Pediatric ocular melanoma: a collaborative multicenter study and meta-analysis.

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multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers.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.

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

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.).

Clinical Characteristics of UM and Association of Metastasis of Uveal Melanoma with Congenital Oculocutaneous Melanosis in Asian Patients: Analysis of 1151 Consecutive Eyes.

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.

Heterogeneity of GNAQ/11 mutation inversely correlates with the metastatic rate in uveal melanoma.

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.

Clinical Spectrum of Uveal Metastasis in Korean Patients Based on Primary Tumor Origin.

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.

Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy.

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, PLCß4, 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.

Screening and identification of key genes and pathways in metastatic uveal melanoma based on gene expression using bioinformatic analysis.

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.

Significance of metastatic topography for the immunotherapy of cutaneous and ocular melanomas.

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.

Chemosaturation with percutaneous hepatic perfusion is effective in patients with ocular melanoma and cholangiocarcinoma.

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.

BILATERAL UVEAL METASTASES SECONDARY TO PROSTATE ADENOCARCINOMA.

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.

Systematic review of liver directed therapy for uveal melanoma hepatic metastases.

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.

Fine-needle aspiration biopsy for suspected uveal metastases.

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.

Uveal Metastasis Based on Patient Sex in 2214 Tumors of 1111 Patients. A Comparison of Female Versus Male Clinical Features and Outcomes.

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.

Jejunojejunal intussusception secondary to metastatic uveal melanoma after 11 years of remission.

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.