Uveal Melanoma Research Articles

Association Between Uveal Melanoma and Allostatic Load.

Allostatic load (AL) is a measure of chronic stress that is associated with worse cancer outcomes. The purpose of this retrospective cohort study was to investigate the relationship between AL and uveal melanoma (UM) clinical features. AL score was calculated as a composite of ten biomarkers in 111 patients with UM from the University of Illinois Hospital. One point was assigned to an AL score for each biomarker based on predetermined cutoff values. Linear and logistic regression analyses evaluated the relationship between AL score and several tumor clinical characteristics. High AL score had a significant relationship with extraocular extension (p=0.015). There was also a significant difference in mean blood glucose levels between the different tumor size groups (p=0.029). Higher AL scores also had a trend of being associated with a smaller tumor size (p=0.069). AL score was significantly associated with the presence of extraocular extension for uveal melanoma, while the smallest tumor size group was associated with the highest blood glucose level. No other significant correlations were found between AL and other clinical features of UM. The relationship between AL score and extraocular extension warrants further investigation. Additional research is needed to evaluate socioeconomic factors and their effect on the relationship between chronic stress and the clinical features of UM.

TCF3 as a multidimensional biomarker: oncogenicity, genomic alterations, and immune landscape in pan-cancer analysis.

Transcription factor 3 (TCF3), a pivotal member of the TCF/LEF family, plays a critical role in tumorigenesis. Nonetheless, its impact on the tumor microenvironment (TME) and cancer phenotypes remains elusive. We perform an exhaustive analysis of TCF3 expression, DNA variation profiles, prognostic implications, and associations with the TME and immunological aspects. This study is based on a large-scale pan-cancer cohort, encompassing over 17,000 cancer patients from multiple independent datasets, validated by in vitro assays. Our results show that TCF3/4/7 exhibits differential expression patterns between normal and tumor tissues across pan-cancer analyses. Mutational analysis of TCF3 across diverse cancer types reveals the highest alteration rates in biliary tract cancer. Additionally, mutations and single nucleotide variants in TCF3/4/7 are found to exert varied effects on patient prognosis. Importantly, TCF3 emerges as a robust predictor of survival across all cancer cohorts and among patients receiving immune checkpoint inhibitors. Elevated TCF3 expression is correlated with more aggressive cancer subtypes, as validated by immunohistochemistry and diverse cohort data. Furthermore, TCF3 expression is positively correlated with intratumoral heterogeneity and angiogenesis. In vitro investigations demonstrate that TCF3 is involved in epithelial-mesenchymal transition, migration, invasion, and angiogenesis. These effects are likely mediated through the interaction of TCF3 with the NF-κB/MMP2 pathway, which is modulated by IL-17A in human uveal melanoma MUM2B cells. This study elucidates, for the first time, the significant associations of TCF3 with DNA variation profiles, prognostic outcomes, and the TME in multiple cancer contexts. TCF3 holds promise as a molecular marker for diagnosis and as a potential target for novel therapeutic strategies, particularly in uveal melanoma.

72206 - Overall Survival after Isolated Hepatic Perfusion in Combination with Ipilimumab and Nivolumab in Patients with Uveal Melanoma (SCANDIUM II trial)

72206 - Overall Survival after Isolated Hepatic Perfusion in Combination with Ipilimumab and Nivolumab in Patients with Uveal Melanoma (SCANDIUM II trial)

Reporting tumor genomic test results to SEER registries via linkages.

Precision medicine has become a mainstay of cancer care in recent years. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program has been an authoritative source of cancer statistics and data since 1973. However, tumor genomic information has not been adequately captured in the cancer surveillance data, which impedes population-based research on molecular subtypes. To address this, the SEER Program has developed and implemented a centralized process to link SEER registries' tumor cases with genomic test results that are provided by molecular laboratories to the registries. Data linkages were carried out following operating procedures for centralized linkages established by the SEER Program. The linkages used Match*Pro, a probabilistic linkage software, and were facilitated by the registries' trusted third party (an honest broker). The SEER registries provide to NCI limited datasets that undergo preliminary evaluation prior to their release to the research community. Recently conducted genomic linkages included OncotypeDX Breast Recurrence Score, OncotypeDX Breast Ductal Carcinoma in Situ, OncotypeDX Genomic Prostate Score, Decipher Prostate Genomic Classifier, DecisionDX Uveal Melanoma, DecisionDX Preferentially Expressed Antigen in Melanoma, DecisionDX Melanoma, and germline tests results in Georgia and California SEER registries. The linkages of cancer cases from SEER registries with genomic test results obtained from molecular laboratories offer an effective approach for data collection in cancer surveillance. By providing de-identified data to the research community, the NCI's SEER Program enables scientists to investigate numerous research inquiries.

72215 - Percutaneous hepatic perfusion as treatment for liver-dominant metastatic uveal melanoma: the first results from a Nordic referral center

72215 - Percutaneous hepatic perfusion as treatment for liver-dominant metastatic uveal melanoma: the first results from a Nordic referral center

71691 - Long-term overall survival after isolated liver perfusion with melphalan in patients with isolated liver metastases of uveal melanoma (SCANDIUM trial)

71691 - Long-term overall survival after isolated liver perfusion with melphalan in patients with isolated liver metastases of uveal melanoma (SCANDIUM trial)

Clinical and pathological characterization of Tebentafusp-associated skin toxicity – a cohort study with 33 patients.

BackgroundTebentafusp is a novel treatment for patients with metastatic uveal melanoma and often causes cutaneous side effects. ObjectivesThe aim of this study was to better characterize these heterogenous cutaneous side effects. MethodsThis prospective cohort study evaluated all patients from a tertiary hospital center who were treated with tebentafusp between January 2019 and June 2023 clinically and assessed skin biopsies histologically. ResultsIn total, 33 patients were analysed. Skin toxicity was observed in 78.8% of patients and was classified in five clinical categories: 1) symmetrical erythematous patches (83.8%), 2) hemorrhagic macules (11.8%), 3) urticarial lesions (7.4%), 4) bullous lesions (1.5%) and 5) skin (8.5%) and hair depigmentation (11.4%). Histopathologic features were focal lymphocytic interface dermatitis with epidermal infiltration of CD8-positive lymphocytes. Patients with skin reactions had a significantly longer median overall survival compared to patients without any cutaneous events (34 versus 4 months, p<0.001). LimitationMonocentric study with a limited number of patients. ConclusionTebentafusp frequently induced cutaneous reactions. Pathogenesis is likely due to binding of tebentafusp to stimulated melanocytes in the skin followed by infiltration and activation of lymphocytes. Development of treatment induced skin reactions may be associated with survival benefit.

Drusen in the macula and parapapillary region.

To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. The study included 106 eyes (age, 62.6 ± 15.2years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1µm versus 34.3 ± 19.8µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3µm versus 108.7 ± 101.0µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44µm versus 2.55 ± 0.88µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480µm versus 32.8 ± 7.5 cells/480µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

Therapeutic strategies in Uveal Melanoma: A comprehensive review of primary and metastatic disease treatment approaches

Therapeutic strategies in Uveal Melanoma: A comprehensive review of primary and metastatic disease treatment approaches

Evaluation of Demographic and Clinical Characteristics of Turkish Patients With Primary Cutaneous Melanoma: A 5-Year Experience of a Tertiary Referral Center.

Data about the demographic and clinical characteristics of melanoma patients in Turkey is limited. Data about the demographic and clinical characteristics of melanoma patients in Turkey is limited. We aimed to review the features of patients with primary cutaneous melanoma (PCM) diagnosed and treated in a tertiary referral center. The medical records of melanoma patients followed up by the Departments of Dermatology and Medical Oncology were retrospectively reviewed. Within a 5-year period, 180 patients had been diagnosed with melanoma. Of all, 158 (87.8%) had PCM, 9 (5%) had mucosal melanoma, 9 (5%) had unknown primary melanoma, and 4 (2.2%) had ocular melanoma. Of 146 patients with PCM, 32.9% had stage I, 28.8% had stage II, 17.8% had stage III, and 20.5% had stage IV disease. The most common subtype was superficial spreading melanoma (38.8%). A statistically significant correlation was found between the patients Breslow thickness and lymph node involvement, histopathological subtype, and tumor ulceration (P < 0.001). Among all PCM patients, those in stage IV had the lowest 5-year survival rate when compared to the other disease stages (P < 0.001). Relatively younger age at melanoma diagnosis, frequent presence of thick (> 4 mm) tumor, and frequent acral lentiginous subtype are the most remarkable features that suggest the low awareness and knowledge of melanoma in our population.

Extended survival in a case of metastatic choroidal melanoma with immunotherapy.

Uveal melanoma is the most common intraocular malignancy in adults. Despite advances in local treatments, approximately 50% of all cases eventually die from metastatic disease. In cases with metastasis, 2- and 5-year survival rates are approximately 10% and <1%, respectively. Advances in molecular biology have led to the identification of a number of promising drugs including immune checkpoint inhibitors (ICIs). Ipilimumab and nivolumab are ICIs targeting the cytotoxic T-lymphocyte-associated antigen-4 and the programmed-cell death protein-1, respectively. Herein, we present a case of choroidal melanoma having liver metastasis treated with nivolumab and ipilimumab and transarterial radioembolization, achieving a 3-year survival.

What's New in Ocular Drug Delivery: Advances in Suprachoroidal Injection since 2023.

Despite significant advancements in ocular drug delivery, challenges persist in treating posterior segment diseases like macular edema (ME) and age-related macular degeneration (AMD). Suprachoroidal (SC) injections are a promising new method for targeted drug delivery to the posterior segment of the eye, providing direct access to the choroid and retina while minimizing systemic exposure and side effects. This review examines the anatomical and physiological foundations of the SC space; evaluates delivery devices such as microcatheters, hypodermic needles, and microneedles; and discusses pharmacokinetic principles. Additionally, advancements in gene delivery through SC injections are explored, emphasizing their potential to transform ocular disease management. This review also highlights clinical applications in treating macular edema, diabetic macular edema, age-related macular degeneration, choroidal melanoma, and glaucoma. Overall, SC injections are emerging as a promising novel route for administering ophthalmic treatments, with high bioavailability, reduced systemic exposure, and favorable safety profiles. Key therapeutic agents such as triamcinolone acetonide, dexamethasone, AAV-based gene therapy, and axitinib have shown promise. The field of suprachoroidal injection is progressing rapidly, and this review article, while attempting to encapsulate most of the published preclinical and clinical studies, mainly focuses on those that are published within 2023 and 2024.

Single-cell hdWGCNA reveals metastatic protective macrophages and development of deep learning model in uveal melanoma

BackgroundAlthough there has been some progress in the treatment of primary uveal melanoma (UVM), distant metastasis remains the leading cause of death in patients. Monitoring, staging, and treatment of metastatic disease have not yet reached consensus. Although more than half of metastatic tumors (62%) are diagnosed within five years after primary tumor treatment, the remainder are only detected in the following 25 years. The mechanisms of UVM metastasis and its impact on prognosis are not yet fully understood.MethodsscRNA-seq data of UVM samples were obtained and processed, followed by cell type identification and characterization of macrophage subpopulations. High-dimensional weighted gene co-expression network analysis (HdWGCNA) was performed to identify key gene modules associated with metastatic protective macrophages (MPMφ) in primary samples, and functional analyses were conducted. Non-negative matrix factorization (NMF) clustering and immune cell infiltration analyses were performed using the MPMφ gene signatures. Machine learning models were developed using the identified metastatic protective macrophages related genes (MPMRGs) to distinguish primary from metastatic patients. A deep learning convolutional neural network (CNN) model was constructed based on MPMRGs and cell type associations. Lastly, a prognostic model was established using the MPMRGs and validated in independent cohorts.ResultsSingle-cell RNA-seq analysis revealed a unique immune microenvironment landscape in primary samples compared to metastatic samples, with an enrichment of macrophage cells. Using HdWGCNA, MPMφ and marker genes were identified. Functional analysis showed an enrichment of genes related to antigen processing progress and immune response. Machine learning and deep learning models based on key genes showed significant effectiveness in distinguishing between primary and metastatic patients. The prognostic model based on key genes demonstrated substantial predictive value for the survival of UVM patients.ConclusionOur study identified key macrophage subpopulations related to metastatic samples, which have a profound impact on shaping the tumor immune microenvironment. A prognostic model based on macrophage cell genes can be used to predict the prognosis of UVM patients.

Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center

PurposeTo evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body. DesignRetrospective observational study. Subjects6,934 consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center. MethodsData on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20-80%), and non-pigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan-Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis. Main Outcome MeasuresExtraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death. ResultsThere were 6,934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n=3,762; 54%), partially pigmented (n=2,115; 31%) or non-pigmented (n=1,057; 15%). Pigmented UM was associated with extraocular extension (p<0.001), ocular melanocytosis (p=0.003), earlier tumor recurrence (p<0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) (p<0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared to 19% for partially pigmented UMs and 16% for non-pigmented UMs (p<0.001). Kaplan-Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis (p<0.001) and melanoma-related death (p<0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared to partially pigmented UMs (p=0.002) and a 54% higher relative risk of developing metastasis compared to non-pigmented UMs (p<0.001). ConclusionPigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and non-pigmented UMs.

Nodular posterior scleritis mimicking melanotic choroidal melanoma: A diagnostic dilemma.

To report a case of atypical nodular posterior scleritis mimicking as a melanotic choroidal melanoma. Descriptive case report. A 38-year-old female presented with sudden onset diminution of vision, severe pain and redness in her right eye. She was diagnosed to have choroidal melanoma in her left eye one year ago and underwent enucleation. On examination, conjunctiva was injected in right eye with cells in anterior vitreous face (AVF). Fundus examination revealed a large pigmented choroidal mass temporal to macula with exudative retinal detachment. Systemic evaluation and multimodal imaging ruled out the possibility of a choroidal melanoma or metastasis, with a presumptive diagnosis of nodular posterior scleritis. Three cycles of intravenous methyl prednisolone (IVMP) with a tapering dose of oral corticosteroids showed drastic improvement in symptoms with resolution of choroidal mass - further confirming the diagnosis. In cases of choroidal mass with an inflammatory component, a trial of steroids is worthwhile to prevent clinical misjudgement and devastating treatment outcomes including enucleation.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification.

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 patients with pUM with stage T2-T4 and at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (N = 24) and the EPIC BeadChip (N = 17). Findings were validated in the TCGA cohort with known metastatic outcome (N = 69). Differentially methylated probes were identified in patients who developed metastasis. Unsupervised consensus clustering revealed three epigenomic subtypes associated with metastasis. To identify a prognostic signature, recursive feature elimination and random forest models were utilized within repeated cross-validation iterations. The 250 most commonly selected probes comprised the final signature, named MethylSig-UM. MethylSig-UM could distinguish individuals with pUM at diagnosis who develop future metastasis with an area under the curve of ~81% in the independent validation cohort, and remained significant in Cox proportional hazard models when combined with clinical features and established genomic biomarkers. Altered expression of immune-modulating genes were detected in MethylSig-UM positive tumors, providing clues for pUM resistance to immunotherapy. The MethylSig-UM model is available to enable additional validation in larger cohort sizes including T1 tumors.

Isolated conjunctival cavernous hemangioma: a rare case report

Vascular conjunctival tumors are uncommon, usually benign lesions. Here, we report a 65-year-old male who presented with a nasal interpalpebral bulbar firm, oval, and dark-brown and non-mobile conjunctival mass. The systemic and ocular examinations including fundoscopy and gonioscopy were within normal limits. With a diagnosis of conjunctival malignant melanoma (CMM), the patient underwent excisional biopsy, partial sclerectomy, and cryotherapy. Microscopic examination revealed dilated vascular channels filled by red blood cells, separated by fibrous interstitium and no sign of malignancy. Therefore, a diagnosis of conjunctival cavernous hemangioma was made. Our case demonstrates that the conjunctival cavernous hemangioma can mimic malignant conjunctival lesions as well as extrascleral extension of uveal melanoma or uveal prolapse due to scleral necrosis.

Iris melanoma in an Australian cohort.

To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

TRP channel-related LncRNAs, AC092535.4 and LINC01637, as novel prognostic biomarkers for uveal melanoma.

Transient receptor potential (TRP) channels function as cellular sensors with a broad impact, and their dysregulation is linked to numerous cancers. The influence of TRP channel-related long noncoding RNAs (TCRLs) on uveal melanoma (UM) remains poorly understood. We employed bioinformatics to examine the RNA-seq data and relevant clinical information of UM in the TCGA databases. By implementing coexpression analysis, we identified differentially expressed TCRLs. Using univariate Cox regression analysis, selection operator (LASSO) algorithm and stepwise regression, five key prognostic biomarkers were chosen. The high- and low-risk groups were divided based on the risk scores. Afterwards, the prediction performance of the signature was evaluated by receiver operating characteristic (ROC) curve and Kaplan-Meier (K-M) survival analysis. The functional enrichment analysis of TCRLs was also investigated. Following that, we examined immune cell infiltration, immune checkpoint expression, and tumor immune microenvironment between patients in high and low risk groups. TCRLs were validated using Random forests and multifactor Cox analysis. Candidate biomarkers were identified and screened. Finally, the effects of the candidate biomarkers on the proliferation, migration and invasion of UM cells were detected by CCK-8 assay, migration assay and perforation invasion assay. The risk score generated by five TCRLs demonstrated robust predictive power. The high-risk group exhibited a poorer prognosis, increased immune cell infiltration, and an active tumor immune microenvironment compared to the low-risk group. Furthermore, two TCRLs of risk score, AC092535.4 and LINC01637, were screened to multiplex modelling. The in vitro experiments demonstrated that UM cells were suppressed following AC092535.4 or LINC01637 knockdown. Two TCRLs, AC092535.4 and LINC01637, serve as novel prognostic biomarkers for uveal melanoma and may present potential therapeutic targets.