The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

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%).

Additional malignancies and mortality in uveal melanoma: A 20-year follow-up of a Norwegian patient cohort.

PURPOSE: The purpose of this study is to explore the frequency of additional primary malignancies in uveal melanoma (UM) patients and cause-specific mortality, to help guide surveillance strategies after UM. METHODS: All patients diagnosed with UM at Oslo University Hospital during 1990-2017 were eligible for inclusion. Linkage to the Cancer Registry of Norway obtained information on additional malignancies and cause of death throughout 2019. UM patients were categorized according to timing of additional malignancy (prior/simultaneously or after UM) or no additional cancer, and by UM stage at diagnosis. Age-adjusted mortality rates were presented per 1000 person-years with 95% confidence intervals (CI). RESULTS: The study population included 960 UM patients: 77% were diagnosed in stage and I/II and 56% were men. Mean age at diagnosis was 63 years. Additional malignancies were observed in 152 patients prior/simultaneous to UM, and in 120 patients >1 year after UM. Overall, mortality per 1000 person-years was 3.5 (95% CI 3.1-3.9) for UM and 3.0 (2.6-3.4) for other causes. Lowest UM mortality [1.3 (0.60-2.1)] was seen in patients with a second malignancy after UM, regardless of stage. Highest UM mortality was seen for UM patients in stage III/IV, both without [16.1 (13.2-19.1)] and with any additional malignancy [16.9 (6.6-27.3)]. CONCLUSION: Our results support that UM patients frequently have additional malignancies, both before and after UM. Low-UM mortality in patients with a primary malignancy after UM, might indicate less aggressive UM. The cumulative UM mortality flattens about 10 years after diagnosis and annual follow-up of patients for 10 years seems adequate.

Fundus Autofluorescence Change as an Early Indicator of Treatment Effect of Brachytherapy for Choroidal Melanomas.

BACKGROUND: Early confirmation of the effect of brachytherapy for choroidal melanoma showing that tumour coverage is valuable. The irradiated retinal pigment epithelium (RPE) commonly develops atrophy. This study compares the fundus autofluorescence (AF) changes to the development of RPE atrophy following brachytherapy. METHODS: Retrospective study of 19 patients treated with 106Ru and 2 with 125I plaques with either a 3- or 6-month follow-up period. Ultra-widefield (UW) composite colour and AF images were obtained with Optomap 200Tx and interpreted as complete, partial, or no RPE changes and complete or partial hyperautofluorescence, hypoautofluorescence, or isoautofluorescence. RESULTS: At the 3-month follow-up, 9 of 13 patients (69%) (95% confidence interval [CI], 0.389-0.896) treated with 106Ru plaques developed complete homogenous hyperautofluorescence surrounding the tumour, but only 1 of 13 (8%) (95% CI, 0.004-0.379) developed complete RPE atrophy at the same time point. Six patients in the 106Ru plaque group had their first follow-up with UW imaging at 6 months. Four of them developed homogenous hyperautofluorescence and none developed complete RPE atrophy around the tumour. The 2 patients treated with 125I did not demonstrate any clear RPE or AF changes. CONCLUSION: The effect of 106Ru plaque treatment on fundus UW imaging is detected as homogenous and well-demarcated hyperautofluorescence before visible RPE atrophy.

Multicellular tumor spheroids of human uveal melanoma induce genes associated with anoikis resistance, lipogenesis, and SSXs.

PURPOSE: Uveal melanoma (UM) has a high propensity for metastatic spread, and approximately 40-50% of patients die of metastatic disease. Metastases can be found at the time of diagnosis but also several years after the tumor has been removed. The survival of disseminated cancer cells is known to be linked to anchorage independence, anoikis resistance, and an adaptive cellular metabolism. The cultivation of cancer cells as multicellular tumor spheroids (MCTS) by anchorage-independent growth enriches for a more aggressive phenotype. The present study examines the differential gene expression of adherent cell cultures, non-adherent MCTS cultures, and uncultured tumor biopsies from three patients with UM. We elucidate the biochemical differences between the culture conditions to find whether the culture of UM as non-adherent MCTS could be linked to an anchorage-independent and more aggressive phenotype, thus unravelling potential targets for treatment of UM dissemination. METHODS: The various culture conditions were evaluated with microarray analysis, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), RNAscope, immunohistochemistry (IHC), and transmission electron microscopy (TEM) followed by gene expression bioinformatics. RESULTS: The MCTS cultures displayed traits associated with anoikis resistance demonstrated by ANGPTL4 upregulation, and a shift toward a lipogenic profile by upregulation of ACOT1 (lipid metabolism), FADS1 (biosynthesis of unsaturated fatty acids), SC4MOL, DHCR7, LSS (cholesterol biosynthesis), OSBPL9 (intracellular lipid receptor), and PLIN2 (lipid storage). Additionally, the present study shows marked upregulation of synovial sarcoma X breakpoint proteins (SSXs), transcriptional repressors related to the Polycomb group (PcG) proteins that modulate epigenetic silencing of genes. CONCLUSIONS: The MCTS cultures displayed traits associated with anoikis resistance, a metabolic shift toward a lipogenic profile, and upregulation of SSXs, related to the PcG proteins.

Malignant melanoma--diagnosis, treatment and follow-up in Norway.

BACKGROUND: The incidence of malignant melanoma in Norway is among the highest in the world and rising, with approximately 1 500 persons receiving the diagnosis annually. Correct surgical primary treatment cures 80-90%, while 10-20% experience relapses. The treatment of a metastatic malignant melanoma has changed considerably in the last 1-2 years as a result of clinical experience with new drugs. The current publication provides an updated overview of the treatment of malignant melanoma in Norway. METHOD: The article is based on a search in PubMed and on the authors' own research and clinical experience. RESULTS: After several decades with almost no change in the treatment of malignant melanoma, we have seen a positive development over the past couple of years. New treatment methods for malignant melanoma with distant spreading metastases have yielded favourable results in selected patients and are currently established in cancer departments in Norway. INTERPRETATION: Rapid and correct primary treatment is curing most patients with malignant melanoma. New drugs offer hope for selected patient groups with metastatic disease. Several new types of targeted treatment are being tested in clinical studies in Norway and elsewhere in the world.

[Retinoblastoma--hereditary eye cancer in children]. / Retinoblastom--arvelig øyekreft hos barn.

BACKGROUND: Retinoblastoma is a malignant tumour of the retina that occurs in early childhood. The aim of this paper is to give an updated review of the disease. MATERIAL AND METHODS: A review is given based on literature published over the last few years and on the authors' own experience. RESULTS: The yearly incidence of retinoblastoma is approximately one per 14 000 live births, which gives four new cases of retinoblastoma per year in Norway. The only known risk factor is heritage. Symptoms of retinoblastoma are strabismus, reduced visual acuity and red eye, but the absolutely most important sign is leukokoria (white pupillary reflex). Important diagnostic tools are ophthalmoscopy, ultrasonography, CT and MRI. The goal of treatment is to destroy all tumour tissue, but not the surrounding tissue. Treatment options are enucleation, chemotherapy, external beam radiation, radioactive isotope plaques, cryotherapy, photocoagulation, or a combination of these depending upon the size and location of the tumour. INTERPRETATION: The overall results in the treatment of retinoblastoma are favourable and have improved over the last few years because of better treatment modalities. The survival rate is approximately 95%. It is important that physicians bear in mind the signs of retinoblastoma and especially the alarming sign of leukokoria and acute strabismus in a child.