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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 -
Progress in Retinal and Eye Research Sep 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are... (Review)
Review
Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
Topics: Clinical Trials, Phase III as Topic; Humans; Liver Neoplasms; Melanoma; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retrospective Studies; Uveal Neoplasms
PubMed: 34999237
DOI: 10.1016/j.preteyeres.2022.101041 -
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 -
Eye (London, England) Feb 2017Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean... (Review)
Review
Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in iris (4%), ciliary body (6%), or choroid (90%). The host susceptibility factors for uveal melanoma include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous or iris or choroidal nevus, and BRCA1-associated protein 1 mutation. Currently, the most widely used first-line treatment options for this malignancy are resection, radiation therapy, and enucleation. There are two main types of radiation therapy: plaque brachytherapy (iodine-125, ruthenium-106, or palladium-103, or cobalt-60) and teletherapy (proton beam, helium ion, or stereotactic radiosurgery using cyber knife, gamma knife, or linear accelerator). The alternative to radiation is enucleation. Although these therapies achieve satisfactory local disease control, long-term survival rate for patients with uveal melanoma remains guarded, with risk for liver metastasis. There have been advances in early diagnosis over the past few years, and with the hope survival rates could improve as smaller tumors are treated. As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma. These observations call attention to an unmet medical need for the early treatment of small melanocytic lesions or small melanomas in the eye to achieve local disease control and vision preservation with the possibility to prevent metastases and improve overall patient survival.
Topics: Age Distribution; Combined Modality Therapy; Humans; Incidence; Iridectomy; Melanoma; Radiosurgery; Radiotherapy; Risk Factors; Sex Distribution; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Ultraviolet Rays; Uveal Neoplasms
PubMed: 27911450
DOI: 10.1038/eye.2016.275 -
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 -
Frontiers in Immunology 2023Uveal melanoma (UVM) is the most invasive intraocular malignancy in adults with a poor prognosis. Growing evidence revealed that immune-related gene is related to...
Identification of a novel immune-related gene signature for prognosis and the tumor microenvironment in patients with uveal melanoma combining single-cell and bulk sequencing data.
INTRODUCTION
Uveal melanoma (UVM) is the most invasive intraocular malignancy in adults with a poor prognosis. Growing evidence revealed that immune-related gene is related to tumorigenesis and prognosis. This study aimed to construct an immune-related prognostic signature for UVM and clarify the molecular and immune classification.
METHODS
Based on The Cancer Genome Atlas (TCGA) database, single-sample gene set enrichment (ssGSEA) and hierarchical clustering analysis were performed to identify the immune infiltration pattern of UVM and classify patients into two immunity clusters. Then, we proposed univariate and multivariate Cox regression analysis to identify immune-related genes that related to overall survival (OS) and validated in the Gene Expression Omnibus (GEO) external validation cohort. The molecular and immune classification in the immune-related gene prognostic signature defined subgroups were analyzed.
RESULTS
The immune-related gene prognostic signature was constructed based on S100A13, MMP9, and SEMA3B genes. The prognostic value of this risk model was validated in three bulk RNA sequencing datasets and one single-cell sequencing dataset. Patients in the low-risk group had better OS than those in the high-risk group. The receiver-operating characteristic (ROC) analysis revealed its strong predictive ability for UVM patients. Lower expression of immune checkpoint genes was presented in the low-risk group. Functional studies showed that S100A13 knockdown via siRNA inhibited UVM cell proliferation, migration, and invasion , with the increased expression of reactive oxygen species (ROS) related markers in UVM cell lines.
DISCUSSION
The immune-related gene prognostic signature is an independent predictive factor for the survival of patients with UVM and provides new information about cancer immunotherapy in UVM.
Topics: Adult; Humans; Tumor Microenvironment; Melanoma; Uveal Neoplasms; Prognosis
PubMed: 36793711
DOI: 10.3389/fimmu.2023.1099071 -
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 -
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 -
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