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During routine dermatologic examination, a 77-year-old male was noted to have a firm blue subcutaneous nodule on his right lateral upper back. His past medical history included metastatic melanoma of unknown primary involving right and left axillary lymph nodes, treated with ipilimumab/nivolumab with complete response, and subsequent primary uveal melanoma. The subcutaneous nodule was located near his previous right axillary scar for metastatic melanoma. Excision of the nodule showed a plexiform neoplasm involving mid and deep dermis composed of spindle and epithelioid atypical cells admixed with numerous melanophages. Central necrosis was present. Immunohistochemical studies revealed the tumor cells to be diffusely positive for HMB45, with retained expression of BAP1 and p16. The tumor cells were negative for PRAME, nuclear expression of β-catenin, LEF1, and BRAF V600E. Molecular studies demonstrated BAP1 and GNA11 somatic mutations, a profile different from that exhibited by his prior melanoma. Collectively, these data were interpreted as a metastasis from uveal melanoma and not a recurrence of his metastatic likely cutaneous melanoma after complete response to immunotherapy. This case emphasizes the importance of molecular studies for definitive diagnosis in challenging clinical situations, especially when there is discordance among histopathological, immunohistochemical, and molecular studies. Integration of clinical, histopathological, and molecular features is warranted., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug., Methods: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival., Results: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred., Conclusions: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: To investigate clinical manifestations and prognoses in pediatric patients (≤12 years old) with ocular melanoma., Methods: This was a retrospective, multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers., Results: There were 133 eyes of 133 pediatric patients with choroidal or ciliary body (n = 66 [50%]), iris (n = 33 [25%]), conjunctival (n = 26 [19%]), and eyelid (n = 8 [6%]) melanoma. Overall, the mean patient age at presentation was 7 years (median, 8; range, 1-12 years), with 63 males (49%). The mean age by tumor site was 6.50 ± 3.90, 7.44 ± 3.57, 9.12 ± 2.61, and 5.63 ± 2.38 years, for choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively (P = 0.001). Association with ocular melanocytosis was seen in 15%, 11%, 4%, and 0%, respectively (P = 0.01). Frequency of ocular melanoma family history did not vary by tumor site (7%, 17%, 9% and 12%, resp. [P = 0.26]). After mean follow-up of 74, 85, 50, and 105 months (P = 0.65), metastasis was seen in 12%, 9%, 19%, and 13% of choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively. Death was reported in 5%, 3%, 8%, and 0%, respectively, with survival analysis indicating higher mortality in choroidal/ciliary body and conjunctival melanoma patients., Conclusions: Ocular melanoma in the pediatric population is rare, with unique clinical features and outcomes. Iris melanoma accounts for about one-third of pediatric uveal melanoma cases., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the clinical characteristics of uveal melanoma (UM) and evaluate the relationship of congenital oculocutaneous melanosis (OCM) to the prognosis of Asian patients with UM., Design: Retrospective cohort study., Participants: We included a total of 1151 Asian patients with UM who were managed at the Beijing Tongren Hospital from June 26, 2005, to July 27, 2020., Methods: I-125 plaque brachytherapy, local resection, thermotherapy, or enucleation., Main Outcome Measures: Melanoma-related metastasis and death., Results: Of 1151 Asian patients with UM, congenital OCM was present in 23 (0.20%). The melanocytosis involved the conjunctiva (78%), sclera (74%), eyelid (70%), face (26%), forehead (2.2%), iris (0.87%), choroid (0.87%), and auricle (0.4%). Univariate analysis of Cox proportional hazards regression model showed that age, tumor thickness, largest tumor basal diameter, and ciliary body involvement were the risk factors for the poor prognosis of Asian patients with UM. By multivariable analysis, the only factor predictive of melanoma-related metastasis and death was the largest tumor basal diameter (hazard ratio [HR], 1.21 [1.11-1.33], P < .001; 1.17 [1.01-1.35], P = 0.033). Probability-of-censoring weighted (IPW) estimation was used to mitigate selection bias due to loss to follow-up. Probability-of-censoring weighted estimation revealed the largest tumor basal diameter and ciliary body involvement were associated with metastasis (HR, 1.29 [1.15-1.45], P < 0.001; HR, 2.64 [1.01-6.90], P < 0.048). During the median follow-up period of 53 (33-67) months, 2 patients with OCM (8.7%) developed melanoma-related metastasis. By using nested case-control design and matched with the factors of age, largest tumor basal diameter, tumor thickness, and ciliary body involvement, Kaplan-Meier survival analysis showed that UM combined with OCM did not increase the risk of melanoma-related metastasis and death (P = 0.68, log-rank test)., Conclusions: The prominent risk for metastasis from UM was the largest tumor basal diameter in Asian patients. Estimation of IPW revealed that the largest tumor basal diameter and ciliary body involvement were the risk factors for UM metastasis. Patients with UM combined with OCM had a similar risk for metastasis compared with those with no OCM., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the clinical features and prognosis of patients with uveal metastasis in Korea., Design: Retrospective, observational case series., Participants: Patients diagnosed at 2 tertiary high-volume centers between November 2005 and November 2019., Methods: Evaluation of multimodal imaging and electronic medical records., Main Outcome Measures: The clinical features and outcomes were assessed based on the primary cancer site., Results: A total of 134 uveal metastases (128 choroidal, 3 iris, and 3 ciliary body tumors) were diagnosed in 95 eyes of 80 patients. Mean age at diagnosis was 56 years (median, 55 years; range, 24-86 years), with a minor preponderance of women (61%). Tumors were bilateral in 15 patients (19%) and the primary origin was established in 49 patients (61%) before ocular detection. The primary tumor originated in the lung (48%), breast (24%), gastrointestinal tract (10%), liver (3%), pancreas (3%), kidney (1%), cervix (1%), and nasopharynx (1%), with some remaining unknown (10%). The overall 5-year survival rate was 21%. Kaplan-Meier analysis revealed that the worst survival was found in pancreatic cancers (mean survival, 5.9 months; P = 0.045), and the best survival was found in gastrointestinal tract cancers (mean survival, 44.5 months)., Conclusions: The primary tumor origins in Korean patients with uveal metastases differed from those reported in primarily population-based studies of White patients, with a higher prevalence of lung and gastrointestinal tract cancers., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether the GNAQ/11 mutation correlated with the outcome of patients with uveal melanoma (UM) when genetic heterogeneity was considered., Methods: We performed a retrospective study of sixty-seven patients with UM. The heterogeneity of GNAQ/11 was examined by using droplet digital PCR. The correlation between metastasis and heterogeneity of the GNAQ/11 mutation was analysed. Disease free survival curves were constructed using the Kaplan-Meier method, and the Wilcoxon log-rank test was used to compare the curves., Results: The GNAQ/11 mutation ratio was varied between each case. Among these patients, 28.35% of them harboured homogeneous mutation of GNAQ/11, 62.69% present heterogeneous mutation and 8.96% didn't present either GNAQ or GNA11 mutation. The tumour with heterogeneous mutation of GNAQ/11 has a higher metastatic rate than that with homogeneous mutation (13/29 vs 1/18, p=0.027). In Kaplan-Meier analysis, metastasis-free survival was not significantly associated with either homogeneous or heterogeneous mutation of GNAQ/11., Conclusion: The mutation ratio of GNAQ/11 in UM was quite variable. The tumour with heterogeneous mutation of GNAQ/11 is more likely to develop a poor prognosis than that with homogeneous mutation of GNAQ/11., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific GNA11 , GNAQ , PLCβ4 , and CYSLTR2 mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions.

Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany., Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation., Results: Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%)., Conclusion: Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.

The current study aimed to elucidate the molecular mechanisms and identify the potential key genes and pathways for metastatic uveal melanoma (UM) using bioinformatics analysis.Gene expression microarray data from GSE39717 included 39 primary UM tissue samples and 2 metastatic UM tissue samples. Differentially expressed genes (DEGs) were generated using Gene Expression Omnibus 2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the online Database for Annotation, Visualization and Integrated Discovery (DAVID) tool. The web-based STRING tool was adopted to construct a protein--protein interaction (PPI) network. The MCODE tool in Cytoscape was used to generate significant modules of the PPI network.A total of 213 DEGs were identified. GO and KEGG analyses revealed that the upregulated genes were mainly enriched in extracellular matrix organization and blood coagulation cascades, while the downregulated DEGs were mainly related to protein binding, negative regulation of ERK cascade, nucleus and chromatin modification, and lung and renal cell carcinoma. The most significant module was extracted from the PPI network. GO and KEGG enrichment analyses of the module revealed that the genes were mainly enriched in the extracellular region and space organization, blood coagulation process, and PI3K-Akt signaling pathway. Hub genes, including FN1, APOB, F2, SERPINC1, SERPINA1, APOA1, FGG, PROC, ITIH2, VCAN, TFPI, CXCL8, CDH2, and HP, were identified from DEGs. Survival analysis and hierarchical clustering results revealed that most of the hub genes were associated with prognosis and clinical progression.Results of this bioinformatics analysis may provide predictive biomarkers and potential candidate therapeutic targets for individuals with metastatic UM.

Purpose: To report a patient with bilateral uveal metastases secondary to previously quiescent prostate adenocarcinoma with a 22-month follow-up., Methods: Retrospective chart review was performed for this patient., Results: Androgen deprivation therapy and external beam radiation therapy were shown to manage ocular symptoms in a sixty-nine-year-old man previously diagnosed with adenocarcinoma of the prostate., Conclusion: Uveal metastases can be the first site of systemic metastasis even long after initial diagnosis and treatment of prostate adenocarcinoma; the 17 years between this patient's treatment for adenocarcinoma and commencement of his ocular symptoms is the longest interval reported. Hormonal therapy, in conjunction with radiation therapy, can successfully reduce tumor burden in these patients and improve visual symptoms over time.

Background: Uveal melanoma (UM) is a rare malignancy with a propensity for metastasis to the liver. Systemic chemotherapy is typically ineffective in these patients with liver metastases and overall survival is poor. There are no evidence-based guidelines for management of UM liver metastases. The aim of this study was to review the evidence for management of UM liver metastases., Methods: A systematic review of English literature publications was conducted across Ovid Medline, Ovid MEDLINE and Cochrane CENTRAL databases until April 2019. The primary outcome was overall survival, with disease free survival as a secondary outcome., Results: 55 studies were included in the study, with 2446 patients treated overall. The majority of these studies were retrospective, with 17 of 55 including comparative data. Treatment modalities included surgery, isolated hepatic perfusion (IHP), hepatic artery infusion (HAI), transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT) and Immunoembolization (IE). Survival varied greatly between treatments and between studies using the same treatments. Both surgery and liver-directed treatments were shown to have benefit in selected patients., Conclusion: Predominantly retrospective and uncontrolled studies suggest that surgery and locoregional techniques may prolong survival. Substantial variability in patient selection and study design makes comparison of data and formulation of recommendations challenging., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

PD-1 is expressed on the surface of activated T lymphocytes and belongs to the category of negative immune stimuli. Its blocking stimulates the immune response to tumor antigens. Ocular melanomas represent 3-4% of the total melanomas and have metastatic potential, especially to the liver but also to the lungs, skin, and bones. In the case of metastatic melanoma, immunotherapy has a unique role due to the lower frequencies of BRAF mutation in choroidal melanomas and consecutive exclusion from treatment with specific BRAF tyrosine kinase inhibitors. A retrospective observational study was performed in 42 patients who received immunotherapy (IT) with nivolumab for cutaneous and ocular metastatic melanomas, aimed at highlighting the association between the topography of metastases and the duration of immunotherapy until progressive disease. The results indicated the presence of liver metastases as a negative predictive factor for IT duration in patients with melanoma and the presence of lymphatic metastases as a predictive factor for longer IT in patients with melanoma under 65 years old., (©Romanian Society of Ophthalmology.)

Objective: One indication of fine-needle aspiration biopsy (FNAB) is the diagnostic confirmatory of a clinical suspicion of uveal metastasis. We analyzed our experience in this clinical setting to assess the effectiveness of FNAB technique., Design: Retrospective study., Participants: 28 patients (28 eyes) underwent FNAB biopsy., Methods: Aspirates were performed using 25-gauge needle and were classified into the following categories: positive, atypical, negative, or nondiagnostic. The electronic medical records provided all clinical data. Subsequent clinical course was considered as the diagnostic standard., Results: Subsequent clinical course was metastatic tumour in 19 cases (68%) and nonmetastatic tumour in other 9 cases, considered as the diagnostic standard. Cytological interpretations for metastases were positive in 19 cases (68%), atypical in 2 cases (7%), negative in 4 cases (14%), and nondiagnostic in 3 cases (11%). The metastasis-positive cases included 9 adenocarcinoma, 3 uveal lymphoma, 3 small cell carcinomas, 3 non-small cell carcinomas, and 1 metastatic paraganglioma. Both of the atypical cases were suggestive for non-Hodgkin lymphoma. The 4 negative cases for metastases included 2 true negative cases, and 2 false negative aspirates that subsequently proved to be metastatic adenocarcinoma. The 3 nondiagnostic cases included 1 schwannoma, 1 low-grade uveal non-Hodgkin lymphoma, and 1 metastatic adenocarcinoma. The overall sensitivity for FNAB was 87.5%, with a specificity of 100%., Conclusions: FNAB of suspected uveal metastases is a reliable diagnostic technique., (Copyright © 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe didactically the local, regional and systemic spread of choroidal melanoma., Patients and Methods: Two patients who had undergone primary enucleation for the management of choroidal melanoma in 2018 at the University Hospital of Nice were included. Extrascleral extension and invasion of the vortex veins were evaluated, as well as synchronous and metachronous metastases, based on our database., Results: Patient 1 was diagnosed with large choroidal melanoma with partial scleral invasion and vortex vein involvement. Cytogenetic analysis demonstrated a loss of chromosome 3, and a gain of chromosome 8q. Systemic work-up was unremarkable. Patient 2 was diagnosed with a large choroidal melanoma with extrascleral extension and vortex vein involvement. Cytogenetic analysis demonstrated a loss of chromosome 3 and a gain of chromosome 8q. Systemic work-up revealed several liver metastases. A total of 1762 patients were included in our database. Eighty-five patients (4.8 %) and 46 patients (2.6 %) experienced vortex vein invasion and extrascleral extension respectively. Patients with vortex vein invasion were diagnosed with synchronous and metachronous liver metastases in 1.2 % and 18.8 % respectively. Patients with extrascleral extension had synchronous and metachronous liver metastases in 6.5 % and 30.4 % respectively. The mean follow-up was 49.4 months (1-180)., Conclusion: Extrascleral extension and vortex vein invasion illustrate the local, regional and systemic spread of choroidal melanoma. The latter are often associated with genetically aggressive tumours associated with high metastatic risk., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Metastatic uveal melanoma is a highly aggressive disease with no standard of care treatment option. A large proportion of patients have liver-only metastatic disease which raises the question if liver-directed therapy can be efficacious in this subpopulation., Aims: The study aims to evaluate the safety and efficacy of radiosensitizing chemotherapy in combination with yttrium-90 microspheres in patients with uveal melanoma with liver-only metastases., Methods and Results: This single arm, open labeled, non-randomized study enrolled 10 patients with liver-only metastatic uveal melanoma between November 2012 and January 2018. Eligible patients received intrahepatic yttrium-90 microspheres followed by intravenous cisplatin (20 mg/m 2 ) for 5 days. Ten patients were enrolled, but nine patients received treatment who were included in the final analysis with a median follow-up of 30 months (range 7 to 44). Five (50%) were female, five (50%) had an elevated lactate dehydrogenase (LDH), and one (10%) had prior anti-PD-1 therapy. The combination was well tolerated with no greater than or equal to grade 3 toxicity observed. The liver objective response rate (ORR) was 33% (3/9), the median progression-free survival (PFS) in the liver was 3 months (95% CI, 3-NA), and the extrahepatic PFS was 3 months (95% CI, 3-NA). Seventy-eight percent (7/9) received an immune checkpoint inhibitor on disease progression, with no responses seen. The median overall survival (OS) was 10 months (95% CI, 7-NA)., Conclusion: The combination of cisplatin with yttrium-90 microspheres was well tolerated; however, it was associated with intrahepatic disease control of relatively short duration. No responses were seen in patients treated with immune checkpoint inhibitors post radioembolization., (© 2019 Wiley Periodicals, Inc.)

Background: Lacking in previous studies on uveal metastasis is a robust statistical comparison of patient demographics, tumor features, and overall survival based on patient sex., Objective: The aim of this study was to evaluate demographics, clinical features, and overall survival of patients with uveal metastasis based on sex., Method: This is a retrospective analysis. All patients were evaluated on the Ocular Oncology Service, Wills Eye Hospital, PA between January 1, 1974 and June 1, 2017., Results: A total of 2214 uveal metastases were diagnosed in 1310 eyes of 1111 consecutive patients. A comparison (female versus male) revealed differences across several demographic and clinical features including, among others, mean age at metastasis diagnosis (58 vs 63 years, P < 0.001), bilateral disease (21% vs 11%, P < 0.001), and mean number of metastases per eye (1.8 vs 1.6 tumors per eye, P = 0.04). There were differences in overall mean survival (20 vs 13 months, P = 0.03) and 5-year survival (Kaplan-Meier estimate) (31% vs 21%, P < 0.001)., Conclusions: There are demographic, clinical, and survival differences when patients with uveal metastases are compared by sex. Understanding these differences can aid the clinician in better anticipating patient outcomes.

Background: Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life-threatening immune-related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies., Case Presentation: We describe herein a patient with metastatic melanoma who developed epididymo-orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo-orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad-spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next-generation sequencing assay, was negative. He received high-dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5-week taper of oral steroids., Discussion: Here, we report a case of epididymo-orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents., Key Points: Epididymo-orchitis is a rare and potentially life-threatening complication of anti-programmed death protein 1 (anti-PD-1) therapy.For patients on anti-PD-1 therapy who develop either epididymo-orchitis or epididymitis without clear infectious cause, immune-related adverse events should be considered in the differential diagnosis.If severe, epididymo-orchitis related to anti-PD-1 therapy may be treated with high-dose corticosteroids., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Malignant cutaneous melanoma frequently metastasises to gastrointestinal tract, small bowel being the most common site likely due to its rich vascular supply. However, most common sites for metastatic uveal melanoma are the liver (93%), lung (24%), bone (16%), skin/subcutaneous tissue (11%) and lymph nodes (10%). 1 We present a case of 46-year-old man with jejunojejunal intussusception secondary to metastatic uveal melanoma status postbrachytherapy after 11 years of remission. We aim to highlight the rare occurrence of adult intussusception secondary to uveal melanoma after a prolonged period of remission., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine the clinical factors that influence survival in patients with metastatic uveal melanoma., Study Design: Single-center, retrospective review of patients' medical records., Methods: The following data of ninety-nine consecutive patients (49 men, 50 women) with metastatic uveal melanoma were registered: patient demographics; primary tumor characteristics; features of first melanoma-related metastasis; symptoms and patient status at distant disease debut and metastasis treatment. Overall survival was analyzed by Kaplan-Meier estimates. A Cox proportional hazards regression model was applied to identify independent predictors associated with survival., Results: Mean patient age at metastatic diagnosis was 60.7 years (standard deviation, 12.8). The liver was the first metastatic site in most (92.9%) cases. The median disease-free interval was 26 months (interquartile range, 34). Median overall survival after detection of the first metastasis was 8 months (interquartile range, 14). The baseline characteristics of the primary uveal melanoma were not associated with survival in patients with stage IV disease. In the multivariate analysis, the following factors at first metastatic diagnosis were associated with improved overall survival: disease-free interval > 36 months; better performance status; and normal serum lactate dehydrogenase and gamma glutamyl transpeptidase levels. Overall survival was not influenced by specific metastatic treatment., Conclusion: Although metastatic uveal melanoma has a poor prognosis, this study reveals the existence of several independent prognostic factors for prolonged overall survival. These findings may help improve survival estimates in patients with advanced disease.

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: To report a unilateral case of what is named bilateral diffuse uveal melanocytic proliferation and consider the consequences of this finding., Methods: The ocular findings were investigated with multimodal imaging to include color fundus photography, fluorescein angiography, autofluorescence imaging, and enhanced depth imaging optical coherence tomography., Results: A 66-year-old woman had a history of breast cancer 23 years previously that was treated and the patient was free of disease since. She developed a recent decrease in visual acuity in her left eye prompting referral. She was seen to have an alteration in the pigmentation of the posterior pole of the left eye with dispersed red placoid spots. Autofluorescence imaging showed nummular areas of absent autofluorescence signal, which corresponded to areas of hyperfluorescence during fluorescein angiography. The placoid spots were hyperautofluorescent and hypofluorescent in autofluorescence and fluorescein angiography, respectively. She had diffuse thickening and infiltration of the choroid in the left eye. Because of the ocular findings, the patient underwent a systemic evaluation and was found to have widely metastatic disease with an unknown primary cancer. No progression of disease was seen in the left eye over a 6-month follow-up, and the right eye never showed any abnormality, except for a modest cataract, by any means of examination., Conclusion: Bilateral uveal melanocytic proliferation has been attributed to a paraneoplastic process, allegedly from a factor in the IgG fraction of the serum. However, unilateral involvement suggests that there are other factors involved in disease manifestation.

Purpose: Nestin, a member of the intermediate filament protein family, has been described as a putative cancer stem cell marker (CSC) in uveal melanoma and poor prognostic factor in a variety of tumours, including cutaneous melanoma. In this study, we examined the expression of nestin in primary (PUM) and metastatic uveal melanoma (MUM) samples, and correlated the findings with histological, clinical and survival data., Methods: Nestin expression was assessed by immunohistochemistry in 141 PUM and 26 MUM samples; 11 PUM cases were matched with their corresponding metastases. The percentage of tumour cells expressing nestin was scored by three independent observers. Statistical analysis of all data was performed with SPSS., Results: Nestin expression was identified in both the cytoplasm and membrane of UM cells. Increased expression of nestin in PUM samples was associated with known poor prognostic parameters, including epithelioid cell morphology (p < 0.001), closed loops (p = 0.001), higher mitotic count (p < 0.001), monosomy 3 (p = 0.007) and chromosome 8q gain (p < 0.001). Primary uveal melanoma (PUM) with nestin expression levels above a cut-off value of 10% [as determined by receiver operating characteristic (ROC) analysis] was associated with a significantly reduced survival time (Log-rank, p = 0.002). In MUM, a higher percentage of nestin-positive tumour cells combined with poor prognostic markers in the PUM led to a shorter survival time following the development of metastases., Conclusion: In conclusion, increased nestin expression in PUM is a predictor of a tumour phenotype associated with metastatic progression and reduced survival time at onset of metastasis., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

We report a rare case of ciliary body metastasis from adenocarcinoma of the lung. Although the metastatic nodule was seen over the surface of the iris near the angle of anterior chamber, ultrasonography confirmed its origin from the ciliary body. Uveal metastasis may be the first sign of lung cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

A woman in her 70's with a background of ocular malignant melanoma treated more than a decade ago was admitted to hospital with symptoms of dysphagia and exertional shortness of breath. Routine ECG showed a grossly abnormal ECG with T wave inversion in inferolateral leads and some anterior leads. Consequently, echocardiography and CT demonstrated the presence of a large pericardial tumour which on biopsy was found to be metastatic melanoma. Patient was treated with palliative radiotherapy with only temporary initial benefit.

Purpose: The purpose of this study is to evaluate patients with uveal metastasis based on primary tumor site., Methods: Retrospective analysis from Wills Eye Hospital, Philadelphia, PA, USA, for uveal metastasis clinical features and outcomes based on the primary tumor site., Results: There were 2214 uveal metastases diagnosed in 1111 consecutive patients. The demographics included mean age of 60 years (median 61 years), Caucasian race (88%), and female gender (64%). The tumor was unilateral (82%) and primary site was established before uveal metastasis (67%). The primary tumor originated in the breast (37%), lung (26%), kidney (4%), gastrointestinal (GI) tract (4%), cutaneous melanoma (2%), lung carcinoid (2%), prostate (2%), thyroid (1%), pancreas (1%), other sites (3%), and unknown (16%). Comparative analysis of the 5 most common primary sites (breast, lung, kidney, GI tract, and cutaneous melanoma), revealed metastasis at mean age (57, 62, 66, 61, 59 years), as unilateral tumor (74%, 86%, 85%, 93%, 85%), with mean number of metastasis/eye (1.9, 1.7, 1.0, 1.1, 2.0), and in females (99%, 46%, 26%, 25%, 30%). Choroidal metastases measured mean base (9.3, 10.2, 9.1, 11.0, 7.3 mm), mean thickness (2.4, 3.6, 4.4, 4.0, 2.9 mm), and demonstrated predominant color yellow (94%, 91%, 56%, 97%, 36%). Of the 769 patients with documented follow-up, mean patient survival was poor (22.2, 11.5, 8.6, 12.4, 11.4 months) and Kaplan-Meier analysis revealed 3-year survival (33%, 19%, 0%, 14%, 21%) and 5-year survival (24%, 13%, 0%, 14%, 21%). The worst survival was found in patients with pancreatic metastasis (mean 4.2 months) and best survival with lung carcinoid (92% at 5 years)., Conclusion: In a tertiary referral service, uveal metastasis originates from cancer in the breast, lung, kidney, GI tract, cutaneous melanoma, or others. Overall prognosis is poor with 5-year survival at 23% and worst survival with pancreatic metastasis whereas best survival with lung carcinoid metastasis., Competing Interests: There are no conflicts of interest.

Purpose: To evaluate clinico-pathological and molecular prognostic factors in a well-defined series of posterior uveal melanoma (UM) with focus on chromosomal aberrations and mutations in the GNAQ, GNA11 and BRCA1-associated protein 1 (BAP1) genes., Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were obtained from 50 consecutive eyes enucleated for UM between 1993 and 2005. The material was tested for loss of chromosome 3 and gain of chromosome 8q gene signatures by selective molecular gene markers using multiplex ligation-dependent probe amplification (MLPA), and for DNA mutations in the GNAQ, GNA11 and BAP1 genes., Results: After a mean follow-up of 83 months (range, 8-205 months), 21 patients had died of metastatic UM and 16 patients of other causes. Tumour diameter, ciliary body involvement, mixed/epithelioid cell types, mitotic index, Ki-67 proliferation index, loss of chromosome 3 and gain of chromosome 8q showed statistically significant associations with metastatic disease. There were no significant differences in the prevalence of GNAQ and GNA11 mutations between patients with or without metastatic disease. Mutational analysis of the BAP1 gene was performed in 32 primary UM and in five UM liver metastases. Nine different BAP1 missense mutations were identified. BAP1 mutations were not more common in metastasizing than in nonmetastasizing UM., Conclusion: The molecular gene markers showing loss of chromosome 3 and gain of 8q gene signatures were associated with an increased risk of metastatic disease. BRCA1-associated protein 1 (BAP1) gene mutation status had no prognostic significance. The frequency and spectrum of BAP1 mutations in UM may be more dependent on ethnicity and demographic variables than hitherto considered., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To examine the BRCA1-associated protein-1 (BAP1) expression of primary uveal melanomas without and with metastasis, and to analyze the correlation between the BAP1 immunoreactivity of primary uveal melanoma and other clinicopathologic features., Design: Retrospective case series., Participants: Forty patients with uveal melanoma (mean age, 57.98±14.75 years) were included in this analysis, of whom 20 had no metastatic disease and 20 had metastasis., Methods: Medical records and histology slides of patients with primary uveal melanoma treated by enucleation were reviewed. BAP1 expression was evaluated by immunohistochemical staining of formalin-fixed, paraffin-embedded sections. Immunoreactivity in the nucleus and cytoplasm were graded by estimating the percentage of primary tumor cells showing a positive staining of their nucleus or cytoplasm per 1 high-power field 200× (grades 0-3)., Main Outcome Measures: Tumor size, histologic features, nuclear and cytoplasmic BAP1 immunoreactivity grade, and patient outcome, including development of metastasis., Results: Significantly lower (P = 0.025) nuclear BAP1 immunoreactivity was observed in the metastatic melanoma group. Greater tumor thickness, basal diameter, and more advanced TNM stage were associated with an increased odds ratio of developing metastasis (P < 0.05). In addition, tumors with a higher proportion of cells expressing nuclear BAP1 had decreased odds of developing metastatic disease in a multivariate model (P = 0.042). Metastasis-free survival was significantly longer in patients with uveal melanoma with high nuclear BAP1 stain (P = 0.004)., Conclusions: Time to metastasis differs in patients with primary uveal melanoma with different grades of nuclear BAP1 immunoreactivity. Nuclear BAP1 stain is the only significant independent predictor of metastatic disease in this study. Our data support the role of BAP1 immunohistochemical staining of primary uveal melanoma to evaluate metastatic risk., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM., Methods: We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies., Results: Out of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3mg/kg in 5 trials (n=186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10mg/kg (n=45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3months and the median overall survival was 5.2-9.8months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2mg/kg) and nivolumab (3mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9months., Conclusions: UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date., Patients and Methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression., Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001)., Conclusions: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To create an interactive web-based tool for the Prediction of Risk of Metastasis in Uveal Melanoma (PRiMeUM) that can provide a personalized risk estimate of developing metastases within 48 months of primary uveal melanoma (UM) treatment. The model utilizes routinely collected clinical and tumor characteristics on 1227 UM, with the option of including chromosome information when available., Methods: Using a cohort of 1227 UM cases, Cox proportional hazard modeling was used to assess significant predictors of metastasis including clinical and chromosomal characteristics. A multivariate model to predict risk of metastasis was evaluated using machine learning methods including logistic regression, decision trees, survival random forest, and survival-based regression models. Based on cross-validation results, a logistic regression classifier was developed to compute an individualized risk of metastasis based on clinical and chromosomal information., Results: The PRiMeUM model provides prognostic information for personalized risk of metastasis in UM. The accuracy of the risk prediction ranged between 80% (using chromosomal features only), 83% using clinical features only (age, sex, tumor location, and size), and 85% (clinical and chromosomal information). Kaplan-Meier analysis showed these risk scores to be highly predictive of metastasis (P < 0.0001)., Conclusions: PRiMeUM provides a tool for predicting an individual's personal risk of metastasis based on their individual and tumor characteristics. It will aid physicians with decisions concerning frequency of systemic surveillance and can be used as a criterion for entering clinical trials for adjuvant therapies.

Importance: Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy., Objective: To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM., Design, Setting, and Participants: An experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between 64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining., Main Outcomes and Measures: Interferon γ production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM., Results: Of the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P = .005), ciliary body involvement (59% vs 26%; P = .008), and amplification of chromosome 8q (66% vs 23%; P = .002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNA in 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I., Conclusions and Relevance: PRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.

Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEK-ERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival., (Copyright 2017 Asia-Pacific Academy of Ophthalmology.)

Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

Purpose: Uveal metastases are ophthalmologic tumors that have historically been treated by fractionated external beam radiation therapy or invasive brachytherapy. The need for rapid response and less invasive management options led the authors to explore the use of Gamma Knife stereotactic radiosurgery (SRS) for this common problem., Design: Interventional case series., Methods: To prevent eye movement during the procedure, all 3 patients underwent a retrobulbar anesthetic block followed by magnetic resonance imaging to detect the target. All tumors were treated in a single procedure using the 4C or Perfexion Gamma Knife. The tumors received a minimal tumor dose of 14-20 Gy. Two patients also underwent SRS for additional intracranial metastases., Results: At follow-up, performed between 4 and 15 months after SRS, all 3 patients demonstrated a reduction in uveal tumor volumes. One patient developed decreased visual acuity secondary to radiation retinopathy., Conclusion: In this early experience, SRS was found to be an effective management option for uveal metastases associated with systemic cancer. Patients can be screened and treated effectively early after diagnosis using a joint approach between ophthalmologists and neurosurgeons. Systemic oncologic care can continue without interruption., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single-agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab. He developed sequential autoimmune transaminitis, diabetes and uveitis, which necessitated discontinuation of maintenance nivolumab 3 months after commencement of treatment. The patient continues to demonstrate an ongoing partial response 10 months from the initial combination immunotherapy, with the evidence of depigmentation of the primary ocular tumour., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To describe a tiny subclinical choroidal melanoma visualized only with enhanced depth imaging optical coherence tomography in a newly symptomatic patient with known oculodermal melanocytosis., Methods: Case report., Results: A 52-year-old white man with heterochromia and known oculodermal melanocytosis of the right eye, followed for 2 years without change, developed blurred vision and was referred for possible central serous chorioretinopathy. On examination, visual acuity was 20/20 in each eye. There was oculodermal melanocytosis in the right eye involving the periocular skin, episclera, iris, and choroid. On ophthalmoscopy and ocular ultrasonography, there was no appreciable mass, but subtle subfoveal fluid and perifoveal orange pigment were detected, as well as equatorial drusen. Enhanced depth imaging optical coherence tomography demonstrated a subtle optically dense focal choroidal mass measuring 4.5 mm in basal dimension and 0.7 mm in enhanced depth imaging optical coherence tomography thickness. There was choroidal vascular compression, obliteration of choroidal details, and related overlying subretinal fluid with shaggy photoreceptors, consistent with early choroidal melanoma in an eye with oculodermal melanocytosis. The patient elected early treatment considering the risk factors for growth and the risk for metastasis associated with melanoma in the setting of oculodermal melanocytosis. Plaque radiotherapy was performed with complete tumor regression clinically and by enhanced depth imaging optical coherence tomography. At 2-year follow-up, visual acuity remains 20/20, with regressed tumor and no systemic metastasis., Conclusion: Enhanced depth imaging optical coherence tomography is a useful tool in the evaluation of eyes with oculodermal melanocytosis, permitting high-resolution visualization of the choroid and detection of submillimeter early melanoma that might not be apparent with indirect ophthalmoscopy or ultrasonography.

Purpose: To present a case of uveal metastases in a patient with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer and the response to systemic ALK inhibitors., Methods: A retrospective case report. A 75-year-old nonsmoker who has ALK-positive left upper bronchus adenocarcinoma-developed uveal metastases during his course of treatment., Results: Initially, the patient's disseminated malignancy showed a significant response to crizotinib. However, because the bone metastases started progressing again and he developed bilateral ocular metastases, he was switched to ceritinib. After initiation of ceritinib therapy, the uveal melanomas have shown a significant decrease in thickness and no new lesions have developed., Conclusion: ALK inhibitors are an effective first-line treatment in patients with ALK-positive uveal metastases secondary to ALK-positive non-small-cell lung cancer. Despite the fact that crizotinib, a first-generation ALK inhibitor, is initially effective in dealing with non-small-cell lung cancer and its metastases, resistance to it seems to develop on a regular basis. A second-generation ALK inhibitor, such as ceritinib, is also effective in overcoming this resistance in treating those with ALK-positive uveal metastases.

Competing Interests: The authors declare that they do not have a conflict of interest.

Objective: To observe the clinical and pathological features of uveal metastatic carcinoma. Methods: It was a retrospective case series study. The clinical manifestation, growth pattern, tumor types and relative pathological features of 13 patients visiting from January 1980 to December 2014 with uveal metastatic carcinoma in Tianjin Eye Hospital were analyzed retrospectively. Results: There were 13 cases, 6 cases of male and 7 of female. Age was from 37.0 to 66.0 years old. The mean age was 52.1 years old. all cases were monocular. There were 5 cases with right eye and 8 cases with left eye. Among 13 cases, 10 tumors were in posterior choroid, one tumor was in anterior choroid and ciliary body, 2 tumors were in the iris. There were 5 patients with lung cancer, 4 patients with breast cancer, 1 patient with prostate cancer, 1 patient with thyroid cancer and 1 patient with esophageal cancer. The primary tumor wasn't found in 1 patient. The rapid decrease of visual acuity showed in 10 patients with posterior choroidal metastatic carcinoma, 8 of them accompanied with extensive retinal detachment and 6 of them had secondary glaucoma. The multiple gray-white nodule or pink cauliflower mass on the papillary margin of iris were showed respectively in 2 patients with iris metastatic carcinoma. The pathological examination found that posterior choroidal metastatic carcinoma mainly located in temporal or nasal side choroids in 10 cases, among them, local or diffuse flat choroidal masses showed in 6cases, extensive mass involving choroid and ciliary body showed in 1 case, large nodular or globular choroidal mass showed in 2 cases, choroidal mass surrounded the optic disc in 1 case, optic nerve invasion showed in 3 cases and extraocular or orbital invasion showed in 3 cases. The scleral and subconjunctival invasion showed in 1 case of anterior choroid and ciliary body metastatic carcinoma. Conclusions: Uveal metastatic carcinoma manifested various growth pattern, the rapid decrease of visual acuity, flat or nodular choroidal solid mass, secondary retinal detachment and glaucoma were common clinical features. Some cases might invade extraocular or orbital tissue. (Chin J Ophthalmol, 2016, 52: 769-774) .