Abstract Introduction/Objective Choroidal metastasis from endometrial cancer is extremely rare. Its clinical presentation can mimic choroidal melanoma, the most common primary intraocular neoplasm. We describe the first reported fine needle aspiration cytology diagnosis of ocular metastasis from endometrial cancer. Methods/Case Report A 60-year-old female with history of metastatic endometrial endometrioid adenocarcinoma status post hysterectomy, chemoradiation, and immunotherapy, presented to ophthalmology with a right eye choroidal lesion. The initial clinical differential included primary uveal melanoma versus metastasis, and observation was recommended. Upon follow-up, the lesion had grown and was clinically favored to be choroidal melanoma. The patient underwent plaque brachytherapy and fine needle aspiration biopsy. Review of the aspirate cytospin slides revealed crowded cohesive groups and single atypical epithelioid cells exhibiting nuclear hyperchromasia, irregular nuclear membranes, and scant dense to focal possibly vacuolated cytoplasm. Immunohistochemistry showed the atypical cells were positive for PAX8 and ER, and were negative for SOX-10, supporting the diagnosis of metastatic endometrial carcinoma. Results n/a Conclusion Ocular metastasis is an uncommon clinical and pathologic diagnosis, and a clinical impression favoring primary ocular neoplasm can be misleading. This case emphasizes the importance of maintaining a broad differential diagnosis during cytologic evaluation and immunohistochemical workup of suspicious choroidal lesions in patients with underlying malignancy.

uveal melanoma (UM) is the most common primary intraocular tumor in adults, with metastasis being the leading cause of death. However, effective treatments for metastatic UM remain limited. Emerging evidence suggests that cholesterol metabolism plays a role in cancer progression, but its impact on UM metastasis is not well understood. we investigated the effects of miR-181a on UM metastasis using multiple UM cell lines and a suprachoroidal injection mouse model. Functional assays, including migration, invasion, and cancer stem-like cell (CSC) formation, were performed. The target of miR-181a was identified through bioinformatics, luciferase assays, and western blotting. Cholesterol levels were measured, and in vitro and in vivo studies assessed the therapeutic potential of combining miR-181a with crizotinib. miR-181a significantly decreases UM cell migration, invasion, and metastasis. Mechanistically, miR-181a was found to target sterol regulatory element-binding protein 2 (SREBP2), thereby inhibiting cholesterol biosynthesis. This decrease in cholesterol levels hindered reduced epithelial-to-mesenchymal transition (EMT) and led to a decline in cancer stem-like cell (CSC) populations in UM. Furthermore, elevated cholesterol or overexpression of SREBP2 abrogated the anti-metastatic effects of miR-181a. Additionally, a combination of miR-181a and crizotinib significantly inhibited metastasis, both in vitro and in vivo. miR-181a inhibits UM metastasis by targeting SREBP2 and reducing cholesterol biosynthesis. Its combination with crizotinib may provide a promising therapeutic strategy for metastatic UM.

Survival Outcomes of Uveal Melanoma Involving the Anterior Chamber of the Eye: A National Retrospective Cohort Study: Denmark, 1943-2022.

Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c-Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c-Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH-responsive nanoparticle named NP@Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual-action mechanism of NP@Oxa/Criz inhibits the HGF/c-Met axis to prevent the nuclear translocation of β-Catenin, thereby reducing the transcription of metastasis-associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP@Oxa/Criz induces immunogenic cell death to boost anti-tumor immunity. In vivo studies demonstrate that NP@Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP@Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.

The aim of the work is to create a subcutaneous PDX model of uveal melanoma, which will be further used to create a uveal melanoma metastasis. In the course of the work, a collection of 3 heterotopic PDX models of uveal melanoma was created, which, upon histological examination, showed that the PDX models of uveal melanoma correspond to the donor tumors. According to the results of our work, the rates of successful engraftment of the first generation tumor were 37.5% (3/8). An assessment of the growth dynamics of the obtained PDX models was carried out as well. According to the results, the growth rate of the first generation xenografts obtained from patients was quite low. Doubling of the tumor volume occurred in 42 days.To maintain the growth of the PDX model, tumors obtained from first generation mice were sequentially transplanted to the next group of mice. Our data show that the first generation models successfully engrafted in second generation mice. Moreover, the growth rate of the tumor node was considered to be higher than in the first generation.

Introduction: Uveal metastasis is the most common form of intraocular malignancy. Most uveal metastais occur in the posterior uvea, and iris metastasis are relatively rare. They may present as stromal nodules or ill-defined iris thickening, or they may be associated with atypical features such as pain or iridocyclitis. Objective and Methodes: We report the case of a 54-year-old patient whose ophthalmological examination revealed a relapse of her neoplastic disease. We emphasize the importance of a detailed medical history and a systematic general examination to establish an accurate diagnosis in the presence of any suspicious iris lesion that could be life-threatening. Results: A 54-year-old female presented with pain and blurred vision in her left eye. She had breast cancer, which was treated 4 years earlier with mastectomy, lymphadenectomy, and systemic chemotherapy. Ocular examination revealed a best corrected vision of 20/40 in the right eye and 20/20 in the left eye. Full extraocular motion was observed. The right pupil was slowly responsive to light, with 5 × 3-mm pinkish-white mass from 8 to 11 o’clock with intrinsic friable vessels. There was an intense anterior chamber inflammation with 3+/4+ cells associated with increased IOP. Fundus examination revealed large choroidal mass occupying the temporal quadrant. The magnetic resonance imaging (MRI) revealed thickness on iris of the right eye associated with choroidal metastasis and multiple brain metastasis. The patient was referred to oncology for reassessment, a general extension workup revealed also secondary pulmonary metastasis. Chemotherapy was initiated, but unfortunatlly the patient passed away 4 months later. Conclusion: This is a rare case of iris metastases associated with chroidal metastais from breast carcinoma. The rapid presentation should alert the clinician to suspect metastases in any unusual anterior segment lesion.

Unveiling the role of ACTL6A in uveal melanoma metastasis and immune microenvironment.

Uveal metastasis: clinical characteristics, treatment, and prognostic factors in a cohort of 161 patients in China.

PurposeUveal melanoma (UM) is adults’ most common primary intraocular malignant tumor. It has been observed that 40% of patients experience distant metastasis during subsequent treatment. While there exist multigene models developed using machine learning methods to assess metastasis and prognosis, the immune microenvironment’s specific mechanisms influencing the tumor microenvironment have not been clarified. Single-cell transcriptome sequencing can accurately identify different types of cells in a tissue for precise analysis. This study aims to develop a model with fewer genes to evaluate metastasis risk in UM patients and provide a theoretical basis for UM immunotherapy.MethodsRNA-seq data and clinical information from 79 μm patients from TCGA were used to construct prognostic models. Mechanisms were probed using two single-cell datasets derived from the GEO database. After screening for metastasis-related genes, enrichment analysis was performed using GO and KEGG. Prognostic genes were screened using log-rank test and one-way Cox regression, and prognostic models were established using LASSO regression analysis and multifactor Cox regression analysis. The TCGA-UVM dataset was used as internal validation and dataset GSE22138 as external validation data. A time-dependent subject work characteristic curve (time-ROC) was established to assess the predictive ability of the model. Subsequently, dimensionality reduction, clustering, pseudo-temporal analysis and cellular communication analysis were performed on GSE138665 and GSE139829 to explore the underlying mechanisms involved. Cellular experiments were also used to validate the relevant findings.ResultsBased on clinical characteristics and RNA-seq transcriptomic data from 79 samples in the TCGA-UVM cohort, 247 metastasis-related genes were identified. Survival models for three genes (SLC25A38, EDNRB, and LURAP1) were then constructed using lasso regression and multifactorial cox regression. Kaplan-Meier survival analysis showed that the high-risk group was associated with poorer overall survival (OS) and metastasis-free survival (MFS) in UM patients. Time-dependent ROC curves demonstrated high predictive performance in 6 m, 18 m, and 30 m prognostic models. Cell scratch assay showed that the 24 h and 48 h migration rates of cells with reduced expression of the three genes were significantly higher than those of the si-NC group. CD8 + T cells may play an important role in tumour metastasis as revealed by immune infiltration analysis. An increase in the percentage of cytotoxic CD8 + T cells in the metastatic high-risk group was found in the exploration of single-cell transcriptome data. The communication intensity of cytotoxic CD8 was significantly enhanced. It was also found that the CD8 + T cells in the two groups were in different states, although the number of CD8 + T cells in the high-risk group increased, they were mostly in the exhausted and undifferentiated state, while in the low-risk group, the CD8 + T cells were mostly in the functional state.ConclusionsWe developed a precise and stable 3-gene model to predict the metastatic risk and prognosis of patients. CD8 + T cells exhaustion in the tumor microenvironment play a crucial role in UM metastasis.

Uveal melanoma is a malignant tumor originating from melanocytes in the eye's uvea, often detected during routine ophthalmic examinations due to its typically asymptomatic nature. Despite effective local treatments, up to 50% of patients develop hematogenous metastases, highlighting the need for better prognostic markers and therapeutic targets. In this study, we developed an innovative Metastasis-Related Gene Signature (MERGS) score to classify patients from various cohorts. By establishing this scoring method, we discovered underlying mechanisms responsible for significant differences between samples with high and low MERGS scores. We identified a set of ten genes to construct MERGS, which showed a high predictive accuracy for patient survival. Further, Monoglyceride Lipase (MGLL) emerged as the most important gene in distinguishing uveal melanoma metastasis. Functional studies demonstrated that knocking down MGLL significantly inhibited proliferation, invasion, and migration of uveal melanoma cells in vitro and in vivo, while overexpression of MGLL enhanced these malignant behaviors. Additionally, MGLL modulated free fatty acid (FFA) levels within these cells. Our findings reveal MGLL as a crucial player in uveal melanoma progression and propose it as a novel therapeutic target, potentially leading to improved management and outcomes for patients with this disease.

Uveal melanoma (UM) patients face a significant risk of distant metastasis, closely tied to a poor prognosis. Despite this, there is a dearth of research utilizing big data to predict UM distant metastasis. This study leveraged machine learning methods on the Surveillance, Epidemiology, and End Results (SEER) database to forecast the risk probability of distant metastasis. Therefore, the information on UM patients from the SEER database (2000-2020) was split into a 7:3 ratio training set and an internal test set based on distant metastasis presence. Univariate and multivariate logistic regression analyses assessed distant metastasis risk factors. Six machine learning methods constructed a predictive model post-feature variable selection. The model evaluation identified the multilayer perceptron (MLP) as optimal. Shapley additive explanations (SHAP) interpreted the chosen model. A web-based calculator personalized risk probabilities for UM patients. The results show that nine feature variables contributed to the machine learning model. The MLP model demonstrated superior predictive accuracy (Precision = 0.788; ROC AUC = 0.876; PR AUC = 0.788). Grade recode, age, primary site, time from diagnosis to treatment initiation, and total number of malignant tumors were identified as distant metastasis risk factors. Diagnostic method, laterality, rural-urban continuum code, and radiation recode emerged as protective factors. The developed web calculator utilizes the MLP model for personalized risk assessments. In conclusion, the MLP machine learning model emerges as the optimal tool for predicting distant metastasis in UM patients. This model facilitates personalized risk assessments, empowering early and tailored treatment strategies.

Uveal melanoma (UM) is the most common intraocular tumor in adults, and nearly 50% of patients develop metastatic disease with a high mortality rate. Therefore, the development of relevant preclinical in vivo models that accurately recapitulate the metastatic cascade is crucial. We exploited the chick embryo chorioallantoic membrane (CAM) xenograft model to quantify both experimental and spontaneous metastasis by qPCR analysis. Our study found that the transplanted UM cells spread predominantly and early in the liver, reflecting the primary site of metastasis in patients. Visible signs of pigmented metastasis were observed in the eyes, liver, and distal CAM. Lung metastases occurred rarely and brain metastases progressed more slowly. However, UM cell types of different origins and genetic profiles caused an individual spectrum of organ metastases. Metastasis to multiple organs, including the liver, was often associated with risk factors such as high proliferation rate, hyperpigmentation, and epithelioid cell type. The severity of liver metastasis was related to the hepatic metastatic origin and chromosome 8 abnormalities rather than monosomy 3 and BAP1 deficiency. The presented CAM xenograft model may prove useful to study the metastatic potential of patients or to test individualized therapeutic options for metastasis in different organs.

Abstract Aim There remains controversy in the literature regarding the choice of treatment of melanoma metastases to the liver. This systematic review aims to compare the survival and morbidity rates of patients undergoing liver metastasectomy with patients undergoing medical treatment. Method A literature search was conducted from inception until June 2022 using Ovid, Medline, Embase and the Cochrane library. Snowball and hand searches were also carried out. Included studies compared survival outcomes between patients undergoing metastasectomy to those undergoing medical management. Meta-analyses were performed comparing the survival at 6 months, 1, 3 and 5 years as well as overall survival. A sub-analysis was performed comparing the overall survival between surgically and medically treated patients which exclusively uveal melanoma hepatic metastases. Results 25 studies with a total of 2990 participants were included in our study. All studies were found to have some degree of risk of bias. Mean Overall survival was 44.31 (SD 46.25) and 21.59 (SD 24.31) in surgically and medically treated patients respectively. Meta-analysis showed a statistically significant benefit overall in favour of surgically treated patients (OR = 1.33, 95% CI 0.29 to 2.3, p =0.01, I²=0). This was also the case at 6 months, 1, 3 and 5 years. Meta-analysis showed no significant differences in survival between surgically and medically treated patients which exclusively uveal melanoma metastases. Conclusions This review demonstrates improved survival in patients undergoing hepatic metastatectomy for melanoma metastases compared to those undergoing medical treatment, but this may not be the case for those with uveal metastases.

Melanoma is an extremely aggressive malignant neoplasm. Uveal melanoma is the most common primary intraocular malignancy in adults, representing 3–5% of all melanomas. Liver metastases can be clinically detected in 10–20% of patients with metastatic disease from cutaneous melanoma. However, while liver is typically not the first site of disease spread in cutaneous melanoma, ocular melanoma has been showed to primarily metastasize from the eye to the liver; indeed, liver metastases are detected in approximately 87% of patients with metastatic uveal melanoma. Therefore, liver metastasis can be challenging to identify in early stages, thus being essentially asymptomatic until the disease has advanced. Here we report the case of a patient who came to our ultrasound unit reporting a large liver mass. Both contrast-enhanced abdominal computed tomography and magnetic resonance imaging did not establish a definitive diagnosis. The final diagnosis was made only through an ultrasound-guided biopsy of the mass, thus revealing a uveal melanoma metastasis. This is followed by a review of the literature on imaging follow-up of patients with melanoma.

We systematically reviewed the case report literature to identify cases of uveal metastases originating from thyroid cancer (TC), evaluate factors and indications in uveal metastases from TC, and provide clinical insights through recent case studies. Web of Science, Medline, and Scopus databases were searched for case reports or series reporting uveal metastasis from a thyroid neoplasm. Articles published in any language from inception through November 2022 were searched and screened independently by two reviewers. The quality of the included studies was assessed using the JBI Critical Appraisal Checklist for Case Reports. A total of 1049 records were screened, resulting in the identification of 46 cases from 43 studies. The mean (SD) age at uveal metastases diagnosis was 58.44 (±17.99) years with the median (interquartile range) of 56.5 (29.75) (range, 20-83 years), with 34.8% of cases (16/46) cases reported in elderly patients (>64 years). The sample consisted of 56.5% (26/46) male patients. Uveal metastases were observed in the right eye in 16 cases, the left eye in 19 cases, and both eyes in 11 cases. Choroidal involvement was present in 84.8% of cases (39/46) cases. Papillary carcinoma was the most common thyroid cancer type (34.8%, 16/46), followed by follicular carcinoma (32.6%, 15/46), and medullary carcinoma (21.7%, 10/46). Uveal metastases have been observed to appear in metastatic TC, and physicians should approach ocular symptoms cautiously in cases that accompany a neck mass or a history of previous TC.

Abstract Photodynamic therapy (PDT) has been widely employed in tumor treatment due to its effectiveness. However, the tumor hypoxic microenvironment which is caused by abnormal vasculature severely limits the efficacy of PDT. Furthermore, the abnormal vasculature has been implicated in the failure of immunotherapy. In this study, a novel nanoparticle denoted as Combo‐NP is introduced, composed of a biodegradable NIR II fluorescent pseudo‐conjugate polymer featuring disulfide bonds within its main chain, designated as TPA‐BD, and the vascular inhibitor Lenvatinib. Combo‐NP exhibits dual functionality by not only inducing cytotoxic reactive oxygen species (ROS) to directly eliminate tumor cells but also eliciting immunogenic cell death (ICD). This ICD response, in turn, initiates a robust cascade of immune reactions, thereby augmenting the generation of cytotoxic T lymphocytes (CTLs). In addition, Combo‐NP addresses the issue of tumor hypoxia by normalizing the tumor vasculature. This normalization process enhances the efficacy of PDT while concurrently fostering increased CTLs infiltration within the tumor microenvironment. These synergistic effects synergize to potentiate the photodynamic‐immunotherapeutic properties of the nanoparticles. Furthermore, when combined with anti‐programmed death‐ligand 1 (PD‐L1), they showcase notable inhibitory effects on tumor metastasis. The findings in this study introduce an innovative nanomedicine strategy aimed at triggering systemic anti‐tumor immune responses for the treatment of Uveal melanoma.

Nomogram of uveal melanoma as prediction model of metastasis risk

Preventing or effectively treating metastatic uveal melanoma (UM) is critical because it occurs in about half of patients and confers a very poor prognosis. There is emerging evidence that hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1) promote metastasis and contribute to the striking metastatic hepatotropism observed in UM metastasis. However, the molecular mechanisms by which HGF and IGF-1 promote UM liver metastasis have not been elucidated. ASAP1, which acts as an effector for the small GTPase ARF6, is highly expressed in the subset of uveal melanomas most likely to metastasize. Here, we found that HGF and IGF-1 hyperactivate ARF6, leading to its interaction with ASAP1, which then acts as an effector to induce nuclear localization and transcriptional activity of NFAT1. Inhibition of any component of this pathway impairs cellular invasiveness. Additionally, knocking down ASAP1 or inhibiting NFAT signaling reduces metastasis in a xenograft mouse model of UM. The discovery of this signaling pathway represents not only an advancement in our understanding of the biology of uveal melanoma metastasis but also identifies a novel pathway that could be targeted to treat or prevent metastatic uveal melanoma.

Abstract Historically, uveal metastasis was thought to be a rare entity; however, recently with improved patient survival, advances in the medical care of cancer patients, and spreading awareness, an increasing number of patients with uveal metastasis are being diagnosed. Uveal metastasis is now considered the most common intraocular malignancy with ocular involvement in 8%–10% of patients with metastatic disease. Early detection and treatment may help avoid significant visual loss and improve quality of life. Moreover, a multidisciplinary approach is crucial in formulating the treatment plan, the recent years have witnessed marked advancement in the management of such patients with marked improvement in outcomes and patient survival. In this review article, we are going to outline the clinical features of uveal metastasis, the diagnostic approach, and different management options.

Uveal melanoma (UM) is a rare but deadly cancer. The main cause of death from UM is liver metastasis. Though the metastasis mechanism remains unclear, it is closely related to the immune microenvironment and gene expression. This study aimed to identify the prognostic genes in primary and metastatic UM and their relationship with the immune microenvironment. Primary and metastatic UM data from the GEO database included GSE22138 and GSE44295 datasets. Kaplan-Meier analysis, Cox regression models, and ROC analysis were applied to screen genes in GSE22138. TIMER2.0 was employed to analyze the immune microenvironment from gene expression. Prognostic immune gene correlation was tested by Spearman. The results were validated in the independent dataset of cohort GSE44295. Metastasis and primary differential gene analysis showed 107 significantly different genes associated with prognosis, and 11 of them were immune-related. ROC analysis demonstrated that our signature was predictive for UM prognosis (AUC > 0.8). Neutrophil and myeloid dendritic cells were closely associated with metastasis with scores that significantly divided patients into high-risk and low-risk groups (log-rank p< 0.05). Of these 11 genes, FABP5 and SHC4 were significantly associated with neutrophils in metastatic tumors, while ROBO1 expression was significantly correlated with myeloid dendritic cells in the primary tumors. The present study constructed an 11-gene signature and established a model for risk stratification and prediction of overall survival in metastatic UM. Since FABP5 and SHC4 are related to neutrophil infiltration in metastatic UM, FABP5 and neutrophil regulation might be crucial in metastatic UM.