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Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group., Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates., Results: The mean age at diagnosis was 17 years (range 5.0-24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018)., Conclusions: We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

Purpose: Uveal melanoma (UM) has a high propensity to metastasize. Prognosis is associated with specific driver mutations and copy number variations (CNVs), but limited primary tumor tissue is available for molecular characterization due to eye-sparing irradiation treatment. This study aimed to assess the rise in circulating tumor DNA (ctDNA) levels in UM and evaluate its efficacy for CNV-profiling of patients with UM., Methods: In a pilot study, we assessed ctDNA levels in the blood of patients with UM (n = 18) at various time points, including the time of diagnosis (n = 13), during fractionated stereotactic radiotherapy (fSRT) treatment (n = 6), and upon detection of metastatic disease (n = 13). Shallow whole-genome sequencing (sWGS) combined with in silico size-selection was used to identify prognostically relevant CNVs in patients with UM (n = 26) from peripheral blood retrieved at the time of diagnosis (n = 9), during fSRT (n = 5), during post-treatment follow-up (n = 4), metastasis detection (n = 6), and metastasis follow-up (n = 4)., Results: A total of 34 patients had blood analyzed for ctDNA detection (n = 18) and/or CNV analysis (n = 26) at various time points. At the time of diagnosis, 5 of 13 patients (38%) had detectable ctDNA (median = 0 copies/mL). Upon detection of metastatic disease, ctDNA was detected in 10 of 13 patients (77%) and showed increased ctDNA levels (median = 24 copies/mL, P < 0.01). Among the six patients analyzed during fSRT, three (50%) patients had detectable ctDNA at baseline and three of six (50%) patients had undetectable levels of ctDNA. During the fSRT regimen, ctDNA levels remained unchanged (P > 0.05). The ctDNA fractions were undetectable to low in localized disease, and sWGS did not elucidate chromosome 3 status from blood samples. However, in 7 of 10 (70%) patients with metastases, the detection of chromosome 3 loss corresponded to the high metastatic-risk class., Conclusions: The rise in ctDNA levels observed in patients with UM harboring metastases suggests its potential utility for CNV profiling. These findings highlight the potential of using ctDNA for metastasis detection and patient inclusion in therapeutic studies targeting metastatic UM.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma," addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's well-being. This review highlights the meeting's presentations in the context of the published literature., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Current standard treatment procedures for Ruthenium-106 (Ru-106) brachytherapy for choroidal melanomas do not use 3D image-guided treatment planning. We evaluated the potential impact of introducing 3D treatment planning and quantified the theoretical clinical benefits in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP)., Materials and Methods: Treatment plans for thirty-two patients were optimized using 3D image-guided treatment planning and compared to the original 2D clinical plans. Optimization of plans was done in an image-based treatment planning system by optimizing the plaque position and treatment time such that the entire tumour received the prescribed dose of 100 Gy. TCP and NTCP for 2D clinical plans and optimized 3D image-guided plans were estimated from published outcome prediction models and compared within patients using Wilcoxon signed-rank test., Results: The median minimum tumour dose (D 99% ) for 2D clinical plans was 93 Gy (range: 23-158 Gy), corresponding to 5-year TCP of 75% (IQR 61-86%), while median tumour D 99% for optimized 3D image-guided plans was 115 Gy (range 103-141 Gy), corresponding to TCP of 82% (IQR 80-84%). This was a statistically significant increase in estimated TCP (median increase in TCP 8% (IQR: -5-23, p = 0.006). While the dose to normal tissue increased somewhat, there was no significant change in NTCP., Conclusion: 3D treatment planning theoretically allows for improved tumour dose delivery for Ru-106 brachytherapy of choroidal melanomas, resulting in a significant increase in expected tumour control compared to traditional approaches using 2D calculations. The deliverability of optimized plans, and potential increased risk of late complications, will have to be confirmed in future clinical studies., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT)., Design: Retrospective study from single, large referral center., Participants: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients., Methods: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes., Main Outcome Measures: Dose-response relationship for VA deterioration and late complications., Results: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland., Conclusions: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures., (Copyright © 2020 American Academy of Ophthalmology. All rights reserved.)

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this. Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D 99% ) as primary dose metric. Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D 99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence ( p  < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D 99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D 1-99% showed D 99% to be the most significant dose metric for local recurrence. Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

Purpose: The use of planar ultra-widefield fundus photography (UWF) may result in distortions and inaccurate measurement. The aim of the study was to evaluate the accuracy of UWF instead of the standard narrow field (SF) for the treatment planning phase of ocular tumours., Methods: Distortions between conformal SF and UWF were assessed in 43 patients with choroidal melanoma treated with either proton therapy or brachytherapy. imagej software was used to measure distortion., Results: The median interquartile range ([IQR]) distortion for all cases was 3.7% [1.7-10.8]. For cases with tumours within 6 mm of the optic disc, distortions appeared clinically nonsignificant. For peripheral and/or large tumours, significantly larger distortions were observed on UWF (median 4.4% [2.7-22.6] for tumours ≥6 mm from the optic disc versus 3.3% [1.6-9.9] for those <6 mm, p = 0.04). Images can be subdivided into three groups: minimal distortion (79.1% of eyes), similar level of major distortion for both measured distances (11.6%) and distortion with unequal level of distortion between the measured distances (9.3%)., Conclusion: Distortions with UWF appeared minimal in posterior regions of the fundus and increased with the distance from the posterior pole. UWF could therefore be used for treatment planning of ocular tumours as the planned radiation dose to the macula and optic disc are not impacted., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye. Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients. We observed previously unknown driver mutations and established the order in which these and known driver mutations undergo selection. Metastases had genomic alterations distinct from their primary tumors; metastatic dissemination sometimes occurred early during the development of the primary tumor. Our study offers new insights into the genetics and evolution of this melanoma subtype, providing potential biomarkers for progression and therapy.

Purpose: Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma., Design: Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries., Participants: All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016., Methods: For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks., Main Outcome Measures: All-cause and melanoma-specific mortality., Results: Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size (P < 0.001) and younger age (P < 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89-1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89-1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients., Conclusions: All-cause and melanoma-specific mortality after primary treatment were similar among biopsied and nonbiopsied patients with posterior uveal melanoma. Our findings do not support an increased metastatic risk after intraocular tumor biopsy., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The American Joint Committee on Cancer (AJCC) staging system has been validated for use as a prognostic parameter in uveal melanoma (UM). We studied whether adding information regarding chromosome 3 and 8q status further enhances the prognostic value of this staging system., Methods: We retrospectively studied a cohort of 522 patients who had been treated for UM in two different centers between 1999 and 2015. The mean follow-up time was 47.7 months. Cumulative incidence curves were generated and regression analyses were performed for different combinations of AJCC staging and chromosome status. Death due to UM metastases was the primary endpoint., Results: In AJCC stage I cases, only patients with monosomy 3 as well as chromosome 8q gain died due to UM metastases (P < 0.001). Among patients with stage II and III tumors, those with monosomy 3 plus gain of chromosome 8q had the worst prognosis, whereas the clinical outcome of those with only one of these aberrations was intermediate (P < 0.001). Patients without monosomy 3 and 8q gain showed favorable prognosis, independent of their tumor's AJCC stage. In cases with monosomy 3, 8q gain, or both, adding AJCC stage improved the predictive value. Multivariable regression analyses demonstrated that AJCC staging and chromosome 3 and 8q status contain independent information about survival status., Conclusions: Combining information on AJCC staging and chromosome 3 and 8q status allows a more accurate prognostication in UM. We conclude that the prognostic value of the AJCC staging system can be improved by adding information regarding chromosome 3 and 8q status.

Purpose: To compare the status of chromosomes 3 and 8 in 25-gauge transvitreal retinochoroidal (TVRC) biopsy specimens and enucleated eyes in order to evaluate for genetic heterogeneity and the utility of TVRC biopsy to obtain an adequate sampling of the tumor., Methods: Genetic heterogeneity was evaluated in 27 patients treated at Rigshospitalet between 2009 and 2013. The TVRC biopsy was performed to confirm diagnosis prior to enucleation and was subsequently analyzed using two techniques for chromosomes 1p, 3, 6, and 8: Fluorescence in situ hybridization (FISH) in all patients, and multiplex ligation-dependent probe amplification (MLPA) in 16 patients. Biopsies were compared with histological sections from matched enucleated eyes, which were microdissected following a hexagonal grid and analyzed with MLPA., Results: Twenty-four tumors were available for analysis. The TVRC biopsy identified chromosome 3 aberrations with MLPA in all cases (sensitivity = 100%), while FISH missed two cases (sensitivity = 89%). Conversely, FISH analysis demonstrated polyploidy of chromosome 3 in three additional cases missed by MLPA. Chromosome 8 aberrations were detected in 75% of cases with MLPA and 68% of cases with FISH. Heterogeneity of chromosomes 3 and 8 was shown in 3 (13%) and 11 tumors (46%), respectively, with an increased frequency of genetic aberrations toward the base of the tumor (P = 0.049). The study showed no difference in tumor size between heterogeneous and homogenous melanomas (P = 0.82)., Conclusions: Regardless of genetic heterogeneity, the TVRC biopsy identified all patients with a high risk of developing metastatic disease when a combination of chromosome 3 and 8 status was assessed.

Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

Purpose: To evaluate the prognostic effect of a combination of American Joint Committee on Cancer (AJCC) staging (7th edition) and genetic status in patients with posterior uveal melanoma., Methods: A consecutive cohort of 153 patients with posterior uveal melanoma treated at Copenhagen University Hospital from January 1, 2009 through December 31, 2012 was followed until October 2014. Survival, AJCC stage, and cytogenetic data were registered. The AJCC stage was available for all patients, and cytogenetic information for chromosomes 3 and 8 was available for 139 patients. The individual and joint prognostic effects of AJCC staging and cytogenetic changes were evaluated by cumulative incidence curves and Cox proportional hazard models., Results: An overall 5-year survival rate of 62% (95% confidence interval [CI]: 0.50-0.73) was observed. A normal genetic status of chromosomes 3 and 8, as found in 42 patients (30%), minimized the additional prognostic effect of AJCC staging. The frequency of tumors with normal genetic status decreased with increasing AJCC stage. Both AJCC stage III (hazard ratio [HR]: 11.0, 95% CI: 1.4-85.6) and abnormal copy number of chromosomes 3 (HR: 6.3, 95% CI: 1.4-28.3) and 8 (HR: 2.8, 95% CI: 1.03-7.8) were identified as significant predictors of a poor prognosis in the multivariate Cox regression analysis., Conclusions: Identification of a normal genetic status of chromosomes 3 and 8 minimized the prognostic effect of AJCC staging, while a combination of genetic status and AJCC staging provided the most accurate prediction of survival in patients with an abnormal chromosomal status., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To determine the association of microRNA expression and chromosomal changes with metastasis and survival in uveal melanoma (UM)., Methods: Thirty-six patients with UM were selected based on the metastatic status, and clinicopathological data were collected. Multiplex ligation-dependent probe amplification (MLPA) was used to identify chromosomal changes. Chromosomal changes and clinicopathological data were correlated with survival and metastasis. The microRNA expression was analysed in 26 of the 36 archived UM samples. Unsupervised analysis, differential expression analysis and Cox regression analysis were performed to determine the association with metastasis and survival., Results: Metastasis and metastatic death occurred in 20 patients, two patients died of other causes and one patient of unknown causes. A significant association between increasing size category (p = 0.002, log-rank), extraocular extension (p = 0.001), chromosome 3 loss (p = 0.033) and 1p loss (p = 0.030) and development of metastases was observed. Tumour, node, metastasis (TNM) staging showed a significant association with survival (p < 0.0001, log-rank). Adjusting for gender and age TNM size category T4 (p = 0.016, Cox regression analysis), mixed (p = 0.029) and epithelioid (p = 0.0058) cell types, chromosome 3 loss (p = 0.014) and 8q gain (p = 0.010) were significant prognosticators for a poor survival. Hierarchical clustering divided the UM into three groups based on microRNA expression. The clusters showed no association with clinical or histopathological features, TNM staging, metastasis or survival. Differential expression analysis did not reveal microRNAs related to metastasis or survival., Conclusions: The prognostic significance of chromosome 3 loss and 8q gain identified by MLPA analysis was confirmed in archived UM samples. The value of microRNA expression as a predictor of metastasis and survival in UM could not be confirmed., (© 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: To determine the applicability and ocular morbidity of the 25-gauge transvitreal retinochoroidal biopsy technique in the management of intraocular tumors., Design: Retrospective, consecutive, observational, single-surgeon case series., Participants: A total of 124 biopsies were performed in 123 patients with intraocular tumors in the posterior segment from January 1, 2009, through December 31, 2011., Methods: The biopsies were performed under general anesthesia with standard 25-gauge vitrectomy equipment. The vitreous body and the retinotomies were left untreated with the exception of 1 patient in whom a complete vitrectomy and oil tamponade were performed. Histopathologic examination of all samples was performed and cytogenetic testing with fluorescence in situ hybridization and multiplex ligation-dependent probe amplification were performed in the uveal melanomas. Median follow-up time was 26.3 months (range, 2.0-47.2 months)., Main Outcome Measures: Histopathologic diagnosis and chromosome 3 analysis of the biopsy-obtained tissue sample. Clinical observations included visual acuity, retinal detachment, vitreous hemorrhage, and secondary enucleation., Results: Histopathologic diagnosis was obtained in 97.6% (n = 121) of the intraocular tumors, and chromosome 3 status could be determined in 97.3% (n = 110) of uveal melanoma patients. Preoperative retinal detachment was present in 65% (n = 55). Apart from in 1 case, all retinal detachments remained stable during surgery. Additionally, 7.1% (n = 6) of cases demonstrated retinal detachment during the follow-up period, and vitreous hemorrhage was observed in 96.5% of cases (n = 82) 1 day after surgery. Both conditions regressed spontaneously in nearly all cases. Retinal detachment surgery and vitrectomy resulting from persistent vitreous hemorrhage was performed in 3.5% (n = 3) and 5.9% (n = 5) of patients, respectively. The frequency of secondary enucleated eyes was 6.7% (n = 5). Free tumor cells after biopsy were described in 15.9% (n = 7), but no tumor recurrence at the sclerotomy sites was observed. A decrease in visual acuity from better than 0.1 (20/200) at diagnosis to 0.1 or worse at 1 and 3 years of follow-up was observed in 21.7% (n = 13) and 41.7% (n = 5) of patients, respectively., Conclusions: The 25-gauge transvitreal retinochoroidal biopsy provides a large sample, adequate for histopathologic examination and cytogenetic analysis. The procedure is associated with a low risk of ocular complications., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose To determine the association of micro RNA expression and chromosomal changes with metastasis and survival in uveal melanoma ( UM). Methods Thirty-six patients with UM were selected based on the metastatic status, and clinicopathological data were collected. Multiplex ligation-dependent probe amplification ( MLPA) was used to identify chromosomal changes. Chromosomal changes and clinicopathological data were correlated with survival and metastasis. The micro RNA expression was analysed in 26 of the 36 archived UM samples. Unsupervised analysis, differential expression analysis and Cox regression analysis were performed to determine the association with metastasis and survival. Results Metastasis and metastatic death occurred in 20 patients, two patients died of other causes and one patient of unknown causes. A significant association between increasing size category (p = 0.002, log-rank), extraocular extension (p = 0.001), chromosome 3 loss (p = 0.033) and 1p loss (p = 0.030) and development of metastases was observed. Tumour, node, metastasis ( TNM) staging showed a significant association with survival (p < 0.0001, log-rank). Adjusting for gender and age TNM size category T4 (p = 0.016, Cox regression analysis), mixed (p = 0.029) and epithelioid (p = 0.0058) cell types, chromosome 3 loss (p = 0.014) and 8q gain (p = 0.010) were significant prognosticators for a poor survival. Hierarchical clustering divided the UM into three groups based on micro RNA expression. The clusters showed no association with clinical or histopathological features, TNM staging, metastasis or survival. Differential expression analysis did not reveal micro RNAs related to metastasis or survival. Conclusions The prognostic significance of chromosome 3 loss and 8q gain identified by MLPA analysis was confirmed in archived UM samples. The value of micro RNA expression as a predictor of metastasis and survival in UM could not be confirmed. [ABSTRACT FROM AUTHOR]

Ruthenium-106 (Ru-106) brachytherapy is an established modality for eye-preserving treatment of choroidal melanoma. To achieve optimal treatment outcomes, there should be a balance between tumour control and the risk of healthy tissue toxicity. In this retrospective study, we examined normal tissue complication probability (NTCP) for visual acuity deterioration and late complications to aid the understanding of dose-dependence after Ru-106 treatments. We considered consecutive patients diagnosed with choroidal melanoma and primarily treated at a single institution from 2005–2014. Treatment plans were retrospectively recreated using dedicated software and image guidance to contour the tumour and determine the actual plaque position. Dose distributions were extracted from each plan for all relevant anatomical structures. We considered visual acuity deterioration and late complications (maculopathy, optic neuropathy, ocular hypertension, vascular obliteration, cataract and retinal detachment). Lasso statistics were used to select the most important variables for each analysis. Outcomes were related to dose and clinical characteristics using multivariate Cox regressions analysis. In total, 227 patients were considered and 226 of those were eligible for analysis. Median potential follow-up time was 5.0 years (95% CI: 4.5–6.0). Visual acuity deterioration was related to optic disc-tumour distance and dose metrics from the retina and the macula, with retina V10Gy showing the strongest correlation. Macula V10Gy was the only dose metric impacting risk of maculopathy, while optic disc-tumour distance also proved important. Optic disc V50Gy had the largest impact on optic neuropathy along with optic disc-tumour distance. Optic disc V20Gy was the only variable associated with vascular obliteration. Lens D2% had the largest impact on the risk of cataract along with older age and the largest base dimension. We found no variables associated with the risk of ocular hypertension and retinal detachment. Visual acuity deterioration and most late complications demonstrated dependence on dose delivered to healthy structures in the eye after Ru-106 brachytherapy for choroidal melanomas. [ABSTRACT FROM AUTHOR]

Increased disease-specific mortality has been observed among patients with local recurrence (LR) from uveal melanoma (UM), but the underlying mechanism is unknown. The purpose of this study was to determine if copy number alterations of chromosomes 3 and/or 8q, at the time of diagnosis, increase the incidence of LR and if disease-specific mortality among patients with LR depends on the chromosome status of the primary tumor. Retrospective cohort study. The study included 239 consecutive patients with primary UM (choroidal or ciliary body) treated with Ruthenium-106 (Ru-106) brachytherapy from January 2009 to December 2019 at a single national referral center. Cox regression modeling and Kaplan–Meier analyses were used to assess the effect of the status of chromosomes 3 and 8q on the incidence of LR and disease-specific mortality after the event of LR. Multistate models were used to illustrate the probabilities over time of patients being alive and disease-free, alive with LR, dead from UM metastases, or dead from other causes split on the status of chromosomes 3 and 8q. Incidence of LR and disease-specific mortality. Local recurrence was observed in 42 patients (16%). Overall incidence of LR was not affected by aberrations of chromosomes 3 and/or 8q (P = 0.87). Although LR occurred earlier in patients with aberrations of chromosomes 3 and/or 8q compared with patients with a normal copy number of chromosomes 3 and 8q, the median time from primary diagnosis to LR was 1.6 years (interquartile range [IQR], 1.0–2.0) and 3.2 years (IQR, 2.1–5.0), respectively. Cox regression found LR to be an independent risk factor for disease-specific mortality (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5–5.0) among all patients, but multistate models demonstrated a low risk of disease-specific death among patients with normal chromosomes 3 and 8q status, even after an LR. Copy number alterations of chromosome 3 and/or 8q in the primary UM did not increase the overall incidence of LR. However, the development of an LR enhanced the risk of disease-specific mortality among patients with copy number alterations of chromosomes 3 and/or 8q. Even after an LR, disease-specific mortality remained low among patients with normal copy numbers of chromosomes 3 and 8q. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]