• Epidemiology
• Incidence
• Uveal melanoma

• Intraocular cancer
• Retinoblastoma
• Treatment
• Uveal melanoma

• Circulating tumor cells (CTCs)
• Heterogeneity
• Liquid biopsy
• Single-cell analysis
• Targeted therapy
• Uveal melanoma (UM)

• Humans
• Melanoma/genetics
• Melanoma/pathology
• Melanoma/therapy
• Melanoma/drug therapy
• Molecular Targeted Therapy/methods
• Genetic Heterogeneity
• Uveal Neoplasms/genetics
• Uveal Neoplasms/therapy
• Uveal Neoplasms/pathology
• Neoplastic Cells, Circulating/metabolism
• Neoplastic Cells, Circulating/pathology
• Biomarkers, Tumor/genetics
• Mutation
• Circulating Tumor DNA/genetics
• Circulating Tumor DNA/blood
• Liquid Biopsy/methods

• 3D printing
• noninvasive
• novel treatment
• radiation treatment
• radiosurgery
• uveal melanoma

• Proton beam therapy
• Radiological response
• Uveal melanoma

• Anticancer drugs
• Copper ionophore
• Cuproptosis
• Uveal melanoma

• Humans
• Copper
• Melanoma
• Uveal Neoplasms
• Cell Death
• Ionophores
• Ions
• Apoptosis
• Tumor Microenvironment

• Natural Science Foundation of Hunan Province

• centrosome amplification
• centrosome clustering
• metastatic
• mitotic spindle
• monosomy 3
• pericentriolar matrix
• primary
• proliferation
• uveal melanoma

• Centrosome/metabolism
• Centrosome/pathology
• Humans
• Melanoma/genetics
• Melanoma/pathology
• Prognosis
• Uveal Neoplasms/genetics
• Uveal Neoplasms/pathology

• Wellcome Trust
• 109307/Z/15/Z Wellcome Trust
• North West Cancer Research Fund
• Unilever
• Wellcome Trust

Uveal melanoma is the most prevalent intraocular tumor in adults, derived from melanocytes; the liver is the most common site of its metastases. Due to troublesome tumor localization, different imaging techniques are utilized in diagnostics, i.e., fundus imaging (FI), ultrasonography (US), optical coherence tomography (OCT), single-photon emission computed tomography (SPECT), positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), or fundus autofluorescence (FAF). Specialists eagerly use these techniques, but sometimes the precision and quality of the obtained images are imperfect, raising diagnostic doubts and prompting the search for new ones. In addition to analyzing the currently utilized methods, this review also introduces experimental techniques that may be adapted to clinical practice in the future. Moreover, we raise the topic and present a perspective for personalized medicine in uveal melanoma treatment.

Uveal melanoma is the most common primary intraocular malignancy in adults, characterized by an insidious onset and poor prognosis strongly associated with tumor size and the presence of distant metastases, most commonly in the liver. Contrary to most tumor identification, a biopsy followed by a pathological exam is used only in certain cases. Therefore, an early and noninvasive diagnosis is essential to enhance patients’ chances for early treatment. We reviewed imaging modalities currently used in the diagnostics of uveal melanoma, including fundus imaging, ultrasonography (US), optical coherence tomography (OCT), single-photon emission computed tomography (SPECT), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF), as well as positron emission tomography/computed tomography (PET/CT) or magnetic resonance imaging (MRI). The principle of imaging techniques is briefly explained, along with their role in the diagnostic process and a summary of their advantages and limitations. Further, the experimental data and the advancements in imaging modalities are explained. We describe UM imaging innovations, show their current usage and development, and explain the possibilities of utilizing such modalities to diagnose uveal melanoma in the future.

• MMP
• Palmd
• Uveal melanoma
• ZNF263
• metastasis

Uveal melanoma (UM) is a highly malignant intraocular tumor. The imbalance of alternative splicing (AS) is a landmark of tumor initiation and progression. However, there are few studies of AS in UM. Thus, this study aimed to identify a new AS-based prognostic signature and reveal its relationship with tumor-infiltrating immune cells. Univariable Cox regression analysis identified survival-related AS events. The prognostic signature was constructed using the univariable and multivariable Cox regression analyses. Kaplan-Meier survival analysis, the proportional hazard model, and receiver operating characteristic curves verified its prognostic value. Single-sample gene set enrichment analysis was used to analyze immune cell enrichment. The correlation of the risk score with tumor-infiltrating immune cells and immune checkpoint blockade (ICB) genes was examined. We screened 2886 survival-related AS events, of which five were selected to build a prognostic predictor. The risk score was positively relevant with ICB key targets (HAVCR2, IDO1, and PDCD1) and the infiltration of T cells, MDSC, and activated B cells. We provided novel and effective indices, including a risk score and clinical nomogram, for prognostic prediction in UM and discussed the potential relationship between survival-related AS events and immune cell infiltration, which is crucial for developing immune-targeted therapy to improve prognosis.

• alternative splicing
• immune checkpoint blockade genes
• immune infiltration
• uveal melanoma

Although rare, uveal melanoma (UM) is the most common cancer that develops inside adult eyes. The prognosis is poor, since 50% of patients will develop lethal metastases in the first decade, especially to the liver. Once metastases are detected, life expectancy is limited, given that the available treatments are mostly unsuccessful. Thus, there is a need to find methods that can accurately predict UM prognosis and also effective therapeutic strategies to treat this cancer. In this manuscript, we initially compile the current knowledge on epidemiological, clinical, pathological and molecular features of UM. Then, we cover the most relevant prognostic factors currently used for the evaluation and follow-up of UM patients. Afterwards, we highlight emerging molecular markers in UM published over the last three years. Finally, we discuss the problems preventing meaningful advances in the treatment and prognostication of UM patients, as well as forecast new roadblocks and paths of UM-related research.

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

• biomarkers
• metastases
• molecular pathology
• prognostic factors
• survival
• uveal melanoma

Uveal melanoma is a rare condition accounting for only 5% of all primary melanoma cases. Still, it is the most frequently diagnosed primary intraocular malignant tumor in adults. Almost 90% of the tumors involve the choroid and only a small percentage affects the ciliary body or the iris. There is a consistent difference in incidence between different regions with individuals of northern European descent having a significantly higher risk as compared to Hispanics, Asians, and Blacks. Among the many risk factors, mutations in the G protein subunit alpha Q (GNAQ) or G protein subunit alpha 11 (GNA11) genes and different receptors are highly suggestive. While iris melanoma can easily be noticed by the patient itself or diagnosed at a routine slit-lamp evaluation, a consistent percentage of posterior uveal tumors are incidentally diagnosed at funduscopic evaluation as they can evolve silently for years, especially if located in the periphery. Uveal melanoma classifications rely on the tumor size (thickness and basal diameter) and also on intraocular and extraocular extension. The differential diagnosis with pseudomelanomas is carried out according to the tumor aspect and position. Iris melanoma has a better prognosis and a lower mortality rate as compared to choroidal melanoma that has a much higher rate of metastasis (50% of the patients) and a subsequent limited life expectancy from 6 to 12 months. While conservative therapeutic options for the primary tumor, relying on different surgical excision techniques and/or irradiation therapies, offer good local tumor control, the treatment options for metastatic disease, although numerous, are still inadequate in preventing a fatal outcome.

• diagnosis
• metastatic disease
• review
• treatment
• uveal melanoma

Magnetic resonance imaging (MRI) is increasingly being used in the diagnosis and treatment planning of uveal melanoma (UM), the most common primary intraocular tumor. Initially, 7 T MRI was primarily used, but more recently these techniques have been translated to 3 T, as it is more commonly available.

Compare the diagnostic performance of 3 T and 7 T MRI of UM.

Prospective.

Twenty‐seven UM patients (19% female).

3 T: T1‐ and T2‐weighted three‐dimensional (3D) spin echo (SE) and multi‐slice (MS) SE, 7 T: T1‐weighted 3D gradient echo (GE), T2‐weighted 3D SE and MS SE, 3 T and 7 T GE dynamic contrast‐enhanced. T1 weighted images: acquired before and after Gadolinium (Gd) administration.

For all sequences, scan and diagnostic quality was quantified using a 5‐point Likert scale. Signal intensities on T1 and T2 relative to choroid and eye muscle respectively were assessed as well as the tumor prominence. Finally, the perfusion time‐intensity curves (TICs) were classified as plateau, progressive, or wash‐out.

Image quality scores were compared between both field strengths using Wilcoxon signed‐rank and McNemar tests. Paired t‐tests and Bland–Altman were used for comparing tumor prominences. P < 0.05 was considered statistically significant.

Image quality was comparable between 3 T and 7 T, for 3DT1, 3DT2, 3DT1Gd (P = 0.86; P = 0.34; P = 0.78, respectively) and measuring tumor dimensions (P = 0.40). 2DT1 and 2DT2 image quality were rated better on 3 T compared to 7 T. Most UM had the same relative signal intensities at 3 T and 7 T on T1 (17/21) and T2 (13/17), and 16/18 diagnostic TICs received the same classification. Tumor prominence measurements were similar between field strengths (95% confidence interval: −0.37 mm to 0.03 mm, P = 0.097).

Diagnostic performance of the evaluated 3 T protocol proved to be as capable as 7 T, with the addition of 3 T being superior in assessing tumor growth into nearby anatomical structures compared to 7 T.

2

Stage 3

• 3 T
• 7 T
• MRI
• eye diseases
• uveal melanoma

Previous studies have shown that light iris color is a predisposing factor for the development of uveal melanoma (UM) in a population of Caucasian ancestry. However, in all these studies, a remarkably low percentage of patients have brown eyes, so we applied deep learning methods to investigate the correlation between iris color and the prevalence of UM in the Chinese population. All anterior segment photos were automatically segmented with U-NET, and only the iris regions were retained. Then the iris was analyzed with machine learning methods (random forests and convolutional neural networks) to obtain the corresponding iris color spectra (classification probability). We obtained satisfactory segmentation results with high consistency with those from experts. The iris color spectrum is consistent with the raters’ view, but there is no significant correlation with UM incidence.

• Chinese population
• artificial intelligence
• iris color
• machine learning
• uveal melanoma

Uveal melanoma (UM) has favorable local tumor control, but once metastasis develops, the prognosis is rather poor. Thus, it is urgent to develop metastasis predicting markers.

Our study investigated a novel gene expression-based signature in predicting metastasis for patients with UM.

In the discovery phase, 63 patients with UM from GEO data set GSE22138 were analyzed using the Weighted Correlation Network Analysis (WGCNA) to identify metastasis-related hub genes. The Least Absolute Shrinkage and Selection Operator (Lasso) Cox regression was used to select candidate genes and build a gene expression signature. In the validation phase, the signature was validated in The Cancer Genome Atlas database.

Forty-one genes were identified as hub genes of metastasis by WGCNA. After the Lasso Cox regression analysis, eight genes including RPL10A, EIF1B, TIPARP, RPL15, SLC25A38, PHLDA1, TFDP2, and MEGF10 were highlighted as candidate predictors. The gene expression signature for UM (UMPS) could independently predict MFS by univariate and multivariate Cox regression analysis. Incorporating UMPS increased the AUC of the traditional clinical model. In the validation cohort, UMPS performed well in predicting the MFS of UM patients.

UMPS, an eight-gene-based signature, is useful in predicting prognosis for patients with UM.

• cell type
• metastases
• prognosis
• survival rate
• uveal melanoma

• Choroid
• TCGA
• The Cancer Genome Atlas
• ciliary body
• cytogenetics
• genetics
• melanoma
• outcomes
• uvea

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Treatment options for UM include radiotherapy, thermotherapy and tumor resection. Electrochemotherapy (ECT) is a new therapeutic modality for local tumor control in various cancer entities. The current study assesses the radiosensitizing effect of concomitant ECT with bleomycin and irradiation on 3D tumor spheroids with primary and radioresistant uveal melanoma cell lines. The evaluation of the radiosensitizing effect of ECT as a drug delivery system was based on the changes in the spheroid growth, the cell viability as well as the cytotoxic long-term effect of the combined treatment. The primary cell lines showed a higher radiosensitivity and required lower irradiation and bleomycin doses in comparison to cell lines originating from previously irratiated tumors. ECT should be further assessed for its applicability in clinical settings as a therapeutic radiosensitizing option for radioresistant tumors.

Electrochemotherapy (ECT) is emerging as a complementary treatment modality for local tumor control in various cancer entities. Irradiation is an established therapeutic option for oncologic patients, which is commonly combined with chemotherapy due to its insufficient targeting ability. The efficiency of radiotherapy for tumors can be enhanced with different radiosensitizers. ECT can potentiate the radiosensitizing effect of chemotherapeutic agents such as bleomycin. The present study aims to evaluate the radiosensitizing effect of concomitant ECT with bleomycin on 3D tumor spheroids with primary and radioresistant uveal melanoma cell lines (UPMD2, UPMM3, UM92.1, Mel270) and irradiation. The changes in the spheroid growth and the cell viability as well the cytotoxic long-term effect of the combination treatment were evaluated with various combinations of electroporation settings and bleomycin concentrations as well as radiotherapy doses. A broad range of radiosensitivity was documented among the spheroids from different uveal melanoma cell lines. The primary cell lines showed a higher radiosensitivity and required lower irradiation and bleomycin doses. The maximal tumor control with a reduction of cell survival <10% was achieved with a 5 Gy irradiation only in the primary uveal melanoma cell lines and in combination with all tested ECT settings, whereas the same result could be obtained in UM92.1 spheroids only after ECT with 20 Gy irradiation. Based on the spheroid growth and the measurement of the cross-sectional area, the Mel270 spheroids, originating from a previously irradiated recurrent uveal melanoma, required higher doses of bleomycin and ECT settings after irradiation with 5 Gy in order to achieve a significant growth reduction. No significant difference could be demonstrated for the reduction of cell viability in the combination therapy with 20 Gy and 1000 V/cm between 1 and 2.5 µg/mL bleomycin even in Mel270 spheroids, underlying the importance of a drug delivery system to potentiate the radiosensitizing effect of agents in lower doses. ECT should be further assessed for its applicability in clinical settings as a therapeutic radiosensitizing option for radioresistant tumors and a sufficient local tumor control with lower chemotherapy and irradiation doses.

• 3D tumor spheroids
• bleomycin
• cytotoxic effects
• electrochemotherapy
• long-time survival
• radiation therapy
• uveal melanoma

• Brachytherapy
• Eye
• Magnetic resonance imaging
• Melanoma
• Proton therapy

Uveal melanoma (UM) represents the most prominent primary eye cancer in adults. With an incidence of approximately 5 cases per million individuals annually in the United States, UM could be considered a relatively rare cancer. The 90-95% of UM cases arise from the choroid. Diagnosis is based mainly on a clinical examination and ancillary tests, with ocular ultrasonography being of greatest value. Differential diagnosis can prove challenging in the case of indeterminate choroidal lesions and, sometimes, monitoring for documented growth may be the proper approach. Fine needle aspiration biopsy tends to be performed with a prognostic purpose, often in combination with radiotherapy. Gene expression profiling has allowed for the grading of UMs into two classes, which feature different metastatic risks. Patients with UM require a specialized multidisciplinary management. Primary tumor treatment can be either enucleation or globe preserving. Usually, enucleation is reserved for larger tumors, while radiotherapy is preferred for small/medium melanomas. The prognosis is unfavorable due to the high mortality rate and high tendency to metastasize. Following the development of metastatic disease, the mortality rate increases to 80% within one year, due to both the absence of an effective treatment and the aggressiveness of the condition. Novel molecular studies have allowed for a better understanding of the genetic and epigenetic mechanisms involved in UM biological activity, which differs compared to skin melanomas. The most commonly mutated genes are GNAQ, GNA11 and BAP1. Research in this field could help to identify effective diagnostic and prognostic biomarkers, as well as novel therapeutic targets.

• uveal melanoma
• staging
• treatment
• diagnosis
• prognosis
• biomarkers
• epigenetics

Choroidal melanoma is the most common primary intraocular malignancy that occurs in adults. Lithium Chloride Promotes Apoptosis in Human Leukemia NB4 Cells by Inhibiting Glycogen Synthase Kinase-3 Beta. In this study, we aimed to understand whether LiCl exerts anticancer effects on choroidal melanoma cells and elucidate the underlying molecular mechanisms.

Human choroidal melanoma cells were treated with LiCl, and cell survival was assessed with MTT assays. Cell reproductive viability was measured by plate colony formation assays. Cell apoptosis was evaluated using flow cytometry, and proteins were detected using western blotting. A human choroidal melanoma xenograft model was established to demonstrate the effect of LiCl on human choroidal melanoma in vivo.

We found that LiCl inhibited cell survival and clonogenic potential and induced apoptosis in human choroidal melanoma cells. LiCl also reduced the proliferation of choroidal melanoma cells in vivo. Moreover, the upregulation of NOXA and downregulation of Mcl-1 were responsible for LiCl-induced apoptosis. Mcl-1 overexpression obviously impaired LiCl-induced apoptosis and cleavage of caspase8, caspase9, caspase3 and PARP. Moreover, the protein expression of endoplasmic reticulum stress markers, including IRE1α, Bip, p-eIF2α, ATF4 and CHOP, were upregulated following treatment with LiCl. When CHOP expression was knocked down and cells were treated with LiCl, the protein level of NOXA was partially increased, and Mcl-1 expression was increased, while the cleavage of caspase8, caspase9, caspase3 and PARP that was induced by the LiCl was reduced compared with the vehicle treated group. Prolonged ER stress results in the activation of the apoptotic pathway.

In summary, LiCl induced an endoplasmic reticulum stress response while activating intrinsic apoptosis. Furthermore, the CHOP/NOXA/Mcl-1 axis contributed to LiCl-induced apoptosis both in vitro and in vivo. The present study provides important mechanistic insight into potential cancer treatments involving LiCl and enhances the understanding of human choroidal melanoma.

• Apoptosis
• Endoplasmic reticulum stress
• Human choroidal melanoma
• LiCl
• NOXA/Mcl-1

• CellSearch
• DEPArray NxT technology
• FFPE
• circulating tumor cells
• melanoma prognostication
• melanoma surveillance
• single-cell analysis
• uveal melanoma

• Epidemiology
• Eye diseases
• Ocular oncology
• Survival
• Uveal melanoma

• uveal melanoma
• cell transduction pathways
• epigenetics
• miRNA
• immunotherapy

• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/metabolism
• Chemoradiotherapy, Adjuvant/methods
• Choroid/pathology
• Ciliary Body/pathology
• Clinical Trials as Topic
• Epigenesis, Genetic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Incidence
• Iris/pathology
• Melanoma/diagnosis
• Melanoma/epidemiology
• Melanoma/etiology
• Melanoma/therapy
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/metabolism
• Molecular Targeted Therapy/methods
• Neoadjuvant Therapy/methods
• Ophthalmologic Surgical Procedures/methods
• Prognosis
• Risk Factors
• Uveal Neoplasms/diagnosis
• Uveal Neoplasms/epidemiology
• Uveal Neoplasms/etiology
• Uveal Neoplasms/therapy

• Bibliometric analysis
• metastasis
• mutations
• publication
• uveal melanoma (UM)

• epidemiology
• eye diseases
• iris colour
• melanin
• oncology
• uveal melanoma

• Aged
• Aged, 80 and over
• Aging/genetics
• Aging/metabolism
• Cohort Studies
• Eye Color/physiology
• Female
• Humans
• Incidence
• Iris/anatomy & histology
• Iris/metabolism
• Iris/radiation effects
• Light/adverse effects
• Male
• Melanins/biosynthesis
• Melanins/radiation effects
• Melanocytes/metabolism
• Melanocytes/pathology
• Melanocytes/radiation effects
• Melanoma/epidemiology
• Melanoma/ethnology
• Melanoma/etiology
• Melanoma/pathology
• Middle Aged
• Netherlands/epidemiology
• Odds Ratio
• Uveal Neoplasms/epidemiology
• Uveal Neoplasms/ethnology
• Uveal Neoplasms/etiology
• Uveal Neoplasms/pathology
• White People

• 667787 UM CURE Horizon 2020

• ECHO-7
• Oncolytic virus
• Rigvir
• Uveal melanoma

• Cell Line, Tumor
• Humans
• Melanoma/therapy
• Oncolytic Virotherapy
• Oncolytic Viruses
• Uveal Neoplasms/therapy

Uveal melanoma (UM) is the most common primary intraocular carcinoma in adults. Cinobufagin, secreted by the Asiatic toad Bufo gargarizans, is a traditional Chinese medicine, widely used in tumor treatment. Here, we explored the potential antitumor function of cinobufagin and investigated its biochemical mechanisms in UM cells. The antitumor potential of cinobufagin was determined via cell viability, cell cycle, and apoptosis assays. Colony formation assays confirmed that cinobufagin exerted potent antitumor activity in a dose-dependent manner. We found that cinobufagin could induce cell apoptosis and upregulate the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-9 in vivo and in vitro. In addition, after treatment with increased concentrations of cinobufagin, the intrinsic mitochondrial apoptosis pathway was also activated, which was demonstrated by increased cell apoptosis with increased expression of Bad and Bax, decreased expression of Bcl-2 and Bcl-xl, and reduced mitochondrial membrane potential (MMP) in OCM1 cells. Taken together, the results of this preclinical study suggest that cinobufagin can both inhibit cell survival and induce cell apoptosis in a dose-dependent manner in UM cells, which provides new insights into the biochemical mechanism of cinobufagin and its potential as a future chemotherapeutic agent for UM.

• MMP
• anticancer agent
• apoptosis
• cinobufagin
• uveal melanoma

Uveal melanoma is the most common primary intraocular malignancy in adults, but its incidence is low in Asian populations. Spontaneous corneal perforation and intratumoral calcification are rare presentations of choroidal melanoma (CM) , and reports regarding these presentations have been limited. Even after complete surgical treatment, the prognosis of CM patients is usually poor if distant metastasis is present. We here present a case of CM with unique presentations and early distant metastasis to the liver.

A 63-year-old Asian woman presented to our hospital with complaint of pain and brownish discharge from her left eye for 3 d. Imaging studies revealed intratumoral calcification within the left eye with eyeball rupture. Enucleation of the left eye was performed and pathological examination confirmed the diagnosis of CM. Systemic surveillance revealed no metastatic diseases. However, the patient was lost to follow-up 3 mo after surgery. At 1.5 years after the operation, she presented to our emergency department with complaint of dull epigastric pain that radiated to the back for 1 d. Imaging studies revealed a large mass at the upper abdomen abutting the pancreatic neck and body as well as several nodular lesions in the liver. Fine needle biopsy was performed and findings confirmed liver and pancreatic metastases.

This case highlights the importance of continued follow-up of patients with CM.

• Uveal melanoma
• Choroidal melanoma
• Corneal perforation
• Calcification
• Enucleation
• Liver metastasis
• Case report

• AJCC
• American joint committee on cancer
• TCGA
• classification
• genetics
• the cancer genome atlas
• uveal melanoma

• Chromosomes, Human, Pair 3/genetics
• Chromosomes, Human, Pair 8/genetics
• Genes, Neoplasm/genetics
• Genome, Human/genetics
• Humans
• Melanoma/classification
• Melanoma/genetics
• Neoplasm Staging
• Prognosis
• Uveal Neoplasms/classification
• Uveal Neoplasms/genetics

• bleomycin
• chick embryo chorioallantoic membrane
• electrochemotherapy
• electroporation
• in vitro
• in vivo
• treatment
• tumor spheroids
• uveal melanoma

• brachytherapy of choroidal melanoma
• choroidal melanoma
• transpupillary thermotherapy
• transscleral and endoresection of choroidal melanoma

• choroidal melanoma
• chromosome
• endoresection
• fine-needle aspiration biopsy
• genomic
• irradiation
• proton beam therapy
• uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and gives rise to metastases in 50% of cases. The presence of an inflammatory phenotype is a well-known risk factor for the development of metastases. This inflammatory phenotype is characterized by the presence of high numbers of lymphocytes and macrophages, and a high expression of the HLA Class I and II antigens. An abnormal expression of HLA Class I may influence cytotoxic T lymphocyte (CTL) as well as Natural Killer (NK) cell responses. We provide a comprehensive review regarding the inflammatory phenotype in UM and the expression of locus- and allele-specific HLA Class I and of Class II antigens in primary UM and its metastases. Furthermore, we describe the known regulators and the role of genetics (especially chromosome 3 and BRCA-Associated Protein 1 (BAP1 status)), and, last but not least, the effect of putative therapeutic treatments on HLA expression.

• BAP1
• HLA Class I
• HLA Class II
• chromosome 3
• inflammation
• uveal melanoma

One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPARγ are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPARγ are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost.

• BAP1
• HLA Class I
• NFkB pathway
• inflammation
• oncology
• uveal melanoma

• BAP1
• HIF1a
• chromosomes
• gene expression
• infiltrate
• ischemia
• oncology
• uveal melanoma

• N.A. Algemene Nederlandse Vereniging ter voorkoming van Blindheid
• N.A. Stichting Blinden-Penning
• N.A. Landelijke Stichting voor Blinden en Slechtzienden
• N.A. Novartis Foundation
• N.A. Stichting Nederlands Oogheelkundig Onderzoek
• N.A. Rotterdamse Stichting Blindenbelangen
• MD/PhD-program grant Leids Universitair Medisch Centrum
• 667787 European Commission (Horizon 2020 UMCure)

• MMP9
• cancer metastasis
• lycorine
• melanoma
• β-catenin

• Amaryllidaceae Alkaloids/pharmacology
• Animals
• Apoptosis/drug effects
• Axin Protein/genetics
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic
• Humans
• Matrix Metalloproteinase 9/genetics
• Melanoma/drug therapy
• Melanoma/genetics
• Melanoma/pathology
• Mice
• Neoplasm Metastasis
• Phenanthridines/pharmacology
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays
• beta Catenin/genetics

• cancer
• chromothripsis
• genetics
• ophthalmology
• uveal melanoma

• EMT
• HOXA11-AS
• ceRNA
• lncRNA
• metastasis
• molecular scaffold
• proliferation