Predicting Choroidal Nevus Transformation to Melanoma Using Machine Learning.

Purpose: To develop and validate machine learning (ML) models to predict choroidal nevus transformation to melanoma based on multimodal imaging at initial presentation. Design: Retrospective multicenter study. Participants: Patients diagnosed with choroidal nevus on the Ocular Oncology Service at Wills Eye Hospital (2007-2017) or Mayo Clinic Rochester (2015-2023). Methods: Multimodal imaging was obtained, including fundus photography, fundus autofluorescence, spectral domain OCT, and B-scan ultrasonography. Machine learning models were created (XGBoost, LGBM, Random Forest, Extra Tree) and optimized for area under receiver operating characteristic curve (AUROC). The Wills Eye Hospital cohort was used for training and testing (80% training-20% testing) with fivefold cross validation. The Mayo Clinic cohort provided external validation. Model performance was characterized by AUROC and area under precision-recall curve (AUPRC). Models were interrogated using SHapley Additive exPlanations (SHAP) to identify the features most predictive of conversion from nevus to melanoma. Differences in AUROC and AUPRC between models were tested using 10 000 bootstrap samples with replacement and results. Main Outcome Measures: Area under receiver operating curve and AUPRC for each ML model. Results: There were 2870 nevi included in the study, with conversion to melanoma confirmed in 128 cases. Simple AI Nevus Transformation System (SAINTS; XGBoost) was the top-performing model in the test cohort [pooled AUROC 0.864 (95% confidence interval (CI): 0.864-0.865), pooled AUPRC 0.244 (95% CI: 0.243-0.246)] and in the external validation cohort [pooled AUROC 0.931 (95% CI: 0.930-0.931), pooled AUPRC 0.533 (95% CI: 0.531-0.535)]. Other models also had good discriminative performance: LGBM (test set pooled AUROC 0.831, validation set pooled AUROC 0.815), Random Forest (test set pooled AUROC 0.812, validation set pooled AUROC 0.866), and Extra Tree (test set pooled AUROC 0.826, validation set pooled AUROC 0.915). A model including only nevi with at least 5 years of follow-up demonstrated the best performance in AUPRC (test: pooled 0.592 (95% CI: 0.590-0.594); validation: pooled 0.656 [95% CI: 0.655-0.657]). The top 5 features in SAINTS by SHAP values were: tumor thickness, largest tumor basal diameter, tumor shape, distance to optic nerve, and subretinal fluid extent. Conclusions: We demonstrate accuracy and generalizability of a ML model for predicting choroidal nevus transformation to melanoma based on multimodal imaging. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluation of ocular and systemic endpoints after radiation of posterior uveal melanoma - A systematic review and meta-analysis.

Background: Due to the large number of radiotherapeutic options for treatment of posterior uveal melanoma (UM), advantages of each option regarding important clinical endpoints have yet to be determined. Therefore, objective of this systematic review was to analyze the numerous pro- and retrospective cohort studies focusing on the efficacy of different radiotherapeutic options for UM in adults, considering local tumor control, overall survival, visual acuity, eye preservation, metastasis, radiation side effects and dose rates. Methods: The Review was performed based on the Cochrane Handbook of Systematic Reviews. The PubMed database was searched for studies published from January 1st, 2000, up to December 31st, 2021. Research, study selection and critical appraisal was performed by two reviewers. The risk of bias assessment was performed through the revised Cochrane risk of bias tools RoB 2 and ROBINS-I. A meta-analysis of proportions was performed using R (R version 4.1.3, library: meta, procedure: metaprop). This systematic review was registered with Prospero (ID CRD42022311758). Results: Of 4886 studies identified in the database, a total of 20 studies with 4979 participants were included in the qualitative synthesis. Through critical appraisal with ROBINS-I and RoB 2, studies received a 'moderate', 'serious' or 'some concerns' overall risk of bias. Heterogeneity analysis allowed for meta-analysis of proportion of 3 outcome-therapy combinations: local tumor control with I-125 Brachytherapy (proportion: 0.94, CI 95 %: 0.91-0.98), local tumor control with proton therapy (proportion: 0.96, CI 95 %: 0.92-1.00) and eye preservation with I-125 brachytherapy (proportion: 0.91, CI 95 %: 0.88-0.93). This shows local tumor control to be at 94 % with I-125 brachytherapy and at 96 % with proton therapy, as well as an eye preservation rate of 91 % with I-125 brachytherapy. Discussion: The evaluation of outcomes of radiotherapy in UM is limited because of missing data on radiation doses as well as great heterogeneity of study protocols. Radiation therapy outcomes are so far not comparable. Therefore, we recommend for upcoming studies on this topic to provide the biological effective dose (BED) or the equivalent dose in 2 Gy fractions (EQD2) per eye structure, thereby enabling a comparison of outcomes of different forms of radiation therapy.

Ang-1 promotes tumorigenesis and mediates the anti-cancer effects of Artesunate on Choroidal melanoma via the regulation of Akt/mTOR signaling pathway.

The impact of Ang-1 on tumors remains a subject of contention, with its mechanism of action exhibiting complexity in the progression of diverse tumor types. Ang-1 has been shown to promote the progression of glioma, glioma, esophageal and human cervical cancer, whereas it exerts inhibitory effects on the growth of breast and colon cancer. However, the specific function of Ang-1 in CM has not been clarified. This research aims to explore the function of Ang-1 on CM and the underlying mechanism. WB and qPCR were utilized to measure the expression levels of different factors in CM cells. Clonogenic, CCK-8 and Transwell migration assay were used to probe CM cells' proliferation and migration ability. Xenograft tumor model was used to testify the effect of Ang-1 and Artesunate (ART) on the growth of CM in vivo. We found Ang-1 promoted CM proliferation and migration, while it was inhibited by ART in vitro. Moreover, both ART treatment and Ang-1 knockdown had the effect of suppressing tumor growth in CM xenograft model. Mechanically, Ang-1 activated Akt/mTOR pathway and induced epithelial-mesenchymal transition (EMT) in CM cells. Furthermore, ART regulated Akt/mTOR pathway by decreasing the expression of Ang-1 in CM cells. Ang-1 promotes tumorigenesis of CM by regulating Akt/mTOR pathway, which can be inhibited by ART.

Choroidal nevi and melanoma doubling times and implications for delays in treatment: A systematic review and meta-analysis.

The prognostic implications of delaying treatment for primary uveal melanoma remain debated. We evaluate the impact of choroidal nevi and melanoma doubling times on metastatic death incidence and compare this impact across different tumor sizes. A literature search in PubMed and Web of Science targeted studies published after 1980 that quantified growth rates for choroidal or ciliochoroidal melanomas or nevi based on serial imaging, encompassing 199 melanomas and 87 growing nevi from 5 studies. In a random effects model, the estimated average volume doubling time was 360 days across all patients, with doubling times of 717, 421, and 307 days for small, medium, and large melanomas, respectively, and 6392 days for growing nevi. A mixed-effects model estimated that the 10-year incidence of metastatic death increases by 0.3, 1.8, and 4.0 percentage points every month a small, medium, and large melanoma remains untreated. Similar results were produced using two independent sources for survival data. These findings suggest that choroidal melanoma growth follows a super-exponential curve, with larger tumors exhibiting shorter doubling times. Based on these growth rates, delaying definitive treatment increases the risk of metastatic death by nearly zero to several percentage points per month, depending on tumor size.

Long Term Follow-Up Observation in Small Choroidal Melanocytic Tumors.

BACKGROUND: The purpose of this study is to analyze the long-term evolution of patients with small choroidal melanocytic tumors (SCMTs) undergoing observation, and to assess their rate of transformation into melanomas and survival. METHODS: A retrospective single-cohort study of patients with SCMTs (1-3 mm in height and 5-10 mm in base) diagnosed from January 1992 to February 2023 was carried out, with observation as the initial treatment. The main criterion for a transformation into melanoma is considered to be an increase in size of more than 1 mm in height and/or more than 1 mm in base measured on an ultrasound/retinography, recorded in two consecutive visits separated by one to three months. RESULTS: 243 patients were included with a mean age of 65.3 years and a mean follow-up of 7.9 years (6 months-27.9 years); 27 patients showed tumor growth. The probabilities of growth at 5, 10, and 15 years are 10%, 14%, and 17%, respectively. Regarding survival, 22 patients died and only 3 deaths were due to melanoma metastasis. Survival rates at 5 and 10 years are 99% and 97%. CONCLUSIONS: Observation is a viable therapeutic option for SCMTs, avoiding the side effects of treatment, considering the majority of these tumors do not progress to melanoma. With close monitoring, patients can be treated promptly upon detecting a transformation. Additionally, the findings confirm that small melanocytic tumors can lead to metastatic disease, albeit at a low rate.

Integrating network pharmacology, molecular docking and experimental verification to reveal the mechanism of artesunate in inhibiting choroidal melanoma.

Background: Artesunate (ART), a natural compound derived from Artemisia annua, has shown promising clinical potentials in the treatment of various tumors, but the exact mechanism is unclear. Choroidal melanoma (CM) is a major malignant ocular tumor in adults, known for its significant malignancy and poor prognosis, with limited efficacy in current treatments. This study explored the anti-CM effects and mechanisms of ART using a combination of network pharmacology, molecular docking and experimental validation. Methods: Potential targets of ART were screened in PubChem, Swiss Target Prediction and Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database Analysis Platform databases, while target genes related to CM prognosis were selected from Online Mendelian Inheritance in Man (OMIM), GeneCards and DisGeNET databases. The intersection of these two groups of datasets yielded the target genes of ART involved in CM. Protein-protein interaction (PPI) network analysis of the intersecting targets, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were conducted to identify core targets and critical pathways. Molecular docking methods were performed to predict the binding interactions between ART and core targets. The effects of ART on CM were evaluated through CCK8, colony formation, transwell, as well as flow cytometry assays to detect apoptosis, cell cycle, reactive oxygen species (ROS). Western blot (WB) assays were conducted to investigate the impact of ART on key proteins and pathways associated with CM. Finally, in vivo assays were conducted to further validate the effects of ART on subcutaneous tumors in nude mice. Results: Research has shown that key pathways and core targets for ART in treating CM were identified through a network pharmacology approach. Molecular docking results verified the strong binding affinity between ART and these core targets. The analysis and predicted results indicated that ART primarily exerted its effects on CM through various tumor-related pathways like apoptosis. The assays in vitro confirmed that ART significantly inhibited the proliferation and migration of CM cells. This was achieved by promoting apoptosis through activation of the p53 signaling pathway, causing cell cycle arrest at the G0/G1 phase by inhibiting the PI3K/AKT/mTOR signaling pathway and increasing the intracellular level of ROS by activating the NRF2/HO-1 signaling pathway. Additionally, the assays in vivo further validated the significant proliferation-inhibitory effect of ART on CM. Conclusion: This study, making the initial exploration, illustrated through network pharmacology combined with molecular docking and in vitro/in vivo assays, confirmed that ART exerted potential anti-cancer effects on CM by promoting apoptosis, inducing cell cycle arrest and increasing intracellular levels of ROS. These findings suggested that ART held significant therapeutic potential for CM.

Managing vitreoretinal complications in uveal melanoma: Surgical treatment and practical considerations.

BACKGROUND: In the past few decades, the primary management for uveal melanoma has evolved from enucleation to eye-preserving treatments. However, despite achieving a high rate of local tumour control, complications following eye-preserving treatments still occur and are partly responsible for functional loss and secondary enucleation. METHODS: A literature review by a broad international panel. RESULTS: We summarised the current literature on utilizing vitreoretinal (VR) surgery for managing the complications of uveal melanoma. We also provided insights from the authors' personal experience and practical recommendations for clinical care. CONCLUSIONS: With the advancement of VR instruments and surgical techniques and the combination of VR and ocular oncology knowledge ("Onco-VR"), it is now possible to manage or even prevent complications such as vitreous haemorrhage, retinal detachment, and toxic tumour syndrome.

Artesunate inhibits vasculogenic mimicry in choroidal melanoma through HIF-1 α/ VEGF/PDGF pathway.

Choroidal melanoma (CM), a highly metastatic eye tumor, exhibits vasculogenic mimicry (VM) facilitated by hypoxia-induced angiogenesis. This study explored the inhibitory impact of the anti-malarial drug Artesunate (ART) on CM VM through modulation of the HIF-1α/VEGF/PDGF pathway. Immunohistochemistry (IHC) confirmed VM in CM with elevated VEGF and PDGF expression. Hypoxia promoted CM proliferation, upregulating HIF-1α, VEGF and PDGF. VEGF and PDGF enhanced CM migration, invasion and VM, with HIF-1α playing a crucial role. ART mitigated VM formation by suppressing the HIF-1α/VEGF/PDGF pathway, highlighting its potential as an anti-tumor agent in CM.

[Epigenetic markers of choroidal melanoma]. / Epigeneticheskie markery melanomy khorioidei.

MicroRNAs (miRNAs) are short non-coding RNAs (18-25 nucleotides in length) that are important participants in the regulation of gene expression. In 2003, their active role in oncogenesis was demonstrated. In 2008, the first report on the isolation of miRNAs from uveal melanoma (UM) tissue was published. Four years later (2012), the presence of miRNAs in the plasma of patients with this category was shown. To date, changes in the expression level of 100 miRNAs in the plasma of cancer patients (with cancer of various localizations) out of the 2654 miRNAs described in mirbase.org have been proven. In the plasma of patients with UM, changes in the expression of only 13 miRNAs have been confirmed. As a rule, studies were conducted in patients at the stage of hematogenous metastasis of UM. PURPOSE: This study analyzed the expression pattern of miRNA-223 and miRNA-126 in patients with localized choroidal melanoma (CM) taking into account biometric parameters in the absence of metastases. MATERIAL AND METHODS: Blood plasma of 84 patients with M0N0 CM aged 35-86 years (mean age 63.4±1.2 years) was investigated. The basis for the diagnosis of CM was the results of ophthalmological examination, optical coherence tomography, and ultrasound scanning. In all cases, the absence of metastases was proven (using computed tomography or magnetic resonance imaging). Control - plasma of 28 volunteers (mean age 62.9±1.42 years, age range 45-78 years), who did not have tumoral, autoimmune, or chronic inflammatory processes. The expression levels of miRNAs circulating in blood plasma were determined by real-time polymerase chain reaction. RESULTS: An increase in the expression levels of miRNA-223 and miRNA-126 in the plasma of all 84 patients with CM was confirmed compared to the control group. Features of the miRNA expression pattern that emerged with changes in the tumor's quantitative parameters were identified. CONCLUSION: Evaluation of the levels of miRNA-223 and miRNA-126 in the blood plasma of patients with CM can be used in clinical practice to clarify the diagnosis of CM, as well as to predict the development of hematogenous metastases.

Using Deep Learning to Distinguish Highly Malignant Uveal Melanoma from Benign Choroidal Nevi.

Background: This study aimed to evaluate the potential of human-machine interaction (HMI) in a deep learning software for discerning the malignancy of choroidal melanocytic lesions based on fundus photographs. Methods: The study enrolled individuals diagnosed with a choroidal melanocytic lesion at a tertiary clinic between 2011 and 2023, resulting in a cohort of 762 eligible cases. A deep learning-based assistant integrated into the software underwent training using a dataset comprising 762 color fundus photographs (CFPs) of choroidal lesions captured by various fundus cameras. The dataset was categorized into benign nevi, untreated choroidal melanomas, and irradiated choroidal melanomas. The reference standard for evaluation was established by retinal specialists using multimodal imaging. Trinary and binary models were trained, and their classification performance was evaluated on a test set consisting of 100 independent images. The discriminative performance of deep learning models was evaluated based on accuracy, recall, and specificity. Results: The final accuracy rates on the independent test set for multi-class and binary (benign vs. malignant) classification were 84.8% and 90.9%, respectively. Recall and specificity ranged from 0.85 to 0.90 and 0.91 to 0.92, respectively. The mean area under the curve (AUC) values were 0.96 and 0.99, respectively. Optimal discriminative performance was observed in binary classification with the incorporation of a single imaging modality, achieving an accuracy of 95.8%. Conclusions: The deep learning models demonstrated commendable performance in distinguishing the malignancy of choroidal lesions. The software exhibits promise for resource-efficient and cost-effective pre-stratification.

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

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

Ultrasound Biomarkers: Contrast-enhanced Ultrasound and Nakagami Imaging to Differentiate Benign and Malignant Choroidal Tumor.

PURPOSE: We hypothesized that contrast-enhanced ultrasound (CEUS) using a microbubble technique to quantify microvascular changes and Nakagami imaging for tissue characterization would provide a new approach for diagnosing and differentiating benign and malignant choroidal lesions. METHODS: Five patients with choroidal melanoma (CM) and five patients with choroidal hemangioma (CH) were selected. Definity®, which contains perflutren microbubbles, was administered as a slow IV bolus (1 ml). CEUS was performed for 1 min postinjection of the contrast agent with ultrasound radiofrequency data acquired from 10 s to 60 s. The contrast value was calculated for the whole tumor region. A gradient magnitude method was used for each postcontrast frames with 1-second interval, and the time-averaged value in pixel intensity gradient of postinjection frames was estimated and reported. Based on the Nakagami statistical distribution model, two Nakagami parameters, m and Ω, where m (shape parameter), representing tissue heterogeneity, and Ω (scale parameter), representing the average energy of backscattered signals, were studied. RESULTS: CEUS analysis showed that the time-averaged estimated contrast was significantly higher (p = 0.008) for CH compared to CM. Furthermore, the time-averaged contrast within the normal choroidal region was significantly higher than the choroidal tumor region for both CH and CM (p = 0.001 for CH cases and p < 0.0001 for CM cases). Nakagami analysis showed that the m estimates were significantly higher (p = 0.032) for CH (m = 0.61) than for CM (m = 0.28), indicating that CH is a more heterogeneous tumor than CM. The Ω estimates were significantly higher (p = 0.0019) for CH (Ω = 0.15) compared to CM (Ω = 0.03). These results may be due to the more vascular structures in CH compared to CM. CONCLUSIONS: Quantitative intensity-based perfusion analysis using CEUS and backscattering tissue analysis using Nakagami imaging can provide valuable insights to differentiate benign and malignant choroidal lesions.

Intralesional Vessel Diameter Measured by Optical Coherence Tomography Angiography Could Improve the Differential Diagnosis of Small Melanocytic Choroidal Lesions.

In this study, we aimed to identify the features of indeterminate choroidal melanocytic lesions visualized on optical coherence tomography angiography (OCTA) and to identify the predictors of growth. We retrospectively evaluated 86 patients with indeterminate lesions treated at our centre from 2016 to 2021. Clinical management involved active surveillance followed by brachytherapy if growth was detected. The lesions were classified into two groups according to whether they grew (small melanomas) or remained stable (choroidal nevi). Growth was detected in 19 (22.1%) lesions. All patients underwent OCTA at baseline. These images were compared to identify the possible predictors of growth. Significant between-group differences were observed in thickness (p = 0.00), greatest basal diameter (p = 0.00), number of risk factors (p = 0.00), symptoms (p = 0.001; relative risk [RR]: 4.3), orange pigment (p = 0.00; RR: 6.02), and ultrasonographic hollowness (Kappa sign); p = 0.000; RR: 5.3). The melanomas had significantly more vessels with a diameter ≥ 76.3 µm (p = 0.02; RR: 2.46). The time to growth in these lesions was significantly shorter (p = 0.05) than in lesions with smaller vessels. These findings show that vessel diameter quantified by OCTA can help differentiate between choroidal nevi and small melanomas, when considered together with clinical risk factors.

Dose-Related Visual Outcomes in the Treatment of Choroidal Melanoma with Stereotactic Radiotherapy.

Introduction: Stereotactic radiotherapy (SRT) in the treatment of choroidal melanoma (CM) may be indicated if the tumour is located close to the optic nerve or is unsuitable for a radiotherapeutic plaque. It is thought that the rate of visual decline and ocular sequelae with SRT is influenced by dose and location of radiation in relation to important visual structures. This study therefore aimed to look at these prognoses with respect to localisation and dose of radiation when treatment of CM with SRT occurs. Methods: A retrospective data analysis was conducted on all patients at Dunedin Hospital (DH) from August 2001 to May 2017 who were followed up for 4 years. SRT consisted of 50 Gy divided into five fractions over 5 days to tumours, with 2-mm treatment margins. The primary outcome measure was retention of functional vision - better than hand movements (HMs) within the treated eye. Secondary outcome measures included time to non-functional vision (HM or less) in relation to location, dose and tumour thickness, the presence of radiation retinopathy, local and metastatic tumour progression, enucleation, and disease-specific mortality. Results: Seventy-five patients were identified in this study. Follow-up was incomplete in 10 patients, and 4 patients became deceased within the 4-year study period. Twenty-nine patients (48%) retained visual acuity (VA) better than HMs in the treated eye at 4 years, and thirty-two (52%) of patients did not. Calculated dose to the optic nerve and macula and proximity of the tumour to the optic nerve and macula were not statistically determinative of vision outcomes, although presenting VA was. Fifty-six per cent of patients developed radiation retinopathy involving the macula. The local progression, metastatic progression and enucleation rates were 4.6%, 6%, and 12.3%, representing 3, 4, and 8 patients, respectively. Conclusion: This study demonstrates that approximately half of patients treated with SRT can expect to maintain functional vision better than HM at 4 years. The rate of visual decline and final vision outcome are independent of location of the tumour in relation to the optic nerve and macula. While it affirms that SRT achieves high rates of local tumour control and eye retention, preservation of functional VA remains an unpredictable endpoint for individual cases and highlights the therapeutic challenge of this treatment modality.

Is It Possible to Preserve Vision without Compromising Metastases-Free Survival by Use of Fully Fractionated Stereotactic Radiotherapy for Posterior Choroidal Melanoma?

Introduction: Stereotactic radiotherapy (SRT) is used for choroidal melanoma (CM) abutting the optic nerve. Visual acuity (VA) deterioration to ≤6/60 is common. We report a pilot study of reduced-dose SRT using 2 Gy/day, aiming to preserve vision without compromising survival. Method: 60 Gy SRT was delivered in 30 fractions over 6 weeks. Liver metastasis surveillance was annual ultrasound. The primary endpoint was 5-year metastasis-free survival (5yMFS). Secondary endpoints were 2-year freedom from local progression (2yFFLP), VA, enucleation rate, and radiation toxicity. Results: Twenty adults aged ≤70 years with T1-T2M0 CM without diabetes mellitus were enrolled. Median follow-up was 5.1 years. About 85% and 90% of tumours were ≤3 mm of the macula and optic disc, respectively. Median tumour height was 2.2 mm (range 1.0-4.4 mm), and median basal diameter was 8.2 mm (range: 4.3-15.0 mm). 5yMFS was 88% (95% CI: 61-97), and the 2yFFLP rate was 90% (95%: CI 66-97). There were three enucleations for disease progression. Final VA in retained eyes was ≥6/7.5 in 6 (30%), 6/9 to 6/12 in 5 (25%), 6/15 to 6/48 in 2 (10%), and ≤6/60 in 4 (20%) eyes. Retinopathy was the main cause of vision loss besides tumour progression. Conclusion: Meaningful vision was preserved 5 years after SRT, despite high-risk tumour locations for vision loss. 2yFFLP and 5yMFS were acceptable. This dose fractionation warrants further investigation.

Case report: Immunotherapy inducing unexpected overall survival in choroidal melanoma: about a case.

Choroidal melanoma (CM) is the most common malignant ocular tumor in adults. The current treatment of metastatic CM is limited by the intrinsic resistance of CM to conventional systemic therapies. Immunotherapy alone or in association with cytotoxic treatment became a realist option treatment. Advancements in molecular biology have resulted in the identification of a number of promising prognostic and therapeutic targets. Herein, we report a rare case of 36-year-old patient with metastatic CM who presented a good long response to treatment with double immunotherapy reaching 3 years of overall survival, which has never been described in the literature.

Nonpigmented Adenoma of the Retinal Pigment Epithelium Mimicking a Retinal Vasoproliferative Tumor Managed With Endoresection.

Purpose: To present a case with signs suggestive of a retinal vasoproliferative tumor. Methods: A case report was evaluated and a surgical video presented. Results: A 61-year-old White man presented with an amelanotic retinal tumor associated with exudation, retinal edema, and overlying telangiectatic vessels, suggestive of a retinal vasoproliferative tumor. Standardized echography showed an irregular mass with medium-to-high internal reflectivity and internal calcification, which suggested chronicity. He was initially treated for an exudative retinal detachment (RD) in the context of a presumed vasoproliferative tumor but later developed combined exudative and rhegmatogenous RD, prompting surgical repair with tumor endoresection. Pathology showed nonpigmented adenoma of the retinal pigment epithelium (RPE). Conclusions: Nonpigmented adenoma of the RPE is a rare tumor, and its clinical similarity to a vasoproliferative tumor should be noted. Endoresection may be considered in cases resulting in RD.

[Circumscribed choroidal hemangioma and non-pigmented choroidal melanoma: clinical, instrumental and molecular genetic features]. / Otgranichennaya gemangioma i bespigmentnaya melanoma khorioidei: kliniko-instrumental'nye i molekulyarno-geneticheskie osobennosti.

Circumscribed choroidal hemangioma (CCH) and early non-pigmented choroidal melanoma (CM) have similar clinical, ultrasound and morphometric features, which in some cases makes their differential diagnosis difficult. There are few studies in the literature devoted to a comparative analysis of the molecular genetic features of CCH and non-pigmented CM, and the results of those studies are contradictory. PURPOSE: This study attempts to develop a method of non-invasive molecular genetic differential diagnostics of CCH and non-pigmented CM. MATERIAL AND METHODS: Based on the results of clinical and instrumental examination methods, 60 patients (60 eyes) with CCH (n=30) and non-pigmented CM (n=30) were included in this prospective study. The control group consisted of 30 individuals without intraocular tumors. Mutations in the GNAQ/GNA11 genes were determined by real-time PCR using the analysis of genomic circulating tumor DNA isolated from peripheral blood plasma. The average follow-up period was 12.1±1.8 months. RESULTS: The study revealed a significant association of mutations in exons 4 and 5 of the GNAQ/GNA11 genes with the presence of non-pigmented CM (27/30; 90%). These mutations were not detected in the group of patients with CCH. Mutations in exons 4 and 5 of the GNAQ/GNA11 genes were also not detected in the control group of healthy individuals. CONCLUSION: This study proposes a method of non-invasive and low-cost differential diagnostics based on molecular genetic analysis and detection of mutations in exons 4 and 5 of the GNAQ and GNA11 genes, which are specific for CM (90%).

[Predicting the effectiveness of organ-preserving treatment of choroidal melanoma using optical coherence tomography data]. / Prognozirovanie effektivnosti organosokhrannogo lecheniya melanomy khorioidei po dannym opticheskoi kogerentnoi tomografii.

Optical coherence tomography (OCT) is currently widely used for the diagnosis of choroidal melanoma (CM), but the problem of predicting the outcomes of planned CM treatment remains unsolved. PURPOSE: This study was conducted to identify OCT signs that adversely affect the outcome of organ-preserving CM treatment. MATERIAL AND METHODS: OCT scan images of 30 patients who underwent organ-preserving treatment and were under observation were selected for this study. Brachytherapy (BT) as monotherapy was performed in 27 patients (in 2 cases - twice, and in 1 case - three times), in one patient - in combination with the previous transpupillary thermotherapy (TTT). Multiple TTT (4 sessions within 4 months) as monotherapy were performed in 2 patients. In 9 cases, a single organ-preserving treatment (BT - 6 patients, TTT - 3 patients) was ineffective. In these cases, the effectiveness of the first stage of organ-preserving treatment was taken into account. RESULTS: Seven signs of an unfavorable prognosis of the performed treatment were identified by analyzis of tomograms and statistical processing of the obtained data. These signs include: the presence of intraretinal edema, detachment of the neuroepithelium (NED) over the tumor, including with a break in the photoreceptors, accumulation of transudate over the tumor, the presence of large cysts, intraretinal cavities and NED near the tumor (secondary retinal detachment). A combination of three or more signs were observed in all cases of inefficiency of the first stage of treatment. Most often, intraretinal edema and NED over the tumor were combined with the accumulation of subretinal transudate and NED near the tumor. The presence of 6 or all 7 signs took place in cases of a negative therapeutic effect after local destruction. CONCLUSION: When planning organ-preserving CM treatment, in addition to biometric parameters, it is necessary to pay special attention to the identification of such morphological signs as NED over and near the tumor, accumulation of transudate under the NED, the presence of intraretinal edema, large intraretinal cysts and cavities.

A prognostic nomogram for the cancer-specific survival rate of choroidal melanoma using the Surveillance, Epidemiology, and End Results database.

Objective: This study was conducted to develop a comprehensive nomogram for individuals with choroidal melanoma (CM) to determine their cancer-specific survival (CSS). Methods: Data of individuals with CM, diagnosed between 2004 and 2015, were accessed at the Surveillance, Epidemiology, and End Results (SEER) database. The selected individuals were randomly categorized into a training and validation cohort. Multivariate Cox regression analysis was applied to screen the relevant variables. Followed by the development of a nomogram based on independent variables. Ultimately, the net reclassification index (NRI), concordance index (C-index), calibration charts, integrated discrimination improvement (IDI), receiver operating characteristic curves (ROC), area under the curve (AUC), and decision-curve analysis (DCA), were utilized to evaluate the discrimination, accuracy, and effectiveness of the model. Results: This study enrolled 3,782 patients. Seven independent factors linked to prognosis were screened via multivariate Cox regression analysis, encompassing age at diagnosis; race; AJCC (American Joint Committee on Cancer) stage; histologic type; and therapy method of radiotherapy, surgery, and chemotherapy. The respective C-indexes of the training and validation cohorts were 0.709 and 0.726, indicative of the excellent accuracy of the nomogram. Furthermore, the AUCs of the training and validation cohorts across 3, 5, and 8 years were 0.767, 0.744, and 0.722 as well as 0.772, 0.770, and 0.753, respectively. Evident of the superiority of the established nomogram over the AJCC staging, both the NRI and IDI values exhibited improvement. The favorable clinical impact and good performance of the nomogram were evident via decision curve analyses (DCAs) and calibration plots, respectively. Conclusion: This research dealt with establishing and validating a nomogram as a prognostic tool for assessing the prognosis of adult patients with CM utilizing the SEER database. A comprehensive assessment of the nomogram via diverse variables demonstrated its accuracy in predicting the CSS probabilities of CM patients across 3, 5, and 8 years in clinical settings. Notably, its performance surpassed that of the AJCC staging system.