the Fovea.

PURPOSE: To report visual outcomes in patients undergoing proton beam irradiation of tumors located within 1 disc diameter of the fovea. DESIGN: Retrospective review. PARTICIPANTS: Patients with choroidal melanoma involving the fovea treated with proton beam therapy between 1975 and 2009. METHODS: Three hundred fifty-one patients with choroidal melanomas located 1 disc diameter (DD) or less from the fovea and more than 1 DD away from the optic nerve were included in this study. In a subgroup of 203 of the patients with small and medium choroidal melanomas, the effect of a reduced dose of radiation, 50 Gy (relative biological effectiveness [RBE]) versus 70 Gy (RBE), on visual outcomes was analyzed. The Kaplan-Meier method and Cox regression analysis were performed to calculate cumulative rates of vision loss and to assess risk factors for vision loss, respectively. MAIN OUTCOME MEASURES: Visual acuity and radiation complications, which included radiation maculopathy, papillopathy, retinal detachment, and rubeosis, were assessed. RESULTS: Three hundred fifty-one patients were included in this study with a mean follow-up time of 68.7 months. More than one-third of patients (35.5%) retained 20/200 or better vision 5 years after proton beam irradiation. For those patients with a baseline visual acuity of 20/40 or better, 16.2% of patients retained this level of vision 5 years after proton beam irradiation. Tumor height less than 5 mm and baseline visual acuity 20/40 or better were associated significantly with a better visual outcome (P < 0.001). More than two-thirds (70.4%) of patients receiving 50 Gy (RBE) and nearly half (45.1%) of patients receiving 70 Gy (RBE) retained 20/200 or better vision 5 years after treatment, but this difference was not significant. Approximately 20% of patients with these smaller macular tumors retained 20/40 vision or better 5 years after irradiation. CONCLUSIONS: The results of this retrospective analysis demonstrate that despite receiving a full dose of radiation to the fovea, many patients with choroidal melanoma with foveal involvement maintain useful vision. A radiation dose reduction from 70 to 50 Gy (RBE) did not seem to increase the proportion of patients who retain usable vision.

Detection of Copy-Number Variation in Circulating Cell-Free DNA in Patients With Uveal Melanoma.

PURPOSE: Somatic chromosomal alterations, particularly monosomy 3 and 8q gains, have been associated with metastatic risk in uveal melanoma (UM). Whole genome-scale evaluation of detectable alterations in cell-free DNA (cfDNA) in UM could provide valuable prognostic information. Our pilot study evaluates the correlation between genomic information using ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA in UM and associated clinical outcomes. MATERIALS AND METHODS: ULP-WGS of cfDNA was performed on 29 plasma samples from 16 patients, 14 metastatic UM (mUM) and two non-metastatic, including pre- and post-treatment mUM samples from 10 patients treated with immunotherapy and one with liver-directed therapy. We estimated tumor fraction (TFx) and detected copy-number alterations (CNAs) using ichorCNA. Presence of 8q amplification was further analyzed using the likelihood ratio test (LRT). RESULTS: Eleven patients with mUM (17 samples) of 14 had detectable circulating tumor DNA (ctDNA). 8q gain was detected in all 17, whereas monosomy 3 was detectable in 10 of 17 samples. TFx generally correlated with disease status, showing an increase at the time of disease progression (PD). 8q gain detection sensitivity appeared greater with the LRT than with ichorCNA at lower TFxs. The only patient with mUM with partial response on treatment had a high pretreatment TFx and undetectable on-treatment ctDNA, correlating with her profound response and durable survival. CONCLUSION: ctDNA can be detected in mUM using ULP-WGS, and the TFx correlates with DS. 8q gain was consistently detectable in mUM, in line with previous studies indicating 8q gains early in primary UM and higher amplification with PD. Our work suggests that detection of CNAs by ULP-WGS, particularly focusing on 8q gain, could be a valuable blood biomarker to monitor PD in UM.

CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration.

OBJECTIVE: The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. DESIGN: Genetic analysis of a randomized, prospective clinical trial. PARTICIPANTS: White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995). METHODS: Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. MAIN OUTCOME MEASURES: The effect of inherited gene polymorphisms on treatment group-specific rate of progression to advanced AMD. RESULTS: Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. CONCLUSIONS: Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy.

Outcomes after Proton Beam Irradiation in Patients with Choroidal Melanoma Eligible for Investigational AU-011 Treatment.

Introduction: Vision loss is common in patients treated with radiotherapy for uveal melanoma. With proton beam irradiation (PBI), the prescribed dose is delivered to the tumor with a sharp dose reduction outside the target volume. However, radiation complications are likely to develop when tumors are located near the optic nerve or fovea. Treatment with light-activated AU-011 (belzupacap sarotalocan), an investigational drug which specifically targets tumor cells, may avoid these complications. We evaluated outcomes in a historical group of patients who fit eligibility criteria for AU-011 therapy and were treated with PBI. Methods: A consecutive series of patients who received PBI for small choroidal melanoma at a single center between 1986 and 2016 were identified. Consistent with eligibility criteria in clinical trials of AU-011, patients were included when tumor dimensions did not exceed 2.5 mm in maximum thickness and 10.0 mm in largest basal diameter (LBD). Snellen visual acuities were converted to logMAR for analysis. Visual acuity outcomes were analyzed in patients with an initial acuity of logMAR 0.7 or better (equivalent to Snellen 20/100). Rates of visual acuity loss and mortality were calculated using the Kaplan-Meier method. Acuity loss by tumor location was compared using log-rank testing. Rates of tumor recurrence, neovascular glaucoma (NVG), and eye loss were also described. Results: Two hundred and 22 patients were included in the study. The median age was 60.7 years (range 21.3-94.8 years). Median tumor thickness was 2.0 mm (range 1.2-2.5 mm), and median LBD was 8.0 mm (range 4.0-10.0 mm). Median follow-up was 6.9 years (range 1.0-30.2 years). In 204 patients with a baseline logMAR visual acuity of 0.7 or better, the mean baseline acuity was 0.15 (equivalent to Snellen 20/25), which decreased to 0.52 (approximately Snellen 20/70) by 5 years after PBI. Visual outcomes were significantly worse for patients with tumors located within 3 mm of the optic disc and/or fovea. Tumor recurrence (1.4%), NVG (4.5%), and eye loss (2.7%) were uncommon. Discussion: Despite the advantageous dose distribution of protons, over half of patients with small choroidal melanomas located near the optic disc or fovea had a visual acuity equivalent to 20/80 or worse at 5 years after PBI. Treatment with AU-011 may allow better vision preservation in small tumors that carry a high risk of vision loss with radiotherapy.

A Comparison of Treatment Outcomes after Standard Dose (70 Gy) versus Reduced Dose (50 Gy) Proton Radiation in Patients with Uveal Melanoma.

OBJECTIVE: To compare outcomes in a large patient cohort with small-medium tumors located within 1 disc diameter (DD) of the optic nerve and/or fovea treated with 50 Gy or 70 Gy proton therapy. DESIGN: Retrospective cohort study. SUBJECTS: A total of 1120 patients with uveal melanomas ≤ 15 mm in largest basal diameter, ≤ 5 mm in height, located within 1 DD of the optic nerve and/or fovea, who received primary treatment with protons between 1975 and 2016 at Massachusetts Eye and Ear/Massachusetts General Hospital. METHODS: The rates of outcomes were estimated using the Kaplan-Meier method. Differences between the radiation dose groups were tested using the log-rank test. MAIN OUTCOME MEASURES: Local tumor recurrence, melanoma-related mortality, and visual acuity preservation (≥ 20/200, ≥ 20/40). RESULTS: Local tumor recurrence was observed in 1.8% of the 50 Gy group and 1.5% of the 70 Gy group. The median time to recurrence was 30.7 months for patients treated with 50 Gy and 32.0 months for those treated with 70 Gy (P = 0.28). Five-year rates of vision retention (≥20/40, ≥ 20/200) were 19.4% and 49.3% for patients treated with 50 Gy and 16.4% and 40.7% in those treated with 70 Gy. Ten-year rates of melanoma-related mortality were 8.4% in the 50 Gy group and 8.9% in the 70 Gy group (P = 0.47). CONCLUSIONS: Comparable rates of local control are achieved treating small-medium tumors near the optic nerve and/or fovea with 50 Gy or 70 Gy proton therapy, supporting the use of the lower dose in patients with these tumor characteristics.

Natural history of radiation papillopathy after proton beam irradiation of parapapillary melanoma.

PURPOSE: To evaluate the natural history of radiation papillopathy after proton beam irradiation of parapapillary choroidal melanoma. DESIGN: Noncomparative case series. PARTICIPANTS: Ninety-three eyes of 93 patients. METHODS: Retrospective chart review of patients with choroidal melanoma within 0 to 1 disc diameter (DD) of the optic nerve and at least 2 DD away from the fovea treated with proton beam irradiation. MAIN OUTCOME MEASURES: Rates of papillopathy, visual loss, and visual improvement. RESULTS: Sixty-eight percent of patients developed papillopathy a median of 1.5 years (17.7 months) after radiation. Among patients who developed papillopathy, 5-year rates of vision retention were 42% for counting fingers or better and 23% for 20/200 or better. At 5 years after the onset of papillopathy, 31% of patients had spontaneous visual improvement of 3 or more lines compared with the time of papillopathy diagnosis. CONCLUSIONS: Even in eyes receiving high doses of radiation to the optic nerve for treatment of intraocular tumors, approximately two thirds of patients develop radiation papillopathy. After the development of papillopathy, 42% of eyes retain useful vision and one third of eyes have significant spontaneous visual improvement over 5 years. The natural history of radiation papillopathy may be more favorable than previously assumed, and therefore treatments for this condition must be compared with an appropriate control group.

Evaluation of the virtual mentor cataract training program.

OBJECTIVE: Evaluate the effectiveness of an interactive cognitive computer simulation for teaching the hydrodissection portion of cataract surgery compared with standard teaching and to assess the attitudes of residents about the teaching tools and their perceived confidence in the knowledge gained after using the tools. DESIGN: Case-control study. PARTICIPANTS AND CONTROLS: Residents at academic institutions. METHODS: Prospective, multicenter, single-masked, controlled trial was performed in 7 academic departments of ophthalmology (Harvard Medical School/Massachusetts Eye and Ear Infirmary, University of Iowa, Emory University, University of Cincinnati, University of Pennsylvania/Scheie Eye Institute, Jefferson Medical College of Thomas Jefferson University/Wills Eye Institute, and the Aravind Eye Institute). All residents from these centers were asked to participate and were randomized into 2 groups. Group A (n = 30) served as the control and received traditional teaching materials; group B (n = 38) received a digital video disc of the Virtual Mentor program. This program is an interactive cognitive simulation, specifically designed to separate cognitive aspects (such as decision making and error recognition) from the motor aspects. Both groups took online anonymous pretests (n = 68) and posttests (n = 58), and answered satisfaction questionnaires (n = 53). Wilcoxon tests were completed to compare pretest and posttest scores between groups. Analysis of variance was performed to assess differences in mean scores between groups. MAIN OUTCOME MEASURES: Scores on pretests, posttests, and satisfaction questionnaires. RESULTS: There was no difference in the pretest scores between the 2 groups (P = 0.62). However, group B (Virtual Mentor [VM]) scored significantly higher on the posttest (P = 0.01). Mean difference between pretest and posttest scores were significantly better in the VM group than in the traditional learning group (P = 0.04). Questionnaire revealed that the VM program was "more fun" to use (24.1% vs 4.2%) and residents were more likely to use this type of program again compared with the likelihood of using the traditional tools (58.6% vs 4.2%). CONCLUSIONS: The VM, a cognitive computer simulation, augmented teaching of the hydrodissection step of phacoemulsification surgery compared with traditional teaching alone. The program was more enjoyable and more likely to be used repetitively by ophthalmology residents.

Posterior uveal melanoma in young patients treated with proton beam therapy.

PURPOSE: The purpose was to study the clinical profile and prognosis of young patients with uveal melanoma treated by proton beam irradiation. METHODS: A retrospective case-control series was studied. Seventeen patients aged 20 years were treated for posterior uveal melanoma between 1975 and 2004. All patients were treated with proton beam irradiation at Harvard Cyclotron. Metastasis and survival of patients were the main outcome measures. RESULTS: Of a total of 3,207 patients with uveal melanoma, 17 patients were

Proton beam irradiation using a light-field technique for the treatment of choroidal hemangiomas.

BACKGROUND/AIMS: To describe the clinical outcomes of patients with circumscribed and diffuse choroidal hemangiomas treated by proton beam irradiation using a nonsurgical light-field technique. METHODS: A retrospective chart review was performed on a series of 19 patients (19 eyes) with choroidal hemangiomas treated with proton beam therapy between July 1988 and August 2005. Choroidal hemangiomas were treated with proton beam irradiation using a light-field technique and doses ranging from 15 to 30 cobalt Gray equivalents (CGE; CGE = proton Gy x relative biological effectiveness 1.1) in 4 fractions. Patients with at least 6 months' follow-up were included in the study. Tumor regression, visual acuity, absorption of subretinal fluid, and treatment-associated complications were evaluated by clinical examination and ultrasonography. RESULTS: Visual acuity improved or remained stable in 14 of 18 eyes (78%). Subretinal fluid was initially present in 16 of 19 eyes (84%), and completely resolved in all 16 eyes. Tumor height, as measured by B-scan ultrasonography, decreased in 18 of 19 eyes and remained stable in 1 of 19, as of the last examination. Complications of radiation developed in 9 of 19 eyes (47%) with the total applied dose ranging from 15 to 30 CGE for these 9 eyes. CONCLUSIONS: Proton beam irradiation using a light-field technique without surgical tumor localization is an effective treatment option in managing both circumscribed choroidal hemangiomas and diffuse hemangiomas associated with Sturge-Weber syndrome. A total proton dose as low as 15 CGE applied in 4 fractions appears to be sufficient to reduce tumor size, promote absorption of subretinal fluid, and improve or stabilize vision in most patients.

Adjuvant interferon therapy for patients with uveal melanoma at high risk of metastasis.

PURPOSE: To examine whether interferon (IFN)-alfa-2a treatment after radiation or enucleation reduces death rates in patients with uveal melanoma. DESIGN: Interventional, comparative case series. PARTICIPANTS: Subjects were identified through the ocular oncology clinic of the Massachusetts Eye and Ear Infirmary. Patients eligible for the study were at increased risk of metastasis because of the presence of at least one of the following characteristics: age >or=65 years, largest tumor diameter (LTD) >or=15 mm, ciliary body involvement of the tumor, or extrascleral tumor extension. METHODS: Between May 1995 and June 1999, 121 patients with choroidal or ciliary body melanoma began a 2-year course of therapy (3 MIU IFN-alfa-2a subcutaneously 3 times per week), initiated within 3 years of primary therapy. All patients underwent regular monitoring for drug toxicity. To evaluate IFN-alfa-2a efficacy, we selected a series of historical controls frequency-matched (2:1) to IFN-alfa-2a-treated patients on age (+/-5 years), LTD (+/-3 mm), gender, and survival time between primary therapy and initiation of IFN therapy. Survival status was ascertained for all patients through December 2006. MAIN OUTCOME MEASURES: Melanoma-related mortality, metastasis, IFN-related toxicities. RESULTS: Fifty-five patients (45%) completed therapy; the median dose for IFN-alfa-2a-treated patients was 792 MIU (85% of the theoretic dose). The median follow-up time in the IFN-alfa-2a-treated group was approximately 9 years. Treatment and control groups were similar with respect to age (P = 0.78), LTD (P = 0.38), and gender (P = 1.0). Of 363 patients, 108 developed metastasis under observation; 42 of these were IFN-alfa-2a-treated patients. Cumulative 5-year melanoma-related death rates were 17% in the radiation or enucleation-only group, 15% in those who completed the entire IFN-alfa-2a course, and 35% in those who discontinued IFN-alfa-2a therapy. In multivariate Cox regression, IFN-alfa-2a had no significant influence on melanoma-related mortality (rate ratio = 1.02, 95% confidence interval, 0.68-1.5, P = 0.91) or all-cause mortality (rate ratio = 0.84, 95% confidence interval, 0.58-1.2, P = 0.34). CONCLUSIONS: Interferon-alfa-2a has no material influence on survival in patients with choroidal melanoma.

Evaluation of choroidal lesions with swept-source optical coherence tomography.

AIMS: The aim of our study was to image choroidal lesions with swept-source optical coherence tomography (SS-OCT) and to identify the morphological characteristics associated with optimal visualisation. METHODS: This was a prospective, cross-sectional study. Patients with choroidal melanocytic lesions <3 mm in thickness on B-scan ultrasonography were recruited. All participants underwent SS-OCT. On SS-OCT we evaluated qualitative (eg, lesion outline, detection of scleral-choroidal interface and quality of the image) and quantitative (measurement of maximum lesion thickness and the largest basal diameter) parameters. Probability of optimal image quality was examined using ordered logistic regression models. The main outcome measure was quality of the choroidal lesion images on SS-OCT, defined as: optimal, suboptimal or poor. RESULTS: We included 85 choroidal lesions of 82 patients. There were 24 choroidal lesions (29%) for which image quality was classified as optimal, 31 lesions (37%) as suboptimal and 30 lesions (36%) as poor. The factors associated with optimal image quality were distance closer to the fovea (OR 0.76, p<0.001), posterior pole location (OR 3.87, p=0.05), lower ultrasonography thickness (OR 0.44, p=0.04), lighter lesion pigmentation (OR 0.12, p=0.003) and smaller lesion diameter (OR 0.73, p<0.001). In the multivariable analysis, closer distance to the fovea (OR 0.81, p=0.005), lighter lesion pigmentation (OR 0.11, p=0.01) and smaller lesion diameter (OR 0.76, p=0.006) remained statistically significant. CONCLUSION: SS-OCT is useful in imaging most choroidal melanocytic lesions. Image quality is best when the choroidal lesion is closer to the fovea, has a smaller diameter and a lighter choroidal pigmentation.

Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration.

PURPOSE: To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort. METHODS: We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified. RESULTS: Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified. CONCLUSIONS: We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.

Survival Rates in Patients After Treatment for Metastasis From Uveal Melanoma.

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.

Genetic Risk Factors for Radiation Vasculopathy.

Purpose: The purpose of this study was to perform a genome-wide scan for polymorphisms associated with risk of vision loss from radiation complications in patients treated with proton beam irradiation for choroidal melanoma. Methods: We identified a cohort of 126 patients at high risk of radiation complications due to tumor location within 2 disc diameters of the optic nerve and/or fovea who provided a blood sample to the Massachusetts Eye and Ear Uveal Melanoma Repository. Controls (n = 76) were defined as patients with visual acuity 20/40 or better 3 years after treatment. Cases (n = 50) were selected as patients with visual acuity 20/200 or worse due to radiation damage 3 years after treatment. Genotyping of these samples was performed using the Omni 2.5 chip (Illumina, Inc.). Results: Hypertension (odds ratio [OR] = 3.749, P = 0.0009), visual acuity at diagnosis of choroidal melanoma (OR = 1.031, P = 0.002), tumor distance to fovea (OR = 0.341, P = 6.52E-05), tumor distance to optic disc (OR = 0.481, P = 5.41E-05), and height of tumor (OR = 1.704, P = 0.0069) were associated with poor vision (20/200 or worse). Individual single nucleotide polymorphism (SNP) analysis was performed controlling for the risk factors identified using stepwise regression and the first principal component. Although this analysis determined that there were 74,529 nominally significant SNPs (P < 0.05), there were no SNPs that reached genome-wide significance (P < 5E-08). The SNP reaching the highest significance level (P < 1E-04) was rs11678387, located on chromosome 2, intergenic between EPB41L5/RALB (P = 4.43E-05). Conclusions: Visual loss from radiation vasculopathy after treatment for choroidal melanoma is not only related to tumor location but may be influenced by hypertension and possibly genetic factors.

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

Long-term Outcomes After Proton Beam Irradiation in Patients With Large Choroidal Melanomas.

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.

Systematic genomic and translational efficiency studies of uveal melanoma.

To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.