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Cancer Aug 2016Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United... (Review)
Review
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.
Topics: Chromosome Aberrations; Combined Modality Therapy; Early Detection of Cancer; Genetic Predisposition to Disease; Genetic Testing; Humans; Melanoma; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Research; Treatment Outcome; Uveal Neoplasms
PubMed: 26991400
DOI: 10.1002/cncr.29727 -
The British Journal of Ophthalmology Jan 2017Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and,... (Review)
Review
Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.
Topics: Humans; Incidence; Liver Neoplasms; Melanoma; Molecular Biology; Molecular Targeted Therapy; Neoplasm Metastasis; Prognosis; Uveal Neoplasms
PubMed: 27574175
DOI: 10.1136/bjophthalmol-2016-309034 -
Nature Communications Jan 2020Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the...
Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8 T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.
Topics: Cell Line, Tumor; Cluster Analysis; DNA Copy Number Variations; Humans; Melanoma; Neoplasm Metastasis; Sequence Analysis, RNA; Single-Cell Analysis; Stochastic Processes; Transcription, Genetic; Tumor Microenvironment; Uveal Neoplasms; V(D)J Recombination
PubMed: 31980621
DOI: 10.1038/s41467-019-14256-1 -
Expert Review of Anticancer Therapy Oct 2022Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal... (Review)
Review
INTRODUCTION
Metastatic uveal melanoma is associated with poor prognosis and few treatment options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal melanoma.
AREAS COVERED
In this review, we describe the mechanism of action of tebentafusp as well as preclinical data showing high tumor specificity of the drug. We also review promising early-phase trials in which tebentafusp demonstrated activity in metastatic uveal melanoma patients with an acceptable toxicity profile that included cytokine-mediated, dermatologic-related, and liver-related adverse events. Finally, we summarize findings from a pivotal phase III randomized trial in which tebentafusp demonstrated significant improvement in overall survival in comparison with investigator choice therapy.
EXPERT OPINION
Tebentafusp has transformed the treatment paradigm for metastatic uveal melanoma and should be the preferred frontline agent for most HLA-A*0201 positive patients. However, patients with rapidly progressing disease or high tumor benefit may not derive the same benefit. Areas of future study should focus on its role in the adjuvant setting as well as strategies to improve the efficacy of tebentafusp in the metastatic setting.
Topics: Adult; Cytokines; HLA-A Antigens; Humans; Immunoconjugates; Melanoma; Recombinant Fusion Proteins; Uveal Neoplasms
PubMed: 36102132
DOI: 10.1080/14737140.2022.2124971 -
Current Opinion in Ophthalmology May 2022This article reviews the latest proteomic research on uveal melanoma. (Review)
Review
PURPOSE OF REVIEW
This article reviews the latest proteomic research on uveal melanoma.
RECENT FINDINGS
Proteomic analysis of uveal melanoma cell lines and tissue specimens has improved our understanding of the pathophysiology of uveal melanoma and helped identify potential prognostic biomarkers. Circulating proteins in patient serum may aid in the surveillance of metastatic disease. The proteomes of aqueous and vitreous biopsy specimens may provide safer biomarkers for metastatic risk and candidate therapeutic targets in uveal melanoma. Proteomic analysis has the potential to benefit patient outcomes by improving diagnosis, prognostication, surveillance, and treatment of uveal melanoma.
SUMMARY
These recent findings demonstrate that proteomic analysis is an important area of research to better understand the pathophysiology of uveal melanoma and improve the personalized management of our patients.
Topics: Biopsy; Humans; Melanoma; Proteomics; Uveal Neoplasms
PubMed: 35102096
DOI: 10.1097/ICU.0000000000000835 -
Nature Medicine Nov 2022In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We...
In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.
Topics: Humans; Uveal Neoplasms; Melanoma; Progression-Free Survival
PubMed: 36229663
DOI: 10.1038/s41591-022-02015-7 -
Indian Journal of Ophthalmology Feb 2015Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent,... (Review)
Review
Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately.
Topics: Disease Management; Global Health; Humans; Melanoma; Morbidity; Neoplasm Staging; Prognosis; Uvea; Uveal Neoplasms
PubMed: 25827538
DOI: 10.4103/0301-4738.154367 -
Frontiers in Immunology 2022Uveal melanoma(UVM) is the most common intraocular malignancy and has a poor prognosis. The clinical significance of necroptosis(NCPS) in UVM is unclear.
A Necroptosis-Related Prognostic Model of Uveal Melanoma Was Constructed by Single-Cell Sequencing Analysis and Weighted Co-Expression Network Analysis Based on Public Databases.
BACKGROUND
Uveal melanoma(UVM) is the most common intraocular malignancy and has a poor prognosis. The clinical significance of necroptosis(NCPS) in UVM is unclear.
METHODS
We first identified necroptosis genes in UVM by single-cell analysis of the GSE139829 dataset from the GEO database and weighted co-expression network analysis of TCGA data. COX regression and Lasso regression were used to construct the prognostic model. Then survival analysis, immune microenvironment analysis, and mutation analysis were carried out. Finally, cell experiments were performed to verify the role of ITPA in UVM.
RESULT
By necroptosis-related prognostic model, UVM patients in both TCGA and GEO cohorts could be classified as high-NCPS and low-NCPS groups, with significant differences in survival time between the two groups (P<0.001). Besides, the high-NCPS group had higher levels of immune checkpoint-related gene expression, suggesting that they might be more likely to benefit from immunotherapy. The cell experiments confirmed the role of ITPA, the most significant gene in the model, in UVM. After ITPA was knocked down, the activity, proliferation, and invasion ability of the MuM-2B cell line were significantly reduced.
CONCLUSION
Our study can provide a reference for the diagnosis and treatment of patients with UVM.
Topics: Humans; Melanoma; Necroptosis; Prognosis; Single-Cell Analysis; Tumor Microenvironment; Uveal Neoplasms
PubMed: 35242144
DOI: 10.3389/fimmu.2022.847624 -
Asia-Pacific Journal of Ophthalmology... 2017Approximately 90% of uveal melanoma develop in the choroid, with the remainder arising in the ciliary body or the iris. The treatment of uveal melanoma is aimed at... (Review)
Review
Approximately 90% of uveal melanoma develop in the choroid, with the remainder arising in the ciliary body or the iris. The treatment of uveal melanoma is aimed at conserving the eye and useful vision, and, if possible, preventing metastatic disease. Enucleation is now reserved for tumors that are large and/or involve the optic disc, having largely been replaced by various forms of radiotherapy (plaque brachy-therapy, proton beam or stereotactic radiotherapy) and laser therapy. Whereas iridectomy and iridocyclectomy are widely performed, transscleral exoresection of choroidal tumors is performed only in a few centers because it requires special skills and hypotensive anesthesia. Transretinal endoresection using vitrectomy equipment is easier but controversial because of concerns about tumor seeding. Long-term postoperative surveillance is necessary to identify and treat local tumor recurrence and any other complications, such as radiation-induced morbidity, and to provide counseling to the patient. Factors predicting metastasis include older age, large tumor size, ciliary body involvement, extraocular spread, epithelioid cytomorphology, chromosome 3 loss and chromosome 8q gain, class 2 gene expression profile, loss of BRCA1-associated protein-1 (BAP1), and the presence of inflammation. Prognostication is enhanced by multi-variable analysis combining clinical, histologic, and genetic factors, also taking the patient's age and sex into account. As there is a lack of options for treating metastases, much research is focused on identifying potential therapeutic targets.
Topics: Combined Modality Therapy; Disease Management; Humans; Melanoma; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Uveal Neoplasms
PubMed: 28399342
DOI: 10.22608/APO.201734 -
Oncology (Williston Park, N.Y.) Jan 2016Ocular melanoma is a rare but potentially devastating malignancy arising from the melanocytes of the uveal tract, conjunctiva, or orbit; it represents less than 5% of... (Review)
Review
Ocular melanoma is a rare but potentially devastating malignancy arising from the melanocytes of the uveal tract, conjunctiva, or orbit; it represents less than 5% of all melanoma cases in the United States. The management of ocular melanoma varies depending on its anatomic origin, since uveal and conjunctival melanoma have distinct biologies and thus different treatment strategies. Uveal melanoma is the most common type of ocular melanoma and is characterized by activation of the mitogen-activated protein kinase (MAPK) pathway (among other signaling pathways) via mutations in GNAQ or GNA11. Despite primary radiation or surgical therapy, up to 50% of patients will eventually develop metastatic disease, for which there is no standard therapy and no treatment that has been shown to improve overall survival. The biology of conjunctival melanoma is less well characterized but has been associated with BRAF and NRAS mutations, and results in metastatic disease in 20% to 30% of cases. Clinical trials are currently ongoing to further evaluate and optimize the role of targeted therapies, as well as immunotherapies, as both adjuvant and metastatic treatment in uveal and conjunctival melanoma.
Topics: Conjunctival Neoplasms; Humans; Melanoma; Uveal Neoplasms
PubMed: 26791842
DOI: No ID Found