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Objective: To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas., Design: Retrospective observational case series., Methods: All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas., Results: Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student's T-tests p = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm, p < 0.0001) and tumor volume (79 mm 3 versus 93 mm mm 3 , p < 0.0001) but greater thickness (3.0 versus 2.5 mm, p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxon p = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5-9.6, p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxon p = 0.82)., Conclusions: There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size., (© 2021. The Author(s).)

Aim: To assess the outcomes of small choroidal melanoma following iodine-125 episcleral brachytherapy (apical height dose of 85 Gy)., Methods: Patients with small choroidal melanoma that underwent iodine-125 episcleral brachytherapy between January 2004 and December 2017 were reviewed. Inclusion criterion for this study was the COMS small tumour size (tumour apical height of 1.0-2.5 mm and largest basal diameter (LBD) <16.0 mm). Patients that received any form of prior therapy or adjuvant transpupillary thermotherapy were excluded. Outcome measures were visual acuity (VA), recurrence, ocular survival and metastasis at 3 years. Kaplan-Meier estimation was calculated for VA, recurrence, ocular survival and survival outcome (overall and metastasis-free survival rate) at 3 years., Results: 161 cases of choroidal melanoma were included in this study, with the mean (SD) age of 59.6 (14.1) years, and 93 (58%) were males. The mean (SD) apical height for the tumours were 2.1 (0.4) mm and mean (SD) LBD was 8.3 (2.2) mm. The mean (SD, median) follow-up was 40.7 months (37.1, 25 months). The VA was 20/50 or better in 69%. Only one recurrence event (1%) and one enucleation event (1%) were observed. Overall survival was 97%, and no metastatic events were observed at 3 years., Conclusion: Small choroidal melanomas treated with iodine-125 episcleral brachytherapy have excellent outcomes. The majority (69%) of patients retained VA of 20/50 or better with very high local control and ocular survival rate (99.3%) with the absence of metastasis (100%)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Episcleral brachytherapy is the most common treatment for medium-sized choroidal melanomas. Although controversial, inadequate brachytherapy dose and dose rates have at least a hypothetical implication on patient survival., Methods: All patients who received ruthenium-106 or iodine-125 brachytherapy for choroidal melanoma at St. Erik Eye Hospital 1996 to 2016 were included (n=1238). Cox regression hazard ratios for melanoma-related mortality across deciles, quartiles and individual integers of apex radiation doses (Gy) and dose rates (Gy/hour) were calculated, adjusted for tumour size and location., Results: The average radiation dose at the tumour apex ranged from 73.0 Gy in the first decile to 108.6 Gy in the tenth. Decreasing apex dose by 1 Gy increments or by decile or quartile group was not associated with melanoma-related mortality (p>0.2) The average radiation dose rate at the tumour apex ranged from 0.5 Gy/hour in the first decile to 2.8 Gy/hour in the tenth. Similarly, decreasing apex dose rate by 1 Gy/hour increments or by decile or quartile groups was not associated with melanoma-related mortality (p>0.5)., Conclusion: There are no increased hazards for choroidal melanoma-related mortality after brachytherapy with decreasing doses between 108.6 and 73.0 Gy, or with decreasing dose rates between 2.8 and 0.5 Gy/hour., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To develop parsimonious models for estimating metastasis mortality in patients with choroidal melanoma for situations where use of the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) or Tumor, Node, Metastasis (TNM) staging system is not possible., Methods: A backward-selection algorithm identified largest basal tumor diameter (LBTD) and chromosome 3 status (C3S) as the most informative predictors of metastatic death. We defined two prognostic models, based on LBTD with or without known C3S, that took into account competing risks of death from other causes by using the Aalen estimator. The bootstrap procedure was used to estimate discrimination accuracy, expressed by the C-index., Results: The cohort was comprised of 8348 patients with choroidal melanoma, 4174 of whom had known chromosome 3 status; of the 1553 deaths that occurred among these patients, 956 were attributed to metastasis. For LBTD with or without known C3S, the metastatic-death-specific C-indices at 2, 5, and 10 years were 0.85, 0.85, and 0.84 and 0.79, 0.77, and 0.74, respectively, as compared with 0.81, 0.79, and 0.76 for Kaplan-Meier prognostication using the 8th edition of the TNM staging system., Conclusions: We have developed parsimonious models for predicting the absolute risks of metastatic death from choroidal melanoma that take into account competing causes of death and which compare favorably with the current version of the TNM staging system. There is a need for further studies to validate the use of these models in situations where use of the TNM or LUMPO is not possible.

Background/objectives: The Scottish Ocular Oncology Service (SOOS) manages all patients with uveal melanoma (UM) in Scotland. Our aim was to determine the long-term all-cause and cause-specific survival of patients with UM, irrespective of treatment modality., Subjects/methods: A retrospective single-centre cohort study including all patients diagnosed with UM by the SOOS between 1/1/1998 and 31/12/2002. Data from the SOOS database were correlated with death records held by National Records of Scotland, which provided date, and all listed causes, of death for all deceased patients., Results: Two hundred and eighteen patients were newly diagnosed with UM between 1/1/1998 and 31/12/2002. One hundred and fifteen (52.8%) were female. The mean (median) age at diagnosis was 63(65) years (range: 16-89). Of 179 choroidal melanomas, melanoma-specific survival was 92.3%, 87.4% and 83.8% at 5, 10 and 15 years, respectively. Cancer-specific survival was 85.8%, 71.8% and 62.3%. All-cause survival was 81.6% (146/179), 62.0% (111/179) and 46.7% (computed, fraction inexpressible). Of 26 ciliary body melanomas, melanoma-specific survival was 87.2%, 81.3% and 81.3% at 5, 10 and 15 years. Cancer-specific survival was 62.9%, 40.6% and 40.6%. All-cause survival was 61.5% (16/26), 38.5% (10/26) and 26.9% (7/26). Of 13 iris melanomas, at all three timepoints (5/10/15 years), melanoma-specific survival was 100%, cancer-specific survival was 92.3%, and all-cause survival was 76.9% (10/13)., Conclusions: Correlation of SOOS and national records survival data confirms 15-year melanoma-specific survival of 83.8%, 81.3% and 100% for choroidal, ciliary body and iris melanomas, respectively. We can now provide accurate survival data to our patients in Scotland.

Purpose: To determine the size at which choroidal melanomas can metastasize and to report the characteristics of small fatal choroidal melanomas (SFCM)., Design: Retrospective case series., Methods: Ten ocular oncology services submitted 45 patients with a choroidal melanoma 3 mm or less in thickness and 9 mm or less in largest basal diameter (LBD), when treated, who developed metastases., Results: Median tumor thickness was 2.4 mm (range, 1.0-3.0 mm) and LBD 7.3 mm (range, 3.0-9.0 mm). Of 14 (31%) tumors that were first observed, 12 grew a median of 0.5 mm (range, 0.1-1.2 mm) in thickness and 1.0 mm (range, 0-3.0 mm) in LBD within a median of 7 months; 3 were initially smaller than 3 mm in LBD. Number of risk factors for growth and metastasis was 0 for 4% of the tumors; 60% were over 2 mm in thickness, 63% had subretinal fluid, 84% caused symptoms, 57% had orange pigment, and 92% were within 3 mm of the disc. Local recurrence occurred in 8 of 31 eyes (26%) treated conservatively. Median metastasis-free survival was 4.5 years (range, 0.8-15.7 years). Kaplan-Meier estimate of metastasis developing was 15% (95% confidence interval [CI], 7-26), 51% (95% CI, 36-64) and 85% (95% CI, 71-92) by 2, 5, and 10 years, respectively. By the time of analysis, 37 patients had died of metastasis after a median of 7 months., Conclusions: Choroidal melanomas less than 3.0 mm in LBD are highly unlikely to metastasize. Risk factors of an SFCM are similar to those for all choroidal melanomas of similar size., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Given the rarity of posterior uveal melanoma in patients younger than 21 years, reporting clinical experience in this area has relevance., Objective: To describe the baseline clinical features, treatment, and clinical course of a group of patients younger than 21 years who have primary posterior uveal melanoma., Design, Setting, and Participants: This retrospective descriptive case series of patients younger than 21 years who have a primary choroidal or ciliochoroidal melanoma was conducted at a single-center subspecialty referral practice. Patients in the relevant age group who were treated in a single practice between July 1980 and December 2013 were included; clinical data collected through December 2017 were captured to permit adequate follow-up time in all cases., Main Outcomes and Measures: Conventional descriptive statistics of relevant clinical variables (eg, demographic, tumor, treatment, and outcome variables) of each patient were recorded. Actuarial metastasis-free and overall survival curves were computed and plotted, as was a postdetection survival curve of patients who developed metastasis during available follow-up., Results: Of 2265 patients with posterior uveal melanoma encountered by the authors during the study interval, 18 (0.8%) were younger than 21 years when diagnosed and treated. Ten were female and 8 male, and the mean (SD) age was 16.6 (4.2) years. Through available follow-up, 8 of these patients had developed metastatic uveal melanoma (44%). All 8 died of metastasis. Actuarial survival analysis showed that the cumulative probability of metastatic death in this group exceeded 50%. The median overall survival time after treatment of the primary intraocular tumor was 11.9 (95% CI, 7.3-16.5) years. The median survival time after detection of metastasis in the 8 patients who developed metastasis was 2.3 months (95% CI, 0.0-5.2) months., Conclusions and Relevance: Posterior uveal melanoma in patients younger than 21 years appears to have a similar if not worse prognosis than patients with PUM in the population overall. Owing to the later onset of metastasis observed, patients younger than 21 years should continue to have surveillance tests for more than 10 years after treatment.

Background/aims: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death., Methods: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure., Results: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance., Conclusions: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment., Design: Prospective nonrandomized multicenter cohort study as an adjunct to COMS randomized clinical trials., Methods: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis., Results: Of 77 patients eligible for COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study (NHS). In all, 42 patients (42 eyes) had medium melanoma, and the median follow-up was 5.3 years (range, 4-10.7 years). In all, 22 patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, Kaplan-Meier estimate of 5-year mortality was approximately 30% [95% confidence interval (CI), 18%-47%]. For COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16%-20%), not statistically significantly different from the NHS patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for NHS patients versus COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in 8 (42%) of 19 deaths., Conclusion: Greater mortality and higher risk of death for NHS patients are probative but not conclusive evidence of a beneficial, life-extending effect of medium melanoma treatment., Competing Interests: There are no conflicts of interest

About 50% of patients with choroidal melanoma develop metastatic disease, despite successful eradication of the primary tumor. Patient care is complicated by the fact that we do not know whether ocular treatment ever influences survival and if so in whom. Some authorities believe that metastatic spread is never preventable, because it has always occurred by the time the ocular tumor is detected. Others hold the view that metastatic spread can occur late, at least in some patients, in whom timely and successful treatment is life-saving. Some melanomas never seem to metastasize, even if they reach an advanced stage. It is likely that many patients are undergoing futile enucleation or experiencing severe ocular morbidity and visual loss from excessive radiation safety margins in the hope of living longer. Some of these patients would do better with tumor resection, often rejected because of concerns about iatrogenic tumor dissemination. At the same time, many patients with a small melanoma are being left untreated for years until growth is documented, possibly missing opportunities for prolonging life. Metastatic disease is highly likely when genetic tumor analysis detects monosomy 3, chromosome 8q gain, a class 2 gene expression profile, and/or BAP1 loss. Do these lethal genetic aberrations ever develop while the patient is under observation? If so, can these be predicted by genetic analysis? Do lethal mutations and metastasis ever occur because ocular treatment has failed to eradicate the tumor completely? Answers to these questions would profoundly change the management of patients with uveal melanoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Purpose: To examine national practice patterns and outcomes of eye plaque brachytherapy compared to proton external beam radiotherapy in the treatment of choroid melanoma., Methods and Materials: Demographic and clinical data for 1224 patients with choroid melanoma treated with either brachytherapy or proton beam therapy from 2004 to 2013 were obtained from the National Cancer Database. Logistic regression and propensity score matching was used to create a 1:1 matched cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate survival in brachytherapy and proton groups., Results: Median followup was 37 and 29 months for brachytherapy and protons, respectively. Most patients were treated with brachytherapy (n = 996) vs. protons (n = 228). Proton patients came from more urban, affluent, and educated zip codes, and they were more likely to be treated at an academic center (all p < 0.004). In the propensity-score matched cohort, 2-year overall survival was 97% vs. 93%, and 5-year overall survival was 77% vs. 51% for brachytherapy and protons, respectively (p = 0.008). Multivariate Cox regression found older age (hazard ratio [HR] = 1.06, 95% confidence interval (CI) = 1.03-1.09), larger tumor diameter (12-18 mm, HR = 2.48, 95% CI = 1.40-4.42, >18 mm, HR = 6.41, 95% CI = 1.45-28.35), and protons (HR = 1.89, 95% CI = 1.06-3.37) were negative prognosticators of survival., Conclusions: Patients selected for proton treatment have inferior survival outcomes compared to brachytherapy in this retrospective analysis. There may be unaccounted variables that influence survival, warranting further prospective studies., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: External beam radiation therapy (RT) is an effective palliative treatment for patients with choroidal metastases and is aimed at preserving vision and obtaining local tumor control. Delivery of 30 to 40 Gy in 2-Gy daily fractions is a standard approach at many centers. This study reports the outcomes of a hypofractionated schedule of 20 Gy in 5 fractions in this palliative setting., Methods and Materials: We conducted a retrospective review of patients who were treated with RT (20 Gy in 5 fractions) for choroidal metastases between January 1999 and November 2012. The primary outcome measures were change in visual acuity and tumor response. Secondary outcomes included toxicities of RT, tumor control, and overall survival (OS) from diagnosis of choroidal metastases. Univariate and multivariable Cox regression modeling was used to investigate the predictors for OS., Results: Fifty-five patients with 71 affected eyes were included. Decreased vision was the presenting symptom in 43 eyes (61%). Visual acuity improved from a median of 20/70 at baseline to 20/40 at last follow-up and remained stable or improved in 56 eyes (80%). Tumor regression was observed in 64 eyes (91%) with complete response in 47 eyes (67%). Local progression occurred in 4 eyes (6%). The median survival after diagnosis of choroidal metastases was 13 months. No acute complications were observed in 49 patients (89%). Mild acute toxicities included transitory dryness in 5 patients and episcleritis in 1 patient. Cataracts, retinopathy, optic neuropathy, pigmentary maculopathy, and neovascular glaucoma developed in 4 eyes (6%), 1 eye, 7 eyes (10%), 5 eyes (7%), and 1 eye, respectively. No variables were statistically significantly associated with OS., Conclusions: A short fractionation schedule of 20 Gy in 5 fractions is a well-tolerated treatment that effectively preserves vision and gains local tumor control for many patients with choroidal metastases. This hypofractionated approach would help reduce the burden of a longer treatment course in this palliative patient population., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Managing juxtapapillary and circumpapillary choroidal melanoma with brachytherapy is challenging because of technical complications with accurate plaque placement and high radiation toxicity given tumor proximity to the optic nerve. We evaluated our center's experience using ultrasound-guided, Iodine (I)-125 notched plaque brachytherapy for treating choroidal melanoma contiguous with (juxtapapillary) and at least partially surrounding the optic disc (circumpapillary)., Methods: All cases of choroidal melanoma treated with I-125 notched plaque brachytherapy at our center from September 2003-December 2013 were retrospectively reviewed. Only patients with ≥18 months of follow-up who had lesions contiguous with the optic disc (0 mm of separation) were included. The tumor apex prescription dose was 85 Gy. Outcomes evaluated included local control, distant metastasis-free survival (DMFS), cancer-specific survival (CSS), overall survival (OS), visual acuity, and radiation toxicity., Results: Thirty-four patients were included with a median follow-up of 44.1 months (range 18.2-129.0). AJCC T-category was T1 in 58.8%, T2 in 26.5%, and T3 in 14.7%. Median circumferential optic disc involvement was 50% (range 10%-100%). Eye retention was achieved in 94.1%. Actuarial 2- and 4-year rates of local recurrence were 3.1% and 7.6%, DMFS were 97.0% and 88.5%, CSS were 97.0% and 92.8%, and OS were 97.0% and 88.9%, respectively. In addition, 23.5% had visual acuity ≥20/200 at last follow-up., Conclusions: I-125 notched plaque brachytherapy provides high eye preservation rates with acceptable longer-term post-treatment visual outcomes. Based on our experience, choroidal melanoma directly contiguous with and partially encasing the optic disc may be effectively treated with this technique.

Purpose: Choroidal melanoma is a rare tumour in adults. The mean age at diagnosis is 60, but the tumour can affect women of childbearing age. A negative effect of pregnancy on patients' survival has not been formally excluded to date. The aim of the present study is to evaluate the effect of pregnancy on the prognosis of choroidal melanoma., Methods: We conducted a single-centre retrospective study at the Institut Curie on the population of women of childbearing age who were diagnosed with choroidal melanoma between June 1980 and October 2013. We took a particular interest in the prognosis of those who were pregnant at the time of diagnosis and in the prognosis of those who chose to get pregnant after the treatment., Results: We found 27 pregnant patients at the time of diagnosis and 13 patients who became pregnant after the treatment. There was no difference in the survival between these two groups of patients and the group of other women of childbearing age diagnosed with choroidal melanoma (p = 0.52). There was also no difference in metastasis-free survival (p = 0.91). Most women were able to carry their pregnancies to term (67% had a term pregnancy, and only 7% had an abortion). For women who were pregnant when they were diagnosed with choroidal melanoma, a conservative treatment was chosen in 85% of cases, and proton beam therapy was the most widely used treatment., Conclusions: Survival in women of childbearing age does not appear to be influenced by pregnancy. We show that proton beam therapy can be used to treat women who are pregnant at the time of choroidal melanoma diagnosis., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI., Design: Retrospective, multicenter observational study., Participants: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults., Methods: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression., Main Outcome Measures: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality., Results: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival., Conclusions: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: No modern randomized trials exist comparing external beam radiotherapy (EBRT) and plaque brachytherapy (BT) for choroidal melanoma, and the optimal treatment modality is currently unknown. This study compares the patterns of care and efficacy of EBRT vs. BT based on data in the Surveillance, Epidemiology, and End Results database., Methods and Materials: The Surveillance, Epidemiology, and End Results database was queried for patients aged 20-79 diagnosed with choroidal melanoma from 2004 to 2011, treated with EBRT or BT; included patients were clinically T1-T4, N0, and M0. Overall survival and cause-specific survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed in the survival and patterns-of-care analyses., Results: A total of 1004 cases (380 EBRT and 624 BT) were included in the survival analysis. There was no difference in the 5-year overall survival (83.3% EBRT vs. 82.5% BT, p = 0.69) and 5-year cause-specific survival (88.3% EBRT vs. 88.3% BT, p = 0.92). In the survival analysis, older age and advanced tumor stage were predictors of increased risk of death. In the patterns-of-care analysis, later year of diagnosis and smaller tumor stage were predictors of BT use., Conclusions: Advanced tumor stage and older age seem to be independent predictors for risk of death from choroidal melanoma. The use of BT favors smaller tumors and later year of diagnosis. There is no difference in survival between those treated with EBRT or BT, and the utilization of BT is increasing., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Aims: The aim of the present study was to immunohistochemically investigate the expression and prognostic significance of putative cancer stem cell markers CD117 (c-kit), CD34, CD20 and CD15 in a cohort of patients with primary choroidal and ciliary body melanoma., Methods: The immunohistochemical expression of these markers was evaluated using 3,3'-diaminobenzidine tetrahydrochloride (DAB) and 3-amino-9-ethylcarbazole (AEC) chromogens on paraffin-embedded tissue samples from 40 patients who underwent enucleation in the period from 1985 through 2000. Thirty-one patients had adequate tissue specimens for the analysis., Results: CD117 overexpression was observed in 12 of the 31 samples (39%) when AEC chromogen was used and in 14 of 26 (54%) samples when DAB was used. CD15 positivity was seen in three out of 30 (10%) samples with AEC and in six out of 26 (23%) samples with DAB. CD20 and CD34 exhibited no positivity in the tested samples. During the average follow-up time of 8.7 years (range 0.5-22 years), 17 patients (55%) died due to metastatic disease. The Kaplan-Meier plots showed a significantly shorter overall and disease-free survival in CD117-positive patients when the AEC chromogen was used. CD15 expression was not associated with patients' survival. In multivariate analysis, patients expressing the CD117 AEC had 4.13 times higher risk of lethal outcome in comparison with CD117 AEC negative patients., Conclusions: Our retrospective cohort study has for the first time demonstrated a small proportion of CD15-positive uveal melanomas. CD117 AEC overexpression was associated with a worse outcome in patients with choroidal and ciliary body melanoma. Further studies should confirm the validity of these observations and their potential for targeted treatment modalities., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aim: To specify indications for brachytherapy (BT) in large choroidal melanoma (CM) so that tumor size and vital prognosis were considered., Material and Methods: We retrospectively analyzed data from 161 CM patients who were treated with BT and followed-up at either the Ophthalmological Clinical Hospital or some other Moscow medical facility and also registered by the City Cancer Registry., Results: Patient age at the time of starting the treatment lied within the range of 17 to 84 years and averaged 56.89±1.93 years. During the follow-up period (12-275 months, 95.65±8.4 months on average) hematogenous metastases were found in 23 (14.29%) patients. Liver involvement was diagnosed in 8 patients within the average of 23.13 months after treatment. Their average survival time was 11 months. A total of 142 patients were followed up for more than 36 months (104.87 months on average). Of them, 15 patients were diagnosed with metastatic CM within 37-167 months after BT (80.27 months on average). Despite metastatic disease they generally survived 2.8 time longer than the aforementioned patients (30.8 months). The cases were then divided into 3 groups according to J. Shields classification of CM. Small melanoma patients did not develop metastases within 99.96±12.47 months of follow-up. In medium melanomas, as many as 13.35% of cases were metastatic (with the average survival time of 20.66 months); in large melanomas - 19.51% (with the average survival time of 13.5 months)., Conclusion: Treatment modality and follow-up periods being the same (7-8 years after BT), larger choroidal melanomas has been shown to be associated with higher risk of hematogenous metastases. For local treatment to be successive, the maximal diameter of the tumor should not exceed 10 mm. Every fifth patient of those with CM larger than 15 mm is likely to develop hematogenous metastases. The results obtained indicate the necessity of decreasing the size thresholds for choroidal melanomas, small and medium in the first place.

Objectives: This retrospective study was carried out to define the clinical features and prognostic differences in non-cutaneous malignant melanoma (non-CMM) originating from different anatomic sites., Methods: Clinical and follow-up data for 71 patients with non-CMM were collected and reviewed., Results: Of the 71 non-CMM patients, 59 were diagnosed with mucosal malignant melanoma (MMM) and 12 with ocular malignant melanoma (OMM). In the 59 MMM patients, the nasal cavity was the most common anatomic site (n = 31, 43.7% of all non-CMM), followed by the oral cavity (n = 9, 12.7%), the genitourinary tract (n = 9, 12.7%), the anorectum (n = 8, 11.3%), and the gastrointestinal tract (n = 2, 2.8%). In the 12 patients with OMM, anatomic sites included the choroid (n = 8, 11.3% of all non-CMM) and the conjunctiva (n = 4, 5.6%). The survival outcome of patients with OMM was much better than that of patients with MMM (P < 0.001). In MMM patients, anorectal melanoma was associated with a worse survival outcome. Age of ≥ 70 years (P < 0.001) and tumor size of > 2 cm (P = 0.02) were significantly poor prognostic factors in MMM. Age (relative risk [RR] 1.068, 95% confidence interval [CI] 1.006-1.133; P = 0.03) and tumor size (RR 1.410, 95% CI 1.038-1.915; P = 0.028) were independent predictors for the postoperative survival of MMM patients. Patients with these two risk factors had a higher risk for recurrence or death (RR 3.107, 95% CI 1.627-5.595)., Conclusions: Our findings demonstrate that prognoses differ in patients with different anatomic sites of primary non-CMM. Advanced age and larger tumor size are the main factors affecting prognosis. Patients with poor risk factors should be treated differently to improve their survival outcome., (© 2015 The International Society of Dermatology.)

Purpose: Relevant clinical data are needed given the increasing national interest in charged particle radiation therapy (CPT) programs. Here we report long-term outcomes from the only randomized, stratified trial comparing CPT with iodine-125 plaque therapy for choroidal and ciliary body melanoma., Methods and Materials: From 1985 to 1991, 184 patients met eligibility criteria and were randomized to receive particle (86 patients) or plaque therapy (98 patients). Patients were stratified by tumor diameter, thickness, distance to disc/fovea, anterior extension, and visual acuity. Tumors close to the optic disc were included. Local tumor control, as well as eye preservation, metastases due to melanoma, and survival were evaluated., Results: Median follow-up times for particle and plaque arm patients were 14.6 years and 12.3 years, respectively (P=.22), and for those alive at last follow-up, 18.5 and 16.5 years, respectively (P=.81). Local control (LC) for particle versus plaque treatment was 100% versus 84% at 5 years, and 98% versus 79% at 12 years, respectively (log rank: P=.0006). If patients with tumors close to the disc (<2 mm) were excluded, CPT still resulted in significantly improved LC: 100% versus 90% at 5 years and 98% versus 86% at 12 years, respectively (log rank: P=.048). Enucleation rate was lower after CPT: 11% versus 22% at 5 years and 17% versus 37% at 12 years, respectively (log rank: P=.01). Using Cox regression model, likelihood ratio test, treatment was the most important predictor of LC (P=.0002) and eye preservation (P=.01). CPT was a significant predictor of prolonged disease-free survival (log rank: P=.001)., Conclusions: Particle therapy resulted in significantly improved local control, eye preservation, and disease-free survival as confirmed by long-term outcomes from the only randomized study available to date comparing radiation modalities in choroidal and ciliary body melanoma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Small choroidal melanomas have a better prognosis than large tumours. However, these small tumours can spread, often late in their course. The aim of the study was to analyse survival and tumour characteristics of six cases of late metastatic diseases after conservative treatment., Methods: A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon among 523 patients treated between 1991 and 2010 by proton beam therapy (508) or brachytherapy with 106 (Ru/Rh) (15) for uveal melanomas. We have selected patients with small choroidal melanoma (thickness≤3 mm and diameter≤9 mm) (59 patients), who have developed hepatic metastases (six of 59)., Results: At the time of diagnosis, median age was 57 years (range, 37-82 years). The mean tumour thickness was 2.9 mm (range 2.5-3 mm), and the mean diameter was 7 mm (5-8 mm). Orange pigment was observed in four cases, subretinal fluid was observed in two cases, and one tumour touched the optic disc. Five patients had proton beam therapy. One patient had beta brachytherapy (106 Ru/106 Rh). Average follow-up was 8.3 years (range 4.2-11.8 years). None of the six patients developed local tumour recurrence. The mean survival time after diagnosis of melanoma was 9.8 years (range, 4.9-14.6 years). The average time from treatment of primary tumour to detection of liver metastasis was 7 years (range 3.9-12 years). The mean survival time from the diagnosis of metastasis was 35.2 months (range 9-101 months). Small melanoma-related death was 0% at 3 years, 1.7% at 5 years, 5.1% at 10 years and 10.2% at 15 years in our series., Conclusions: Despite a small tumoral size and an early and effective local treatment, six of 59 small choroidal melanomas have developed metastasis after local treatment. Small tumours represent a significant risk of metastasis., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To determine the frequency of discordant gene expression profile (GEP) classification of posterior uveal melanomas sampled at 2 tumor sites by fine-needle aspiration biopsy (FNAB)., Design: Prospective single-institution longitudinal study performed in conjunction with a multicenter validation study of the prognostic value of GEP class of posterior uveal melanoma cells for metastasis and metastatic death., Methods: FNAB aspirates of 80 clinically diagnosed primary choroidal and ciliochoroidal melanomas were obtained from 2 tumor sites prior to or at the time of initial ocular tumor treatment and submitted for independent GEP testing and classification. Frequency of discordant GEP classification of these specimens was determined., Results: Using the support vector machine learning algorithm favored by the developer of the GEP test employed in this study, 9 of the 80 cases (11.3% [95% confidence interval: 9.0%-13.6%]) were clearly discordant. If cases with a failed classification at 1 site or a low confidence class assignment by the support vector machine algorithm at 1 or both sites are also regarded as discordant, then this frequency rises to 13 of the 80 cases (16.3% [95% confidence interval: 13.0%-19.6%])., Conclusion: Sampling of a clinically diagnosed posterior uveal melanoma at a single site for prognostic GEP testing is associated with a substantial probability of misclassification. Two-site sampling of such tumors with independent GEP testing of each specimen may be advisable to lessen the probability of underestimating an individual patient's prognostic risk of metastasis and metastatic death., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Collateral damage to upper eyelid margin during proton beam radiotherapy (PBR) for choroidal melanoma may cause squamous metaplasia of the tarsal conjunctiva with keratinisation, corneal irritation, discomfort and, rarely, corneal perforation. We evaluated transpalpebral PBR as a means of avoiding collateral damage to the upper eyelid margin without increasing the risk of failure of local tumour control., Methods: Retrospective study of consecutive patients who underwent PBR for choroidal melanoma between 1992 and 2007 at the Royal Liverpool University Hospital and the Douglas Cyclotron at Clatterbridge Cancer Centre, UK., Results: Sixty-three patients were included in this study. Mean basal tumour diameter and tumour thickness were 11.8 mm and 3.6 mm, respectively. PBR mean beam range and modulation were 26.5 mm and 16.9 mm respectively. The eyelid margin was included in the radiation field in 15 (24%) eyes. The median follow-up was 2.5 years. Local tumour recurrence developed in 2 (3.2%) patients. In these two cases that developed tumour recurrence the transpalpebral treatment did not involve the eyelid margin. Six (9.5%) patients died of metastatic disease. No eyelid or ocular surface problems developed in any of the 48 patients who were treated without eyelid rim involvement, while 7 of the 15 patients with unavoidable irradiation of the eyelid rim developed some degree of madarosis. These seven patients all received more than 26.55 proton Gy to the eyelid margin. Symptoms, such as grittiness occurred in 12% of 48 patients without eyelid margin irradiation as compared with 53% of 15 patients whose lid margin was irradiated., Conclusions: Transpalpebral PBR of choroidal melanoma avoids eyelid and ocular surface complications without increasing failure of local tumour control., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To determine underlying correlations in multiplex ligation-dependent probe amplification (MLPA) data and their significance regarding survival following treatment of choroidal melanoma (CM)., Methods: MLPA data were available for 31 loci across four chromosomes (1p, 3, 6, and 8) in tumor material obtained from 602 patients with CM treated at the Liverpool Ocular Oncology Center (LOOC) between 1993 and 2012. Data representing chromosomes 3 and 8q were analyzed in depth since their association with CM patient survival is well-known. Unsupervised k-means cluster analysis was performed to detect latent structure in the data set. Principal component analysis (PCA) was also performed to determine the intrinsic dimensionality of the data. Survival analyses of the identified clusters were performed using Kaplan-Meier (KM) and log-rank statistical tests. Correlation with largest basal tumor diameter (LTD) was investigated., Results: Chromosome 3: A two-cluster (bimodal) solution was found in chromosome 3, characterized by centroids at unilaterally normal probe values and unilateral deletion. There was a large, significant difference in the survival characteristics of the two clusters (log-rank, p<0.001; 5-year survival: 80% versus 40%). Both clusters had a broad distribution in LTD, although larger tumors were characteristically in the poorer outcome group (Mann-Whitney, p<0.001). Threshold values of 0.85 for deletion and 1.15 for gain optimized the classification of the clusters. PCA showed that the first principal component (PC1) contained more than 80% of the data set variance and all of the bimodality, with uniform coefficients (0.28±0.03). Chromosome 8q: No clusters were found in chromosome 8q. Using a conventional threshold-based definition of 8q gain, and in conjunction with the chromosome 3 clusters, three prognostic groups were identified: chromosomes 3 and 8q both normal, either chromosome 3 or 8q abnormal, and both chromosomes 3 and 8q abnormal. KM analysis showed 5-year survival figures of approximately 97%, 80%, and 30% for these prognostic groups, respectively (log-rank, p<0.001). All MLPA probes within both chromosomes were significantly correlated with each other (Spearman, p<0.001)., Conclusions: Within chromosome 3, the strong correlation between the MLPA variables and the uniform coefficients from the PCA indicates a lack of evidence for a signature gene that might account for the bimodality we observed. We hypothesize that the two clusters we found correspond to binary underlying states of complete monosomy or disomy 3 and that these states are sampled by the complete ensemble of probes. Consequently, we would expect a similar pattern to emerge in higher-resolution MLPA data sets. LTD may be a significant confounding factor. Considering chromosome 8q, we found that chromosome 3 cluster membership and 8q gain as traditionally defined have an indistinguishable impact on patient outcome.

Objective: This study aimed to assess the ocular and metastatic outcomes of patients with choroidal indeterminate melanocytic lesions treated by primary transpupillary thermotherapy (TTT)., Design: Retrospective case series., Participants: Eight patients presenting choroidal indeterminate melanocytic lesions treated by primary TTT., Methods: A retrospective chart review was conducted for patients with a newly diagnosed choroidal indeterminate melanocytic lesion treated by at least 3 TTT sessions from 2002 to 2011. Best-corrected visual acuity and lesion dimensions were measured at baseline and during follow-up. Complications were recorded including lesion growth, metastasis, melanoma-related mortality, and treatment-related complications., Results: Mean initial thickness was 2.0 ± 0.8 mm. Patients had an average of 3.0 ± 0.9 risk factors for lesion growing. Three patients (38%) had lesion growth. Two patients (25%) had severe visual loss (>1.0 logMAR) directly related to TTT treatment. There were no fatalities due to metastasis., Conclusions: Despite careful patient selection and systematic treatment with at least 3 TTT sessions, the use of primary TTT to treat patients with choroidal indeterminate melanocytic lesions with ≥ 1 risk factor for lesion growth yielded poor local lesion control and the possibility for severe ocular complications., (Copyright © 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess tumor control, complications, and vision after brachytherapy for posterior choroidal melanoma <10 mm in largest basal diameter with the 10-mm ruthenium plaque., Methods: This was a retrospective cohort study of consecutive choroidal melanomas <10 mm by largest basal diameter in a national ocular oncology service in 1998 to 2010. The median dose was 116 Gy (range, 80-194 Gy) to the apex and 327 Gy (range, 201-824 Gy) to the sclera. The median tumor height and largest basal diameter were 1.9 mm (range, 0.4-5.2 mm) and 7.0 mm (range, 3.3-9.6 mm), respectively. The median distance to disk and foveola was 3.0 mm (range, 0-7.5 mm) and 2.0 mm (range, 0-8.5 mm), respectively., Results: Four recurrences occurred at a median of 1.4 years (range, 0.6-3.1 years) after irradiation. Five-year cumulative incidence of local recurrence was 9% (95% confidence interval [CI], 3-20). Six patients died at a median of 4.2 years (range, 0.28-8.6 years) after treatment, one with evidence of metastases. At 5 years, 57% (95% CI, 31-79), 72% (95% CI, 58-85), and 97% (95% CI, 88-100) of eyes were free of any maculopathy, radiation maculopathy, and optic neuropathy, respectively. Cumulative incidence of developing low vision and blindness were 17% (95% CI, 7-31) and 3% (95% CI, 2-12) at 5 years, respectively. Thickness >3.0 mm, largest basal diameter >7.0 mm, and location ≤ 1.5 mm of foveola were associated with visual loss., Conclusion: Local tumor control and vision outcomes support the use of 10-mm ruthenium plaques in managing smallest choroidal melanomas.

Unlabelled: Choosing the treatment method for patients with large choroidal melanomas remains a subject of debate. No literature data can be found on survival of such patients after either eye-preserving surgery or enucleation that takes into account the initial tumor size. The purpose of the study was to analyze the five-year survival rates for large choroidal melanomas (by J.A. Shields) in respect of the provided treatment., Material and Methods: Medical records of 103 patients who had undergone treatment for choroidal melanoma (initial prominence 5.0-10.2 mm, initial diameter 7.3-20 mm) were studied. Eye-preserving surgery was performed on 60 patients, of whom 46 patients received brachytherapy (single session in 37 cases) and the other 14 patients--brachytherapy in combination with transpupillary thermotherapy (with subsequent endoresection of the tumor in one case). A total of 16 patients from this group required secondary enucleation. Primary enucleation was performed on 63 patients. Histopathological results confirming choroidal melanoma were analyzed in all 79 cases., Results and Discussion: The 5-year melanoma-specific cumulative survival rate in the group of eye-preserving surgery was 0.8146, while in the group of primary enucleation it reached 0.8951. The 8-year rate was 0.6921 and 0.7558 correspondingly. However, according to Gehan-Wilcoxon test, the differences were statistically insignificant (p = 0.11). The five-year survival of large choroidal melanoma patients who underwent eye-preserving surgery and no enucleation was 0.7708, 9-year - 0.6175., Conclusion: Since the five-year melanoma-specific survival rate after primary enucleation is higher than that after eye-preserving surgery and secondary enucleation (though the difference is statistically insignificant), treatment options for large choroidal melanomas have to be chosen individually, taking into account the age and attitude of the patient as well as the size of the tumor.

Objective: To determine whether treatment of choroidal melanoma influences survival by correlating age at death, cause of death, age at treatment, and survival predictors., Design, Setting, and Participants: Prospective cohort study performed at the Liverpool Ocular Oncology Centre, a supraregional, tertiary referral service in England. We included 3072 patients treated for choroidal melanoma from January 15, 1993, through November 23, 2012, and who reside in the mainland United Kingdom., Exposures: A diagnosis of choroidal melanoma (ie, any uveal melanoma involving the choroid)., Main Outcomes and Measures: Largest basal tumor diameter, tumor thickness, TNM stage, ciliary body involvement, extraocular spread, melanoma cytomorphological findings, closed connective tissue loops, mitotic count, chromosome 3 loss, chromosome 6p gain, chromosome 8q gain, age at treatment, age at death, and cause of death., Results: The largest basal tumor diameter correlated with all survival predictors except for chromosome 6p gain. Older age at treatment correlated with ciliary body involvement, extraocular spread, largest basal tumor diameter, tumor thickness, TNM stage, epithelioid cells, chromosome 3 loss, and chromosome 8q gain. A total of 1005 patients had died by the close of the study. The cause of death was metastatic disease due to uveal melanoma in 561 patients. Among the 561 patients, survival time after treatment correlated with sex, basal tumor diameter, ciliary body involvement, extraocular spread, TNM stage, closed loops, and mitotic count. In this group of patients, none of the survival predictors correlated with age at death except for mitotic count, which showed a weak correlation. All survival predictors correlated with an increased likelihood of metastatic melanoma as the cause of death., Conclusions and Relevance: Patients who are younger at the time of treatment tend to have a smaller, less extensive tumor with a lower degree of malignancy. A tentative explanation for these findings is that ocular treatment prevents tumor growth, dedifferentiation, and metastatic disease in some patients, especially those with a smaller tumor.

Purpose: To investigate, in the treatment of uveal melanomas, how tumor control, radiation toxicity, and visual outcomes are affected by the radiation dose at the tumor apex., Methods and Materials: A retrospective review was performed to evaluate patients treated for uveal melanoma with (125)I plaques between 1988 and 2010. Radiation dose is reported as dose to tumor apex and dose to 5 mm. Primary endpoints included time to local failure, distant failure, and death. Secondary endpoints included eye preservation, visual acuity, and radiation-related complications. Univariate and multivariate analyses were performed to determine associations between radiation dose and the endpoint variables., Results: One hundred ninety patients with sufficient data to evaluate the endpoints were included. The 5-year local control rate was 91%. The 5-year distant metastases rate was 10%. The 5-year overall survival rate was 84%. There were no differences in outcome (local control, distant metastases, overall survival) when dose was stratified by apex dose quartile (<69 Gy, 69-81 Gy, 81-89 Gy, >89 Gy). However, increasing apex dose and dose to 5-mm depth were correlated with greater visual acuity loss (P=.02, P=.0006), worse final visual acuity (P=.02, P<.0001), and radiation complications (P<.0001, P=.0009). In addition, enucleation rates were worse with increasing quartiles of dose to 5 mm (P=.0001)., Conclusions: Doses at least as low as 69 Gy prescribed to the tumor apex achieve rates of local control, distant metastasis-free survival, and overall survival that are similar to radiation doses of 85 Gy to the tumor apex, but with improved visual outcomes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To report and compare the outcomes of brachytherapy and endoresection in the conservative treatment of medium sized choroidal melanoma., Methods: A retrospective cohort study. Medium tumours were defined as 2.5-10 mm in height and less than 16 mm in the widest diameter. Consecutive patients undergoing brachytherapy at Groote Schuur Hospital were compared with a cohort undergoing endoresection from a national database., Results: 148 brachytherapy and 22 endoresection patients were followed for a median of 55.4 and 62.4 months, respectively. Tumours undergoing endoresection were thicker (7.3 vs 4.9 mm, p<0.001, Wilcoxon rank-sum test) and further from the fovea (5.2 vs 3.7 mm, p=0.05, Wilcoxon rank-sum test) than those treated with brachytherapy. Visual acuity of 6/18 or better was maintained in 41% of the endoresection group and 35% of the brachytherapy group. The likelihood of achieving a final visual acuity of better than 2/60 was 22% higher in the endoresection group (risk ratio 1.22, 95% CI 1.02 to 1.28, p=0.034). Rates of local recurrence (18.2% vs 14.9%, p=0.75) and metastases or death (18.2% vs 14.2%, p=0.75) were higher in the endoresection group, and the enucleation rate was lower in this group (4.6% vs 10.8%, p=0.70) but these were not statistically significant., Conclusions: The outcomes observed in this small cohort of endoresection patients suggest that endoresection of selected tumours may achieve better visual outcomes than brachytherapy. Rates of local recurrence, enucleation and metastases following endoresection require further research. Local recurrence is likely to be influenced by consolidation treatment methods.

Objective: To determine the relative sufficiency of paired aspirates of posterior uveal melanomas obtained by FNAB for cytopathology and GEP, and their prognostic significance for predicting death from metastasis., Methods: Prospective non-randomized IRB-approved single-center longitudinal clinical study of 159 patients with posterior uveal melanoma sampled by FNAB in at least two tumor sites between 09/2007 and 12/2010. Cases were analyzed with regard to sufficiency of the obtained aspirates for cytopathologic classification and GEP classification. Statistical strength of associations between variables and GEP class was computed using Chi-square test. Cumulative actuarial survival curves of subgroups of these patients based on their cytopathologic versus GEP-assigned categories were computed by the Kaplan-Meier method. The endpoint for this survival analysis was death from metastatic uveal melanoma., Results: FNAB aspirates were insufficient for cytopathologic classification in 34 of 159 cases (21.9 %). In contrast, FNAB aspirates were insufficient for GEP classification in only one of 159 cases (0.6 %). This difference is statistically significant (P < 0.001). Six of 34 tumors (17.6 %) that yielded an insufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2, while 43 of 125 tumors (34.7 %) that yielded a sufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2. To date, 14 of the 49 patients with a GEP class 2 tumor (28.6 %) but only five of the 109 patients with a GEP class 1 tumor (5.6 %) have developed metastasis. Fifteen of 125 patients (12 %) whose tumors yielded sufficient aspirates for cytopathologic classification but only four of 34 patients (11.8 %) whose tumors yielded insufficient aspirates for cytopathologic classification developed metastasis. The median post-biopsy follow-up time for surviving patients in this series was 32.5 months. Cumulative actuarial 5-year probability of death from metastasis 14.1 % for those with an insufficient aspirate for cytopathologic classification versus 22.4 % for those with a sufficient aspirate for cytopathologic classification (log rank P = 0.68). In contrast, the cumulative actuarial 5-year probability of metastatic death was 8.0 % for those with an insufficient/unsatisfactory aspirate for GEP classification or GEP class 1 tumor, versus 45.0 % for those with a GEP class 2 tumor (log rank P = 0.005)., Conclusion: This study confirmed that GEP classification of posterior uveal melanoma cells obtained by FNAB is feasible in almost all cases, including most in which FNAB yields an insufficient aspirate for cytodiagnosis. The study also confirmed that GEP classification is substantially better than cytologic classification for predicting subsequent metastasis and metastatic death.

Purpose: To identify modifying factors and dose-/volume-response relationships for the retina and optic nerve related to highly conformal hypofractionated radiotherapy., Patients and Methods: Seventy-three patients undergoing hypofractionated stereotactic photon radiotherapy of choroidal melanoma were included in this retrospective study. The volumes of the optic nerve receiving doses of more than 7.5 or 12 Gy, respectively, were defined. Optic nerve circumference included in the 30%, 40%, 50%, or 80% isodose (ON%) and retina included in 30% or 40% were determined as quantal effects. Univariate and multivariate analyses were performed for clinical variables as well as probit analysis to define EDx (doses where a positive response is expected in x% of the cases)., Results: Median follow-up was 90.0 (interquartile range 69.0-98.0) months. Fifty-two (71%) and 49 (67%) patients developed radiation retinopathy and optic neuropathy (any grade). Age, length of follow-up and diabetes were significant parameters regarding retinopathy. Optic neuropathy was significantly influenced by age, length of follow-up, and ON30. The probability of optic neuropathy (any grade and grade ≥ 2) significantly increases with the dose (p ranges from 0.0126 to 0.0211)., Conclusion: Treatment planning should aim at minimizing encompassing isodoses particularly in the low dose region, without compromising PTV coverage., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To refine the anatomic classification and staging of ciliary body and choroidal melanomas in the TNM classification., Patients and Methods: Tumor largest basal diameter and thickness of 7,369 patients were analyzed based on registry data from five ocular oncology centers. T categories were derived empirically by dividing data into blocks representing 3- × 3-mm fractions. Blocks with similar survival were grouped together so that no T category comprised a large majority of tumors, and each was uniform in survival, using randomly drawn 60% building and 40% validation data sets. Presence of ciliary body involvement (CBI) and extraocular extension (EXE) was analyzed among 5,403 patients to define T subcategories. Stages were generated by iteratively combining subcategories with similar survival., Results: Of the 7,369 tumors analyzed, 24% were classified as T1, 33% as T2, 31% as T3, and 12% as T4. Ten-year Kaplan-Meier survival estimates for the T categories were 89%, 77%, 58%, and 39%, respectively (P < .001). Survival of patients in four subcategories based on presence or absence of CBI and EXE differed significantly within each T category (P = .018 for T1; P < .001 for T2 to T4). EXE exceeding 5 mm in largest diameter carried a worse prognosis than smaller extensions (P < .001) and was assigned a separate subcategory. Ten-year Kaplan-Meier survival estimates for stages I, IIA to IIB, and IIIA to IIIC were 88%, 80%, 67%, 45%, 27%, 10%, respectively (P < .001)., Conclusion: This evidence-based anatomic classification provides a basis for staging ciliary body and choroidal melanomas in the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer.

Purpose: To evaluate long-term safety and efficacy of hypofractionated stereotactic photon radiotherapy with 5 five fractions at 10 Gy each in patients with centrally located choroidal melanoma., Materials and Methods: Ninety-one patients with centrally located choroidal melanoma were treated stereotactically at a linear accelerator with 6 MV photon beams with 5 fractions at 10 Gy each. Examinations were performed at baseline and every 3 months in the first 2 years, then every 6 months until 5 years and yearly thereafter. Median follow-up was 37.8 months (IQR 19.2-49.9). They included visual acuity assessment, routine ophthalmological examinations with fundoscopy, echography for measurement of tumor dimensions, medical examinations and, if necessary, fluorescein angiography., Results: Initial tumor base diameters, height and volume were 11.20mm (IQR 9.10-13.70), 9.80 mm (IQR 7.80-11.70), 4.53 mm (IQR 3.33-6.43) and 253.8mm(3) (IQR 127.5-477.0). Local tumor control and eye retention rates were 97.7% and 86.4% after 5 years, respectively. Eight patients developed metastatic disease and 3 of them died due to metastatic disease during the follow-up period. Median visual acuity decreased from 0.67 initially to 0.05 at the last individual follow-up (p<0.001). The most common toxicities (any grade) were radiation retinopathy (n=39), optic neuropathy (n=32), radiogenic cataract (n=21), neovascular glaucoma (n=15) and dry eye syndrome (n=10). The 5 year probabilities to remain free of these side effects (any grade) were 26.0%, 45.4%, 55.4%, 72.6% and 80.5%, respectively. The most important prognostic factors for toxicities were the largest tumor base diameter, tumor height and tumor distance to the optic disk., Conclusion: Hypofractionated stereotactic photon radiotherapy with a total dose of 50 Gy delivered in 5 fractions is a highly effective treatment option in patients with centrally located choroidal melanoma and has a moderate toxicity profile., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG)., Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose of C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients., Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels., Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To evaluate outcomes in patients with posterior choroidal melanoma treated with ruthenium ((106)Ru) brachytherapy., Methods and Materials: A retrospective single institutional analysis of 83 of 94 consecutive patients who underwent (106)Ru brachytherapy was performed. Disease was mainly staged as small- and medium-sized nonmetastatic melanoma. The main parameters evaluated were tumor control (local control [LC] and progression-free survival [PFS]) and ocular preservation (enucleation-free survival [EFS]). Besides, functional evaluation was performed and complications were described., Results: The median follow-up was 39 (6-83) months. The median values of height and maximal basal diameter were 4.3 and 9.3mm, respectively. Median apical and basal doses were 100 and 307Gy, respectively. The actuarial 2-year LC, PFS, and EFS were 96.2%, 96.2%, and 95.5%, respectively. Actuarial 5-year LC, PFS, and EFS were 93.6%, 93.6%, and 84.1%, respectively. Preinsertion visual acuity (VA) maintenance was 34% (equal or better than before treatment). Approximately 56% of patients stayed with a minimum functional VA of 0.1 or more, from whom more than half stayed with 0.5 or more. Cataract was seen in 16% of treated eyes, and glaucoma was the rarest complication, with an incidence of 3%., Conclusions: Small- and medium-sized choroidal melanomas can be adequately treated with (106)Ru brachytherapy, with high rates of tumor control and ocular preservation. Moreover, acceptable incidence of complications such as glaucoma and cataract are seen, and a reasonable part of patients stay with a minimum functional VA., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Determine the mortality ratios and excess deaths associated with the two therapeutic options for both the small and the large tumor groups and for subsets of age and tumor size within each group as presented in the Collaborative Ocular Melanoma Study (COMS)., Methods: Mortality ratios and excess deaths are determined using standard mortality methodology. Expectant mortality is determined from appropriate general population life mortality tables., Results: The smaller tumor group comparing brachytherpy to enucleation revealed similar mortality ratios (MR) of 134% and 137% for each treatment approach and respective Total Excess Deaths per Thousand (Total ED/K) of 131 and 128. The larger tumor group comparing results of pre-enucleation radiation therapy (PERT) followed by enucleation to enucleatic alone revealed respective mortality ratios of 291% and 305% and Total ED/K of 520 and 547. Those over 60 years of age having a maximum basal tumor diameter (MBTD) < or = 11 mm had MR = 101% and Total ED/K = 26, the best mortality experience in the study. Those over 60 years of age had better relative mortality, depending on the MBTD, when compared to the younger group., Conclusions: Mortality associated with ocular melanoma does not vary according to whether brachytherapy (smaller melanomas) or PERT followed by enucleation (larger melanomas) is used vs simple enucleation. Mortality increases as the MBTD increases.

Objective: To determine the long-term safety of pars plana vitrectomy (PPV) in eyes with plaque-irradiated posterior uveal melanoma., Methods: In this retrospective case series, patients with plaque-irradiated posterior uveal melanoma subsequently underwent PPV for vitreous hemorrhage. The main outcome measures are the rates of intraocular melanoma dissemination, extrascleral extension of melanoma, local melanoma recurrence, and systemic melanoma metastasis after PPV., Results: Forty-seven eyes of 47 patients underwent PPV for vitreous hemorrhage after iodine 125-labeled plaque radiotherapy for choroidal melanoma. The mean interval between the onset of vitreous hemorrhage and PPV was 13 (median, 10; range, 0-52) months. The mean time from PPV to last follow-up was 5 (range, 0.5-16) years. There were no cases of intraocular melanoma dissemination or extrascleral extension of melanoma. One patient (2%) developed local choroidal melanoma recurrence (2 years after PPV and 5 years after initial plaque radiotherapy) and was successfully managed with transpupillary thermotherapy. Systemic melanoma metastasis occurred in 4 patients (9%) during a mean interval of 5 years after plaque radiotherapy. During follow-up, 43 patients (91%) were alive without systemic metastasis and 4 patients (9%) were alive with metastasis., Conclusion: Management of vitreous hemorrhage by PPV in eyes with previously irradiated uveal melanoma appears to be safe and without increased risk for intraocular, local, orbital, or systemic dissemination of the tumor.

Purpose: To report toxicity, local control, enucleation, and survival rates for patients with peripapillary choroidal melanoma treated with proton therapy in Canada., Methods and Materials: We performed a retrospective analysis of patients with peripapillary choroidal melanoma (≤ 2 mm from optic disc) treated between 1995 and 2007 at the only Canadian proton therapy facility. A prospective database was updated for follow-up information from a chart review. Descriptive and actuarial data are presented., Results: In total, 59 patients were treated. The median age was 59 years. According to the 2010 American Joint Committee on Cancer TNM classification, there were 20 T1 tumors (34%), 28 T2 tumors (48%), and 11 T3 tumors (19%). The median tumor diameter was 11.4 mm, and the median thickness was 3.5 mm. Median follow-up was 63 months. Nineteen patients received 54 cobalt gray equivalents (CGE) and forty patients received 60 CGE, each in 4 fractions. The 5-year actuarial local control rate was 91% (T1, 100%; T2, 93%; and T3, 59%) (p = 0.038). There was a suggestive relationship between local control and dose. The local control rate was 97% with 60 CGE and 83% with 54 CGE (p = 0.106). The metastasis-free survival rate was 82% and related to T stage (T1, 94%; T2, 84%; and T3, 47%) (p < 0.001). Twelve patients died, including eleven with metastases. The 5-year actuarial rate of neovascular glaucoma was 31% (23% for T1-T2 and 68% for T3, p < 0.001), and that of enucleation was 0% for T1, 14% for T2, and 72% for T3 (p < 0.001). Radiation retinopathy (74%) and optic neuropathy (64%) were common within-field effects., Conclusions: Proton therapy provides excellent local control with acceptable toxicity while conserving the globe in 80% of cases. These results are consistent with other single-institution series using proton radiotherapy, and toxicity rates were acceptable. T3 tumors carry a higher rate of both local recurrence and metastasis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the outcome of children with different degrees of choroidal invasion, to compare different systems for grading the extent of choroidal invasion, and to assess the role of concomitant prelaminar optic nerve and anterior segment invasion as predictors of extraocular relapse., Design: Retrospective analysis of children included in 4 prospective protocols (January 1, 1989, through June 31, 2010). Children with postlaminar optic nerve or scleral involvement and overt extraocular disease were excluded. Adjuvant chemotherapy was not scheduled. All slides were reviewed, and massive involvement was classified according to 3 definitions: (1) extending at least 3 mm in any dimension, (2) through the choroid's whole thickness, and (3) more than 50% of the thickness and/or more than 1 cluster., Results: One hundred sixty-seven children (35 with massive invasion) were studied (136 did not receive adjuvant therapy). The probability of 5-year event-free survival was 98.1% and the probability of overall survival was 98.7% because 1 patient relapsed. Children with massive invasion had a significantly lower event-free survival probability (94.2%) compared with those with focal invasion (99.2%) (P = .04). However, no significant difference was found in overall survival probability (98.7% vs 99.2%; P = .29). No significant effect of other risk factors was found., Conclusions: Survival was excellent without adjuvant therapy, and no other factors correlated with survival. Children with massive invasion have a higher relapse rate but comparable survival to those with focal invasion provided that aggressive therapy for extraocular relapse is available with adequate safety conditions.

Purpose: To evaluate survival and clinical outcome for patients with a large uveal melanoma treated by either enucleation or proton beam radiotherapy (PBRT)., Procedures: This retrospective non-randomized study evaluated 132 consecutive patients with T3 and T4 choroidal melanoma classified according to TNM stage grouping., Results: Cumulative all-cause mortality, melanoma-related mortality and metastasis-free survival were not statistically different between the two groups (log-rank test, p = 0.56, p = 0.99 and p = 0.25, respectively). Eye retention of the tumours treated with PBRT at 5 years was 74% (SD 6.2%). In these patients at diagnosis, 73% of eyes had a best-corrected visual acuity (BCVA) of 0.1 or better. After 12 and 60 months, BCVA of 0.1 or better was observed in 47.5 and 32%, respectively., Conclusion and Message: Although enucleation is the most common primary treatment for large uveal melanomas, PBRT is an eye-preserving option that may be considered for some patients., (Copyright © 2012 S. Karger AG, Basel.)

Purposes: To determine the relationship between immunohistochemical reactivity to osteopontin, vimentin, keratin 8/18, LZTS1, and beta-catenin and clinical and histopathological prognostic factors for metastasis and death in archival specimens of primary uveal melanomas, and the prognostic value of the evaluated study variables for death from metastasis., Methods: Retrospective analysis of clinical records and formalin-fixed, paraffin-embedded slides of primary uveal melanomas treated by enucleation during May 1 1999, through June 30 2009. Immunofluorescent staining of each tumor was assessed on newly prepared histologic slides after the application of antibodies directed against five biomarkers associated with unfavorable prognosis in uveal melanoma., Results: After exclusions, our study group consisted of 82 cases. Immunofluorescence was observed in 40.2% of specimens evaluated for keratin, 50.0% evaluated for osteopontin, 26.8% evaluated for β-catenin, 65.9% evaluated for vimentin, and 70.7% evaluated for LZTS1. Through available follow-up, 27 patients (32.9%) were dead of confirmed or suspected metastatic uveal melanoma. None of the patients whose tumor exhibited strong immunoreactivity to β-catenin died of metastasis. In contrast, patients whose tumor exhibited immunoreactivity of any intensity to LZTS1 were more likely to develop metastasis. In multivariate Cox proportional hazards modeling, a composite variable that took into account the immunostaining for both β-catenin and LZTS1 had a statistically significant relationship with patient's survival time., Conclusions: Our study suggests that conventional clinical and histopathological prognostic factors, and immunoexpression of β-catenin and LZTS1 combined may allow better prognostication of metastasis than clinical and histomorphological factors alone.

Purpose: To report our experience with linear accelerator-based stereotactic fractionated radiotherapy in the treatment of juxtapapillary choroidal melanoma., Methods and Materials: We performed a retrospective review of 50 consecutive patients diagnosed with juxtapapillary choroidal melanoma and treated with linear accelerator-based stereotactic fractionated radiotherapy between April 2003 and December 2009. Patients with small to medium sized lesions (Collaborative Ocular Melanoma Study classification) located within 2 mm of the optic disc were included. The prescribed radiation dose was 60 Gy in 10 fractions. The primary endpoints included local control, enucleation-free survival, and complication rates., Results: The median follow-up was 29 months (range, 1-77 months). There were 31 males and 29 females, with a median age of 69 years (range, 30-92 years). Eighty-four percent of the patients had medium sized lesions, and 16% of patients had small sized lesions. There were four cases of local progression (8%) and three enucleations (6%). Actuarial local control rates at 2 and 5 years were 93% and 86%, respectively. Actuarial enucleation-free survival rates at 2 and 5 years were 94% and 84%, respectively. Actuarial complication rates at 2 and 5 years were 33% and 88%, respectively, for radiation-induced retinopathy; 9.3% and 46.9%, respectively, for dry eye; 12% and 53%, respectively, for cataract; 30% and 90%, respectively, for visual loss [Snellen acuity (decimal equivalent), <0.1]; 11% and 54%, respectively, for optic neuropathy; and 18% and 38%, respectively, for neovascular glaucoma., Conclusions: Linear accelerator-based stereotactic fractionated radiotherapy using 60 Gy in 10 fractions is safe and has an acceptable toxicity profile. It has been shown to be an effective noninvasive treatment for juxtapapillary choroidal melanomas., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate long-term local tumor control, visual acuity, and survival after hypofractionated linear accelerator-based stereotactic photon radiotherapy in patients with choroidal melanoma., Methods and Materials: Between 1997 and 2007, 212 patients with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated stereotactically at a linear accelerator with 6-MV photon beams at the Medical University of Vienna in five fractions over 7 days. Twenty-four patients received a total dose of 70 Gy (five fractions of 14 Gy), 158 a total dose of 60 Gy (five fractions of 12 Gy) and 30 patients a total dose of 50 Gy (five fractions of 10 Gy) applied on the 80% isodose. Ophthalmologic examinations were performed at baseline and every 3 months in the first 2 years, every 6 months until 5 years, and once a year thereafter until 10 years after radiotherapy. Assessment of visual acuity, routine ophthalmologic examinations, and measurement of tumor base dimension and height using standardized A-scan and B-scan echography were done at each visit. Funduscopy and fluorescein angiography were done when necessary to document tumor response., Results: Median tumor height and volume decreased from 4.8 mm and 270.7 mm3 at baseline to 2.6 mm and 86.6 mm3 at the last individual follow-up, respectively (p<0.001, p<0.001). Median visual acuity decreased from 0.55 at baseline to hand motion at the last individual follow-up (p<0.001). Local tumor control was 95.9% after 5 years and 92.6% after 10 years. Thirty-two patients developed metastatic disease, and 22 of these patients died during the follow-up period., Conclusion: Hypofractionated stereotactic photon radiotherapy with 70 to 50 Gy delivered in five fractions in 7 days is sufficient to achieve excellent local tumor control in patients with malignant melanoma of the choroid. Disease outcome and vision are comparable to those achieved with proton beam radiotherapy. Decreasing the total dose below 60 Gy seems to be possible., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Gefitinib is an inhibitor of the epidermal growth factor receptor, which is frequently expressed on both choroidal and nonchoroidal melanoma cells. We evaluated the clinical efficacy of gefitinib in patients with metastatic melanoma. Patients with stage IV or unresectable stage III melanoma and Zubrod performance status of less than or equal to 2 were eligible. Previous systemic treatment for metastatic disease was required. The dose of oral gefitinib was 250 mg administered daily, and tumor response was evaluated every 6 weeks. Forty-six patients with nonchoroidal melanoma and six with choroidal melanoma were treated, and 48 were evaluable for response. The median age was 62.5 years. Forty-one patients (79%) had stage M1c disease. There were no drug-related grade 4 or 5 adverse events, and fatigue was the only grade 3 adverse event that occurred in more than 5% of patients. Two patients (4%) had partial responses and 13 patients (27%) had disease stabilization. The two responders had a median duration of response of 10.9 months. The median overall progression-free survival was 1.4 months and the median overall survival was 9.7 months. Among the patients with sufficient tissues obtained before and 6 weeks after starting gefitinib administration, there were no notable trends in the changes of the tumoral expression of p-ERK1/2, p-AKT, PAK1, and serum levels of vascular endothelial growth factor or IL-8 with treatment. We concluded that gefitinib was well tolerated but had minimal clinical efficacy as a single-agent therapy for unselected patients with metastatic melanoma.

Objective: To evaluate the clinical presentation, tumor characteristics, and response to palladium 103 plaque radiation therapy for subfoveal choroidal melanomas., Methods: Retrospective case series of 50 patients diagnosed as having subfoveal melanoma and treated with plaque brachytherapy. Patients underwent evaluation for tumor characteristics, visual acuity, radiation damage, local tumor control, and metastatic disease., Results: Patients were followed up for a median of 54 (SD, 49.3) months. Forty-nine tumors (98%) were dome shaped. Subretinal fluid (overlying or a dependent exudative retinal detachment) was evident in 34 of 45 patients (76%). Treatment involved an apical radiation dose of 82.8 Gy (delivered across 5-7 days), resulting in a mean dose of 157.7 Gy to the fovea. Pretreatment median visual acuity was 20/50, which declined to 20/180 at last follow-up. Visual acuity was better than 20/200 in 33 patients (66%) at baseline and 25 (50%) at last follow-up; 13 patients (26%) lost 6 or more lines of vision. Twenty-eight patients (56%) developed radiation retinopathy; 16 (32%) required secondary intervention for radiation retinopathy, including intravitreal antivascular endothelial growth factor therapy, laser treatment, cryotherapy, or pars plana vitrectomy. The local tumor control rate of subfoveal tumors was 92%. Four patients (8%) required secondary enucleation. Metastasis developed in 2 patients (4%)., Conclusions: Subfoveal choroidal melanomas in this series are almost exclusively dome shaped and likely to have an associated exudative retinal detachment. They are amenable to plaque radiation therapy. However, this tumor location is associated with a high incidence of radiation maculopathy and a low incidence of radiation cataract.

Purpose: To evaluate treatment of juxtapapillary choroidal melanoma with plaque radiotherapy and to investigate the role of supplemental transpupillary thermotherapy (TTT)., Design: Retrospective, comparative case series., Participants: We included 650 consecutive eyes with juxtapapillary choroidal melanoma within 1 mm of the optic disc., Methods: Eyes with juxtapapillary choroidal melanoma receiving plaque radiotherapy over a 31-year period from October 1974 to November 2005 were included in the study. The TTT and no TTT groups were analyzed separately and compared., Main Outcome Measures: Local tumor control, metastasis, and tumor-related mortality., Results: The median basal tumor diameter was 10 mm (range, 1.5-21) and median thickness was 3.5 mm (range, 0.5-14.8). In 481 eyes (74%), the tumor was directly adjacent to the optic disc and in 169 eyes (26%) the posterior tumor margin was between 0.1 and 1.0 mm from the optic disc. The circumpapillary extent of the tumor was <4 clock-hours in 321 eyes (50%), 4-8 clock-hours in 250 eyes (38%), and >8 clock-hours in 79 eyes (12%). Plaque radiotherapy using iodine-125 in 616 eyes (95%), cobalt-60 in 19 eyes (3%), iridium-192 in 12 eyes (2%), and ruthenium-106 in 3 eyes (<1%) delivered a median radiation dose of 8000 cGy (range, 3600-15 500) to the tumor apex and adjunctive TTT was used in 307 eyes (56%). Kaplan-Meier estimates for tumor recurrence, metastasis, and death were 14%, 11%, and 4% at 5 years and 21%, 24%, and 9% at 10 years, respectively. Eyes treated with additional TTT showed slight (statistically nonsignificant) reduction in recurrence and metastasis. Using multivariable analysis, factors predictive of tumor recurrence included foveolar tumor requiring TTT (hazard ratio, 5.07; P<0.001) and greater tumor thickness (hazard ratio, 1.29 per mm increase; P<0.001). Factors predictive of metastasis included greater tumor base (hazard ratio, 1.21 per mm increase; P<0.001) and increasing intraocular pressure (hazard ratio, 1.11 per mmHg increase; P = 0.020)., Conclusions: Plaque radiotherapy for juxtapapillary melanoma provides local tumor control in approximately 80% of eyes at 10 years. In subjects who received TTT, there was slight but nonsignificant improved local tumor control and lower metastatic rate., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)