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.
To determine the applicability and ocular morbidity of the 25-gauge transvitreal retinochoroidal biopsy technique in the management of intraocular tumors.
Retrospective, consecutive, observational, ...single-surgeon case series.
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.
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).
Histopathologic diagnosis and chromosome 3 analysis of the biopsy-obtained tissue sample. Clinical observations included visual acuity, retinal detachment, vitreous hemorrhage, and secondary enucleation.
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.
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.
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).
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.
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.
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.
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.
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).
Retrospective study from single, large referral center.
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.
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.
Dose-response relationship for VA deterioration and late complications.
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.
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.
To estimate the risk of developing rhegmatogenous retinal detachment (RRD) in the fellow eye in patients with RRD in the first eye and to identify potential risk factors.
We used the Danish National ...Patient Registry to identify all surgeries performed for RRD in Denmark in the period from January 2000 to July 2011.
In 11,451 cases of RRD in the study period, 8,553 cases in 8,081 patients were identified as primary RRD with an annual incidence of 13.7 per 100,000 citizens. There was a significant increase in the number of cases with RRD during the study period that was mainly explained by an increase of cataract surgeries. Four hundred and seventy-one of 7,941 patients with primary RRD on one eye and no other previous eye disease developed an additional RRD in the fellow eye with an overall incidence of 1% per year. Cox analysis revealed male gender, surgery on the lens, and young age as significant risk factors (P < 0.0001).
Patients with RRD on the first eye have a 100 times greater risk of developing RRD on the second eye, and the risk increases with male gender and surgery on the lens but decreases with age.
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.
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 (D99%) for 2D clinical plans was 93 Gy (range: 23–158 Gy), corresponding to 5‐year TCP of 75% (IQR 61–86%), while median tumour D99% 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.
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.
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.
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.
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.
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