Search

Uveal melanoma (UM) is a rare yet lethal primary intraocular malignancy affecting adults. Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that FGFR1 expression was increased in UM tumor tissues and was linked to aggressive behavior and a poor prognosis. This study assessed the anti-tumor effects of Erdafitinib, a selective pan-FGFR inhibitor, in both in vitro and in vivo UM models. Erdafitinib exhibited a robust anti-cancer activity in UM through inducing ferroptosis in the FGFR1-dependent manner. Transcriptomic data revealed that Erdafitinib mediated its anti-cancer effects via modulating the ferritinophagy/lysosome biogenesis. Subsequent research revealed that Erdafitinib exerted its effects by reducing the expression of FGFR1 and inhibiting the activity of mTORC1 in UM cells. Concurrently, it enhanced the dephosphorylation, nuclear translocation, and transcriptional activity of TFEB. The aggregation of TFEB in nucleus triggered FTH1-dependent ferritinophagy, leading to lysosomal activation and iron overload. Conversely, the overexpression of FGFR1 served to mitigate the effects of Erdafitinib on ferritinophagy, lysosome biogenesis, and the activation of the mTORC1/TFEB signaling pathway. In vivo experiments have convincingly shown that Erdafitinib markedly curtails tumor growth in an UM xenograft mouse model, an effect that is closely correlated with a decrease in FGFR1 expression levels. The present study is the first to demonstrate that Erdafitinib powerfully induces ferroptosis in UM by orchestrating the ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling. Consequently, Erdafitinib emerges as a strong candidate for clinical trial investigation, and FGFR1 emerges as a novel and promising therapeutic target in the treatment of UM. [Display omitted] • FGFR1 is up-regulated in UM tissues and associated with malignant behaviors and poor prognosis. • Erdafitinib inhibits UM cells' proliferation by inducing FGFR1-dependent ferroptosis. • Erdafitinib induces ferritinophagy/lysosome activation by FGFR1/mTORC1/TFEB signaling. • Erdafitinib inhibites tumor growth in UM xenograft mouse model by decreasing FGFR1 expression. [ABSTRACT FROM AUTHOR]

To investigate if the interval between diagnosis and treatment of posterior uveal melanoma (UM) is associated with metastatic death. Retrospective, single-center cohort study. A total of 1145 patients consecutively diagnosed with posterior UM at St. Erik Eye Hospital, Stockholm, Sweden, from 2012 to 2022, with recorded dates of diagnosis and primary treatment. This cohort represents 81% of all diagnosed patients in Sweden during this period. Data on the interval between diagnosis and treatment were collected for all patients. Its prognostic importance was examined with univariate and multivariate competing risks regressions, and cumulative incidence analyses. Incidence of metastatic death (UM mortality) for patients with prompt (< 1 month from diagnosis) versus delayed treatment (≥ 1 month) and subdistribution hazard ratios (exp(β j)) for every additional 10-day delay in treatment. The mean interval between diagnosis and treatment was 34 days (SD, 56, range, 0–932). Patients treated promptly had larger tumors at diagnosis, but there were no differences in patient age, tumor distance to the optic disc, rates of ciliary body involvement (CBI) or extraocular extension (EXE), or symptom duration before diagnosis. Those who were treated more than 1 month after diagnosis had greater UM mortality in American Joint Committee on Cancer (AJCC) stage II and III. In stage I, UM mortality for delayed treatment was lower for the first 10 years, followed by a marked spike in the 11th year. In multivariate competing risks regressions of all 1145 patients with tumor diameter, thickness, CBI, and EXE as covariates, the risk for UM mortality increased with 1% for every additional 10-day delay in treatment (exp(β j) 1.01). Among 355 patients treated with enucleation, this delay was associated with UM mortality, independent of AJCC stage, cytomorphology, and level of immunohistochemical BAP-1 expression. Increasing time between diagnosis and treatment of UM is associated with a higher risk of metastatic death. These results challenge a central concept in the understanding of metastatic progression and may indicate the existence of late metastatic seeding. They also underscore the importance of prompt treatment. Validation in independent cohorts is recommended. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Tebentafusp is a novel treatment for patients with metastatic uveal melanoma and often causes cutaneous side effects. The aim of this study was to better characterize these heterogenous cutaneous side effects. This prospective cohort study evaluated all patients from a tertiary hospital center who were treated with tebentafusp between January 2019 and June 2023 clinically and assessed skin biopsies histologically. In total, 33 patients were analyzed. Skin toxicity was observed in 78.8% of patients and was classified into 5 clinical categories: (1) symmetrical erythematous patches (83.8%), (2) hemorrhagic macules (11.8%), (3) urticarial lesions (7.4%), (4) bullous lesions (1.5%), and (5) skin (8.5%) and hair depigmentation (11.4%). Histopathologic features were focal lymphocytic interface dermatitis with epidermal infiltration of CD8-positive lymphocytes. Patients with skin reactions had a significantly longer median overall survival compared to patients without any cutaneous events (34 versus 4 months, P <.001). Monocentric study with a limited number of patients. Tebentafusp frequently induces cutaneous reactions. Pathogenesis is likely due to binding of tebentafusp to stimulated melanocytes in the skin, followed by infiltration and activation of lymphocytes. Development of treatment-induced skin reactions may be associated with survival benefits. [ABSTRACT FROM AUTHOR]

The current, 8th edition of the American Joint Committee on Cancer (AJCC) anatomic classification and staging model for uveal melanoma does not fully separate survival estimates for patients with advanced stages of the disease (e.g., IIIB and IIIC). Furthermore, some tumors in higher size categories have a smaller volume than tumors in lower categories. Therefore, we developed a novel model for prognostication of metastatic mortality based on estimations of tumor volume. Retrospective, multicenter case series of patients with uveal melanoma involving the choroid, ciliary body, or both. Six thousand five hundred twenty-eight consecutively registered patients treated at 3 tertiary ocular oncology centers on 2 continents between 1981 and 2022. Data on survival, tumor size, and extent were collected for all 6528 patients. Tumor volume was estimated using a simple equation based on largest basal diameter and thickness. Volume-based size categories and stages were developed and validated in independent patient cohorts using competing risk analyses, and correlations with cytogenetic and cytomorphologic features were examined. Cumulative incidence of metastatic death. The 6528 patients were distributed over 7 stages based on estimated tumor volume and anatomic extent (V stages IA, IB, IIA, IIB, IIIA, IIIB, and IIIC), with a 15-year incidence of metastatic death ranging from 7% to 77%. A new category, V1 min , and corresponding stage IA, were introduced, indicating an excellent prognosis. Metastatic mortality in V stage IIIC was significantly higher than that in V stage IIIB (P = 0.03), whereas incidence curves crossed for patients in AJCC stages IIIC vs. IIIB (P = 0.53). Univariable and multivariable competing risk regressions demonstrated higher Wald statistics for V stages compared with AJCC stages (1152 vs. 1038 and 71 vs. 17, respectively). The frequency of monosomy 3, gain of chromosome 8q, and epithelioid cytomorphologic features increased with tumor volume (R 2 = 0.70, R 2 = 0.50, and R 2 = 0.71, respectively; P < 0.001) and showed similar correlations with both AJCC and V stages. Anatomic classification and staging of ciliary body and choroidal melanomas based on estimation of tumor volume improves prognostication of metastatic mortality. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is uncommon in African Americans. Owing to its rarity, UM may not be suspected in African Americans leading to delayed diagnosis. In addition, socioeconomic factors may also play a role in delayed diagnosis. Clinical and ultrasonographic features may be atypical due to racial pigmentation, necessitating diagnostic fine needle aspiration biopsy. Herein, we report an illustrative case series of 12 African Americans with UM highlighting clinical features and diagnostic challenges. [ABSTRACT FROM AUTHOR]

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma (UM). Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions. In search of genetic vulnerability for UM, we found that inhibition of euchromatic histone lysine methyltransferase 2 (EHMT2) expression or activity significantly reduced the proliferation and migration capacity of cancer cells. Notably, elevated expression of EHMT2 had been validated in UM samples. Furthermore, Kaplan–Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage. Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2. Its transcription was suppressed by EHMT2 in a methyltransferase-dependent pattern in GNAQ/11- mutant UM cells, leading to elevated RhoA activity. Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes. Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth, suggesting the driver role of these two key molecules. In summary, our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11- mutant UM. EHMT2-dependent epigenetic program promotes RhoA signaling in GNAQ/11 -mutant uveal melanoma and targeting EHMT2 and MEK/ERK simultaneously is a therapeutic strategy to overcome resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

To determine the presence of circulating tumor cells (CTCs) in patients with indeterminate small choroidal melanocytic lesions (SCMLs). Retrospective case series. Forty-seven patients with choroidal melanocytic lesions 2.5 mm or less in tumor thickness and ≤ 10 mm in largest basal diameter (LBD). Blood samples were analyzed for CTCs and the presence of monosomy-3 (M3) in CTCs. Tissue biopsy was performed in the patients who were CTC-positive (pCTC). Presence and M3 status of the CTCs with regard to the clinical characteristics and results from tissue biopsy. Median thickness of all (n = 47) lesions was 1.1 mm (range: 0.2–2.5 mm), and LBD was 5.6 mm (range: 2.0–10.0 mm). Circulating tumor cells were found in 25 patients (n = 25). This group was classified as pCTC and compared with the CTC-negative (nCTC) group consisting of 22 patients (n = 22). Median tumor dimensions in the pCTC versus the nCTC group were 1.6 mm (range: 0.6–2.5 mm) versus 0.5 mm (range: 0.2–2.5 mm) for thickness and 6.6 mm (range: 4.1–10.0 mm) versus 4.0 mm (range: 2.0–8.0 mm) for LBD, respectively. Both LBD and thickness were positively associated (P < 0.001) with the presence of CTC. Compared with the nCTC group, a higher percentage of the pCTC group exhibited LBD > 5 mm (36% vs. 88%), subretinal fluid (9.1% vs. 56%), orange pigment (4.5% vs. 60%), sonographic hollowness (9.1% vs. 60%), and the presence of multiple risk factors (0% vs. 68% for ≥3 factors) with P < 0.001 for all parameters. No significant difference was detected in the clinical parameters of the patients who had disomy-3 (D3) (n = 7) versus M3 (n = 17) in their CTC. The tissue biopsy confirmed the uveal melanoma (UM) in 22 of the 25 pCTC patients (88%), whereas no conclusive diagnosis could be determined in the remaining 3 cases because of insufficient or invalid material. We report compelling evidence for the potential of liquid biopsy as an additional tool to screen SCMLs for malignancy. These findings pave the way toward the implementation of liquid biopsy to detect small UM and monitor melanocytic lesions. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Eye plaque brachytherapy is a mainstay treatment for uveal melanomas despite potential toxicities to normal tissues. This work proposes a nanoparticle ferrofluid as a novel intraocular shielding device. With a modified magnetic plaque, the shielding particles are drawn to the tumor surface, attenuating dose beyond the tumor while maintaining prescription dose to the target. Ferromagnetic nanoparticles suspended in a silicone polymer were synthesized to provide a high-density shielding medium. The ferrofluid's half-value layer (HVL) was quantified for 125I photons using radiochromic film and Monte Carlo methods. A magnetic COMS plaque was created and evaluated in its ability to attract ferrofluid over the tumor. Two ferrofluid shielding mediums were evaluated in their ability to attenuate dose at adjacent structures with in vitro measurements using radiochromic film, in addition to Monte Carlo studies. The shielding medium's HVL measured approximately 1.3 mm for an 125I photon spectrum, using film and Monte Carlo methods. With 0.8 mL of shielding medium added to the vitreous humor, it proved to be effective at reducing dose to normal tissues of the eye. Monte Carlo-calculated dose reductions of 65%, 80%, and 78% at lateral distances 5, 10, and 18 mm from a tumor (5-mm apical height) in a modeled 20-mm COMS plaque. The magnitude of dose reduction could reduce the likelihood of normal tissue side effects for plaque brachytherapy patients, including patients with normal tissues close to the plaque or tumor. Additional studies, safety considerations, and preclinical work must supplement these findings before use. [ABSTRACT FROM AUTHOR]

To investigate the treatment outcome, visual outcome, and adverse effects of five-fraction stereotactic radiosurgery (SRS) to medium- and large-sized uveal melanoma with a non-invasive eye immobilization device. Medical records of 14 patients with uveal melanoma receiving SRS with a total dose of 50 Gy in five fractions from 2008 to 2017 were retrospectively reviewed. A non-invasive eye fixation device was used to achieve and monitor eye immobilization. Local tumor control rates were 85.7% and 75.0% at 2 and 5 years, respectively. The average tumor diameter decreased significantly from 10.0 ± 3.21 mm to 8.36 ± 3.71 mm (p = 0.038) 15 months after SRS, while the average tumor thickness decreased significantly from 5.45 ± 2.21 mm to 4.34 ± 2.29 (p = 0.036) 21 months after SRS. The 5-year metastasis-free survival was 87.5%. The mean best-corrected visual acuity (BCVA) deteriorated from logMAR 0.296 at baseline to logMAR 1.112 at the last individual follow-up visits (p < 0.001). Adverse effects of SRS were comparable to those reported with proton-beam radiotherapy or Gamma knife therapy. SRS combined with a non-invasive eye immobilization device is an effective and safe alternative eye-preserving treatment for medium- to large-sized uveal melanoma. BCVA at 3 months may be a predictor for BCVA at 1 year. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the primary ocular cancer with upto 50% of patients dying from metastasis. Although rare, it is deadly as patients with metastatic UM seldom survive beyond 18 months after diagnosis. Chemotherapeutics have no proven efficacy, including immunotherapies that have been tried as current treatment options but produce marginal improvement in overall survival for UM patients. While therapeutics are low in efficacy, there is an urgent need to explore novel targets in the treatment of UM. This review provides an update on the contribution of inflammation to UM with a focus on exploring potential therapeutic targets related to the inflammatory tumour microenvironment. As a tumour promoting event, inflammation is one of the hallmarks of cancers. The presence of the inflammatory phenotype characterised by the abundance of immune mediators and proinflammatory cytokines surrounding UM tumours, is a potential area to explore novel therapeutic targets. Despite decades of investigation regarding the role UM tumour microenvironment has played, that of inflammation in UM progression remains poorly understood. With advancement of technologies, an understanding of the prognosis of UM has been accelerated. Excitingly, novel therapeutic targets related to the inflammatory tumour microenvironment have been identified and relevant studies are underway in their preliminary phases, illustrating optimistic results. [Display omitted] • Uveal melanoma (UM) is a highly metastatic intraocular cancer. • Inflammation plays a role in inflammatory UM tumour microenvironment. • Inflammation greatly contributes to UM prognosis and progression. • Novel therapeutics may be developed against UM inflammatory tumour microenvironment. [ABSTRACT FROM AUTHOR]

Uveal melanoma prognostication studies have mainly included posterior uveal melanomas located in the ciliary body and choroid, often excluding iris melanoma. In this study, we report prognostic status and survival outcomes in a series of 35 patients with biopsy-proven iris melanoma. Fluorescence in situ hybridization was performed in 10 (29%) cases and 2 (5%) underwent multiplex ligation-dependent probe amplification. In total, 9 cases demonstrated disomy 3, 2 cases with monosomy 3 (fluorescence in situ hybridization), and 1 had a technical failure. On gene expression profile testing, 20 of the 23 cases (90%) were gene expression profile class 1A, and the remaining 3 (10%) were class 1B. No patient had a Class 2 status. The median follow-up period was 49 months (mean 59, range 2–156 months). No metastasis was reported during follow-up, and metastasis-free survival was 100%. A review of the published literature revealed 47 cases with high-risk status on molecular prediction, of which only 6 (13%) developed metastasis. Ciliary body involvement was reported in 5 cases and was unknown in 2 cases. We conclude that molecular prognostication of iris melanoma demonstrates low-risk prognostic status in the majority of cases irrespective of the technique used. Even those with high-risk status do not develop metastasis unless the tumor involves the ciliary body. [ABSTRACT FROM AUTHOR]

Increased disease-specific mortality has been observed among patients with local recurrence (LR) from uveal melanoma (UM), but the underlying mechanism is unknown. The purpose of this study was to determine if copy number alterations of chromosomes 3 and/or 8q, at the time of diagnosis, increase the incidence of LR and if disease-specific mortality among patients with LR depends on the chromosome status of the primary tumor. Retrospective cohort study. The study included 239 consecutive patients with primary UM (choroidal or ciliary body) treated with Ruthenium-106 (Ru-106) brachytherapy from January 2009 to December 2019 at a single national referral center. Cox regression modeling and Kaplan–Meier analyses were used to assess the effect of the status of chromosomes 3 and 8q on the incidence of LR and disease-specific mortality after the event of LR. Multistate models were used to illustrate the probabilities over time of patients being alive and disease-free, alive with LR, dead from UM metastases, or dead from other causes split on the status of chromosomes 3 and 8q. Incidence of LR and disease-specific mortality. Local recurrence was observed in 42 patients (16%). Overall incidence of LR was not affected by aberrations of chromosomes 3 and/or 8q (P = 0.87). Although LR occurred earlier in patients with aberrations of chromosomes 3 and/or 8q compared with patients with a normal copy number of chromosomes 3 and 8q, the median time from primary diagnosis to LR was 1.6 years (interquartile range [IQR], 1.0–2.0) and 3.2 years (IQR, 2.1–5.0), respectively. Cox regression found LR to be an independent risk factor for disease-specific mortality (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5–5.0) among all patients, but multistate models demonstrated a low risk of disease-specific death among patients with normal chromosomes 3 and 8q status, even after an LR. Copy number alterations of chromosome 3 and/or 8q in the primary UM did not increase the overall incidence of LR. However, the development of an LR enhanced the risk of disease-specific mortality among patients with copy number alterations of chromosomes 3 and/or 8q. Even after an LR, disease-specific mortality remained low among patients with normal copy numbers of chromosomes 3 and 8q. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Uveal melanoma represents the most common intraocular neoplasia among adults. Brachytherapy (interventional radiotherapy; IRT) has a great advantage, when compared with enucleation, both in terms of organ and function sparing. The Collaborative Ocular Melanoma Study introduced into clinical practice a standardised procedure that allowed the equivalence of IRT with enucleation in terms of overall survival to be demonstrated. IRT is carried out by placing a plaque in direct contact with the sclera under the uveal melanoma. Several radioactive sources may be used, including 106-ruthenium, 125-iodine, 103-palladium and 90-strontium. It is a multidisciplinary procedure requiring the collaboration of interventional radiation oncologists and ophthalmologists in the operating theatre and medical physicists for an accurate treatment time calculation. It also relies on ultrasound imaging to identify the lesion and verifiy the correct plaque placement. An emerging tool of paramount importance could be the use of artificial intelligence and predictive models to identify those patients at higher risk of developing late side-effects and therefore who may deserve preventive and supportive therapies. [ABSTRACT FROM AUTHOR]

To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. Retrospective analysis. Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. Metastasis-free survival (MFS). Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61–6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86–4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%–62.8%). Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most frequent and life-threatening ocular malignancy in adults. Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis. However, a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic. Herein, using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers, we observed that disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of histone H3 lysine 79 (H3K79), was activated in UM, especially in the high-risk group. Concordantly, a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells, both in vitro and in vivo. Combining Cleavage Under Targets and Tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and bioinformatics analysis, we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase (NAPRT) and epigenetically activated its expression. Importantly, NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide (NAD+) synthesis. Therapeutically, DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79 (H3K79me2) in the NAPRT promoter, thereby inhibiting the malignant behaviors of UM. Conclusively, our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming. [Display omitted] • Revealing an integrated landscape of histone methylation in uveal melanoma. • DOT1L activates NAPRT through enhancing H3K79 methylation. • DOT1L fuels NAD + synthesis and promotes malignant transformation. [ABSTRACT FROM AUTHOR]

Evasion of pyroptosis is an effective survival strategy employed by cancer cells to evade immune cell attacks and drug-induced cytotoxicity. Exploring potent molecules capable of inducing pyroptosis in cancer cells has significant clinical implications for the control of cancer progression. Unexpectedly, we found that the local anesthetic tetracaine hydrochloride (TTC) induced pyroptosis, specifically in uveal melanoma but not in acral or cutaneous melanoma. We investigated the effects of TTC on various melanoma cell lines and performed transcriptome sequencing of TTC-treated uveal melanoma cells. The role of gasdermin E (GSDME), an executive protein responsible for pyroptosis, was explored using CRISPR-Cas13d knockdown, caspase-3 inhibitor treatment, and western blot analysis. Differential gene expression and pathway enrichment analyses were performed. Furthermore, we used tissue microarrays to assess GSDME expression levels in melanoma tissues from different anatomical sites. TTC significantly induced pyroptosis specifically in uveal melanoma cells with high GSDME expression levels. TTC treatment could lead to GSDME cleavage by the caspase-3 in uveal melanoma C918 cells. GSDME knockdown or caspase-3 inhibition suppressed TTC-induced pyroptosis. Transcriptome analysis revealed differentially expressed genes enriched in signaling pathways related to pyroptosis, immunity, and cytokines. This study showed that the local anesthetic TTC effectively induces pyroptosis in uveal melanoma through the caspase-3/GSDME pathway, highlighting its potential application in immunotherapy. Notably, the use of TTC has potential as an agent for inducing pyroptosis and as an adjuvant anticancer therapy in uveal melanoma. [Display omitted] • Local anesthetic tetracaine hydrochloride induces pyroptosis in uveal melanoma. • Uveal melanoma exhibits higher gasdermin E expression than other melanoma types. • The caspase-3/gasdermin E pathway mediates pyroptotic cell death induced by tetracaine hydrochloride in uveal melanoma. [ABSTRACT FROM AUTHOR]

This research aimed to identify the function of fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), and explore its possible mechanisms in uveal melanoma (UVM). We performed quantitative real-time PCR (qPCR), Western blotting and gene correlation analysis with GEPIA2 to assess FTO expression and identify its potential targets in UVM. CCK-8, colony formation, cell cycle, cell apoptosis, wound healing and Transwell invasion assays were utilized to assess cell viability, cell cycle distribution, apoptosis, migration and invasion. Western blotting, qPCR and methylated RNA immunoprecipitation–qPCR (MeRIP–qPCR) were carried out to explore the underlying mechanism of FTO in 2 UVM cell lines. FTO, a key m6A demethylase, was found to be upregulated in human UVM tissues compared with normal choroid tissues. Knockdown of FTO in Mel270 and OMM2.3 cells significantly promoted proliferation and migration and suppressed apoptosis. Mechanistically, knockdown of FTO decreased the expression of ATG5, an autophagy-related gene, leading to attenuation of autophagosome formation, thereby inhibiting autophagy. Upon FTO knockdown, increased levels of methylated ATG5 and decreased ATG5 stability were detected. Furthermore, ATG5 dramatically alleviated FTO downregulation-induced tumor growth and metastasis. Our research highlights the importance of the m6A demethylase FTO in UVM by demonstrating that it direct regulates ATG5-induced autophagy in an m6A-dependent manner. These findings suggest that FTO may serve as a potential therapeutic target for UVM. A graphical abstract illustrating our findings on FTO-mediated ATG5 to inhibit malignant progression of UVM was shown. [Display omitted] • RNA N6-methyladenosine demethylase FTO was upregulated in human UVM. • FTO-mediated m6A acted as a key factor in controlling uveal melanoma cell phenotype in vitro. • Overexpression of ATG5 rescued the FTO-induced promotion of UVM tumorigenesis. [ABSTRACT FROM AUTHOR]

I125 Eye Plaque brachytherapy is the standard treatment for medium-sized uveal melanomas (UM). Patients develop radiation toxicities (RTT), including radiation maculopathy (RM), radiation neovascular glaucoma/iris neovascularization (RNGI) and radiation optic neuropathy (RON). We aim to investigate demographics, pretreatment tumor characteristics and posttreatment complications as predictors of RTT. An IRB-approved single-institution retrospective chart review was performed from 2011 to 2019 for patients with posterior UM treated with brachytherapy. We collected demographics, pretreatment tumor characteristics and posttreatment complications. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using logistic regression model. Hazard ratios (HR) and corresponding p-values were reported. All tests were two-sided; statistical significance was considered when p <0.05. Two hundred and fifty eight patients were evaluated. Median follow-up was 33.50 months (range 3.02–97.31). 178 patients (69.0%) had RTT. 131 patients (50.8%) developed RM. Fifty-six patients (21.7%) developed RON. Nineteen patients (7.4%) developed RNGI. UVA found shorter distance to fovea (DF) (p = 0.04), posttreatment exudative retinal detachment (PERD) (p = 0.001) and posttreatment vitreous hemorrhage (PVH) (p = 0.001) are associated with RTT. MVA found shorter DF (HR=1.03, p = 0.04), PERD (HR=2.52, p = 0.01) and PVH (HR=3.34, p = 0.006) are associated with RTT. MVA found female sex (HR=1.731, p = 0.031) and tumor height (HR=1.13, p = 0.013) are associated with RM and pretreatment retinal detachment (HR=3.41, p <0.001) is associated with RON. Shorter DF, PERD and PVH are associated with RTT; female sex and tumor height are associated with RM and tumor height is associated with RON. These findings serve as prognostic tools to counsel patients and promote early intervention in management of RTT. [ABSTRACT FROM AUTHOR]

• After a median 74-month follow-up, the overall LC rate was 83% in UM treated with SRS/FSRT. • A dose of ≥45 Gy and BED10Gy ≥112.5 yielded higher LRFS and EFS rates. • Every other day treatment approach decreases the rates of toxicity and enucleation. To report the long-term results of stereotactic radiosurgery and fractionated stereotactic radiation therapy (SRS/FSRT) in patients with uveal melanoma (UM). We retrospectively evaluated the results of patients treated between 2007 and 2019. The primary endpoints were local control (LC), local recurrence-free survival (LRFS), enucleation-free survival (EFS) and treatment toxicity. 443 patients with 445 UMs were treated via CyberKnife®. According to the COMS classification, 70% of the tumors were small/medium and 30% were large. Median total RT dose was 54 Gy, median BED10 was 151 Gy. After a median 74-months follow-up, SRS/FSRT yielded an 83% overall LC rate. The 5- and 10-year LRFS rate was 74% and 56%, respectively. Patient age and the COMS size were prognostic for all survival endpoints. An increased SRS/FSRT dose was associated with higher LRFS and EFS rates. SRS/FSRT-related toxicity was observed in 49% of the eyes. Median visual acuity (VA) significantly deteriorated after SRS/FSRT in 76% of the treated eyes. The overall eye preservation rate was 62%, and the 5- and 10-year EFS rate was 64% and 36%, respectively. The delivery of FSRT every other day resulted in a significantly lower rate of toxicity and enucleation compared to FSRT on consecutive days. A total dose of ≥45 Gy and BED 10Gy ≥ 112.5 SRS/FSRT is associated with a higher LC rate in patients with UM. Despite the favorable outcomes, treatment toxicity is the major limitation of this treatment. Toxicity and enucleation can be minimized by treating the eye every other day. [ABSTRACT FROM AUTHOR]

Since molecular assays are not accessible to all uveal melanoma patients, we aim to identify cost-effective prognostic tool in risk stratification using machine learning models based on routine histologic and clinical variables. We identified important prognostic parameters in a discovery cohort of 164 enucleated primary uveal melanomas from 164 patients without prior therapies. We then validated the prognostic prediction of top important parameters identified in the discovery cohort using 80 uveal melanomas from the Tumor Cancer Genome Atlas database with available gene expression prognostic signature (GEPS). The performance of three different survival analysis models (Cox proportional hazards (CPH), random survival forest (RSF), and survival gradient boosting (SGB)) was compared against GEPS using receiver operating curves (ROC). In all three selection methods, BAP1 status, nucleoli size, age, mitotic rate per 1 mm2, and ciliary body infiltration were identified as significant overall survival (OS) predictors; and BAP1 status, nucleoli size, largest basal tumor diameter, tumor-infiltrating lymphocyte density, and tumor-associated macrophage density were identified as significant progression-free survival (PFS) predictors. ROC plots for the median survival time point showed that significant parameters in SGB studied model can predict OS better than GEPS. For PFS, SGB model performed similarly to GEPS. The time-dependent area under the curve (AUC) showed SGB model performing better than GEPS in predicting OS and metastatic risk. Our study shows that routine histologic and clinical variables are adequate for patient risk stratification in comparison with not readily accessible GEPS. [Display omitted] • Molecular assays are not accessible to all uveal melanoma patients. • We investigate machine learning models on clinicopathologic variables for risk stratification. • Machine learning models included random survival forest and survival gradient boosting. • They performed similarly or better than gene expression prognostic signature. • Readily accessible clinicopathologic variables can provide adequate prognostic information. [ABSTRACT FROM AUTHOR]

• Ocular dose limits are necessary to evaluate a novel intraocular shielding method. • Retrospective study reviewed dosimetry and toxicity data for eye plaque patients. • Doses>52 Gy to the macula and 42 Gy to the optic disc should be avoided. • Further work is needed to reduce high doses and improve patients' quality of life. The aim of this study was to relate common toxicity endpoints with dose to the macula, optic disc, and lens for uveal melanoma patients treated with Iodine-125 Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy. A cohort of 52 patients treated at a single institution between 2005 and 2019 were retrospectively reviewed. Demographics, dosimetry, and clinical outcomes were recorded. Univariate, relative risk, and Kaplan-Meier analyses were performed to relate dose to toxicity endpoints including retinopathy, vision decline, and cataracts. By the end of follow up (Median = 3.6 years, Range = 0.4 – 13.5 years), 65 % of eyes sustained radiation retinopathy, 40 % demonstrated moderate vision decline (>5 Snellen lines lost), and 56 % developed cataracts. Significant (p < 0.05) risk estimates exist for retinopathy and VA decline for doses >52 Gy to the macula and >42 Gy to the optic disc. Moreover, dose to the lens > 16 Gy showed a significant risk for cataract formation. Kaplan-Meier analysis demonstrated significantly different incidence of radiation retinopathy for > 52 Gy to the macula and > 42 Gy to the optic disc. In addition, the Kaplan-Meier analysis showed significantly different incidence of cataract formation for patients with lens dose > 16 Gy. Dose-effect relationships exist for the macula and optic disc with respect to the loss of visual acuity and the development of retinopathy. To better preserve vision after treatment, further research is needed to reduce macula, optic disc, and lens doses while maintaining tumor control. [ABSTRACT FROM AUTHOR]

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated G α q/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting G α q/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as G α q/11 inhibitors, and identified GQ262 with improved G α q/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase (ERK), and yes-associated protein (YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting G α q/11 directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting G α q/11 may be an efficient strategy against uveal melanoma. Constitutively activated G α q/11 proteins drive the vast majority of uveal melanoma (UM). GQ262 effectively combats UM both in vitro and in vivo by targeting G α q/11 directly. [Display omitted] [ABSTRACT FROM AUTHOR]

Mutations in the Gα-genes GNAQ and GNA11 are found in 85–90% of uveal melanomas (UM). Aim of the study is to understand whether the mutations in both genes differentially affect tumor characteristics and outcome and if so, to identify potential mechanisms. We analyzed the association between GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. We used tandem-affinity-purification, mass spectrometry and immunoprecipitation to identify protein interaction partners of the two G-proteins and analyzed their impact on DNA-methylation. GNA11 mutation was associated with: i) an increased frequency of loss of BRCA1 -associated protein 1 (BAP1) expression (p = 0.0005), ii) monosomy of chromosome 3 (p < 0.001), iii) amplification of chr8q (p = 0.038), iv) the combination of the latter two (p = 0.0002), and inversely with v) chr6p gain (p = 0.003). Our analysis also showed a shorter disease-specific survival of GNA11 -mutated cases as compared to those carrying a GNAQ mutation (HR = 1.97 [95%CI 1.12–3.46], p = 0.02). GNAQ and GNA11 encoded G-proteins have different protein interaction partners. Specifically, the Tet Methylcytosine Dioxygenase 2 (TET2), a protein that is involved in DNA demethylation, physically interacts with the GNAQ protein but not with GNA11 , as confirmed by immunoprecipitation analyses. High-risk UM cases show a clearly different DNA-methylation pattern, suggesting that a different regulation of DNA methylation by the two G-proteins might convey a different risk of progression. GNA11 mutated uveal melanoma has worse prognosis and is associated with high risk cytogenetic, mutational and molecular tumor characteristics that might be determined at least in part by differential DNA-methylation. • GNA11 mutations are associated with increased risk of death in uveal melanoma. • GNA11 mutated uveal melanoma shows high risk cytogenetics and gene expression. • GNAQ but not GNA11 protein physically interacts with the demethylating enzyme TET2. • GNAQ and GNA11 mutated uveal melanoma shows different DNA-methylation patterns. [ABSTRACT FROM AUTHOR]

Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology strategy in routine clinical practice. Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program. Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was >1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit. A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing. • Demonstration of the feasibility of precision oncology for advanced uveal melanoma. • Complete whole-genome and RNA sequencing data were generated for 87% of patients. • Following treatment recommendations, 60% of patients received ≥1 matched therapy. • First-line therapies included inhibitors of MEK, MET, sorafenib, and nivolumab. • Clinical benefit rate in 56% of patients with one partial response under nivolumab. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a highly metastatic ocular cancer that arises from the melanocytes of the uveal tract (the choroid, ciliary body and iris). Despite a growing understanding of UM biology, effective systemic treatments are currently lacking and the cancer has an extremely poor prognosis. Therefore, identifying novel agents that act by new tumorigenic mechanisms in UM is essential to address this unmet clinical need. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the organelle, and the unfolded protein response (UPR) is the cellular mechanism that is activated so that cells may adapt to the situation. Dysregulated UPR signalling has been detected in UM tumors and has been associated with an increase in immune evasion and metastatic activity. A number of established and novel oncology drugs act in part by modulating ER stress and the UPR. The induction of protein-folding stress and the UPR could be a novel approach for the development of new therapeutics in UM. Further studies are now warranted to understand the mechanisms and consequences of UPR signalling in UM. [Display omitted] • Uveal melanoma (UM) is a highly metastatic ocular cancer without systemic treatment. • Sustained unfolded protein response (UPR) activation has been demonstrated in UM. • Many aspects of UM biology are related to the persistent UPR activation. • Understanding how UPR signalling contributes to UM biology. • It enables the development of effective therapeutics in treating UM. [ABSTRACT FROM AUTHOR]

• A two-beam arrangement in ocular proton therapy has been investigated. • T1 and T2 posterior choroidal tumors would benefit most from this strategy. • This leads to improved anterior region and sclera sparing. • The cost to the optic nerve is clinically acceptable. • Delivering the two beams the same day is radiobiologically better. To investigate the potential clinical benefit of a two-beam arrangement technique using three-dimensional (3D) imaging of uveal melanoma (UM) patients treated with proton therapy and a dedicated eyeline. Retrospective CT-based treatment plans of 39 UM patients performed using a single beam (SB) were compared to plans with two beams (TB) optimized for better trade-offs in organs-at-risk sparing. The RBE-weighted prescribed dose was 60 Gy (D RBE, GTV = 60 Gy) in four fractions, assuming an RBE of 1.1. Dosimetric findings were analyzed for three patient groups based on tumor-optic nerve distance and UM staging (group GrA: ≤3 mm, T1 T2 UM; GrB: ≤3 mm, T3 UM; GrC: >3 mm, T1 T2 T3 UM). Finally, two schedules were compared on biologically effective dose (BED): both beams being delivered either the same day (TB), or on alternate days (TBalter). All strategies resulted in dosimetrically acceptable plans. A dose reduction to the anterior structures was achieved in 23/39 cases with the two-beam plans. D 25% was significantly lowered compared to SB plans by 12.4 and 15.4 Gy RBE-weighted median dose in GrA and GrB, respectively. D 2% was reduced by 18.6 and 6.0 Gy RBE-weighted median dose in GrA and GrB, respectively. A cost to the optic nerve was observed with a median difference up to 3.8 Gy RBE-weighted dose in GrB. BED differences were statistically significant for all considered parameters in favor of two beams delivered the same day. A two-beam strategy appears beneficial for posterior tumors abutting the optic nerve. This strategy might have a positive impact on the risk of ocular complications. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a rare disease and the most common primary intraocular malignancy in adults, with a high risk of metastases. Reliable prognostication systems are based on anatomic features, as in the tumor–node–metastasis staging of the American Joint Committee on Cancer (AJCC) system, or on genetic information, as in The Cancer Genome Atlas (TCGA) system. Prior evidence suggests that combining both systems may be beneficial. We evaluated the benefit of combining the TCGA and AJCC systems in a large cohort of patients. Retrospective case series of patients with UM. Nine hundred seventy-nine patients with a choroidal or ciliary body melanoma treated at the Wills Eye Hospital between 1998 and 2020, 94% of whom received eye-sparing treatment. Tumors were classified into 4 TCGA groups based on chromosome copy number: A (disomy 3, normal 8q), B (disomy 3, any 8q gain), C (monosomy 3, 1 extra copy of 8q), and D (monosomy 3, multiple 8q gain). The eighth edition of the AJCC staging manual was used for AJCC staging. Cox regression and the log-rank test were used for survival analysis. Metastasis-free survival. Combining information of the 2 systems improved prognostication in intermediate groups: in TCGA group C, we saw an increased rate of metastasis in AJCC stage III (28%) compared with stage II (8.9%); the same was seen in AJCC stage II, going from TCGA group C (8.9%) to group D (46%), and in AJCC stage III, going from group C (28%) to group D (49%). In patients with AJCC stage II or III disease, loss of chromosome 3 and gain of 8q (TCGA groups C and D) significantly worsened the prognosis, with multiple 8q gain (TCGA group D) having a greater impact. Combining information from AJCC stages and TCGA groups yields a better predictive power even in this set of relatively small tumors. We propose that physicians take both systems into account whenever possible, especially in moderate-risk groups. [ABSTRACT FROM AUTHOR]

Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases. [ABSTRACT FROM AUTHOR]

• EPB is the most frequently used eye-sparing treatment option for small to medium sized UMs. • We present a systematic review of the literature from the last sixteen years on EPB treatment of UM. • Ru-106 EPB provided high local control outcomes minimizing radiation induced complications. • TCP and NTCP on pooled clinical outcomes was performed for 5-year LTC, cataract and optic neuropathy. Uveal melanoma (UM) represents the most common primary intraocular tumor, and nowadays eye plaque brachytherapy (EPB) is the most frequently used visual acuity preservation treatment option for small to medium sized UMs. The excellent local tumor control (LTC) rate achieved by EPB may be associated with severe complications and adverse events. Several dosimetric and clinical risk factors for the development of EPB-related ocular morbidity can be identified. However, morbidity predictive models specifically developed for EPB are still scarce. PRISMA methodology was used for the present systematic review of articles indexed in PubMed in the last sixteen years on EPB treatment of UM which aims at determining the major factors affecting local tumor control and ocular morbidities. To our knowledge, for the first time in EPB field, local tumor control probability (TCP) and normal tissue complication probability (NTCP) modelling on pooled clinical outcomes were performed. The analyzed literature (103 studies including 21,263 UM patients) pointed out that Ru-106 EPB provided high local control outcomes while minimizing radiation induced complications. The use of treatment planning systems (TPS) was the most influencing factor for EPB outcomes such as metastasis occurrence, enucleation, and disease specific survival, irrespective of radioactive implant type. TCP and NTCP parameters were successfully extracted for 5-year LTC, cataract and optic neuropathy. In future studies, more consistent recordings of ocular morbidities along with accurate estimation of doses through routine use of TPS are needed to expand and improve the robustness of toxicity risk prediction in EPB. [ABSTRACT FROM AUTHOR]

It was aimed to investigate the dosimetric differences among linac-based and robotic stereotactic radiotherapy (SRT) techniques for the treatment of uveal melanoma and to evaluate secondary malignancy risks for these different SRT techniques. Ten patients who received robotic SRT with CyberKnife were retrospectively included in this study. A total dose of 54 Gy in three fractions was prescribed to the planning target volume (PTV). For each patient, non-coplanar micro-multileaf collimator based dynamic conformal arc (DCA), intensity-modulated radiotherapy (IMRT) and circular cone based DCA (cDCA) plans were generated. During the analysis dose-volume histogram (DVH) parameters, homogeneity index, new conformity index, the volume received more than or equal to 30% and 50% of the prescribed dose were compared. Additionally, secondary malignancy risk for each technique was estimated using the risk factors recommended by The International Commission on Radiological Protection. Robotic SRT plans provided a high degree of conformity within the PTV and better normal tissue sparing compared to linac-based treatment plans. However, dose distribution was more heterogeneous in robotic SRT plans than that in linac-based techniques. Estimated secondary malignancy risk was also found as 3.4%, 1.4%, 1.4% and 1.6% for robotic SRT and linac-based IMRT, DCA, cDCA plans, respectively. Treatment parameters of uveal melanoma patients planned with robotic SRT had superior conformity and organ-at-risk (OAR) sparing compared with those planned with the linac-based system. However, estimated secondary malignancy risk was almost two-times higher in robotic SRT than that in linac-based techniques. [ABSTRACT FROM AUTHOR]

To investigate local and systemic outcomes after enucleation, brachytherapy with ruthenium-106, iodine-125, notched and non-notched plaques and transpupillary thermotherapy (TTT) of choroidal melanomas touching the optic disc. All patients treated for choroidal melanoma touching the optic disc at St. Erik Eye Hospital, Stockholm, Sweden between 1984 and 2015 (n = 165) were included. Retrospective clinicopathological data was collected and 3D dosimetry performed. Ninety-five patients (58 %) had been treated with ruthenium-106 brachytherapy, 21 (13 %) with iodine-125 brachytherapy and 49 (30 %) with enucleation. Median follow-up was 12.3 years. In simulations, some tumor areas were underdosed with non-notched plaques. Fifty of 116 patients (43 %) underwent a secondary brachytherapy (n = 5), enucleation (n = 29) or TTT (n = 16). In multivariate Cox Regressions, there were no significant differences in the risk for tumor progression or lack of regression between radioisotopes and notched and non-notched plaques. Adding TTT did not reduce the risk for a second treatment. The number of clock hours of circumpapillary tumor growth did not correlate to the risk for treatment failure or mortality. There were no significant differences in melanoma-related mortality for any treatment including enucleation. Kaplan-Meier disease-specific survival was 77 % at 5 years, 72 % at 10 years and 67 % at 20 years. Plaque brachytherapy of choroidal melanomas touching the optic disc entails a two to threefold increased risk for treatment failure. This risk is similar between radioisotopes, notched and non-notched plaque designs and if TTT is used or not. The high rate of treatment failure does not lead to increased mortality. [ABSTRACT FROM AUTHOR]

• This is the first study showing mitochondrial DNA variations and haplogroup identification in uveal melanoma (UM) cell lines. • The entire mtDNA genome sequencing showed differences in heteroplasmic SNPs in primary and metastatic cell lines. • Modulation in mitochondrial biogenesis genes and mtDNA copy number were seen in primary and metastatic UM cell lines. Purpose: This study was designed to identify mitochondrial (mt) DNA variations in primary and metastatic uveal melanoma (UM) cell lines and their relation with cell metabolism to gain insight into metastatic progression. Method: The entire mtDNA genomes were sequenced using Sanger sequencing from two primary UM cell lines (92.1 and MEL270) and two cell lines (OMM2.3 and OMM2.5) derived from liver metastases of the MEL270 patient. The mtDNA copy numbers determined by the ratio of nDNA versus mtDNA. qRT-PCR was used to evaluate expression levels of mitochondrial biogenesis genes. Results: Sequencing showed that cell line MEL270 and metastases-derived OMM2.3 and OMM2.5 cell lines had homoplasmic single nucleotide polymorphisms (SNPs) representing J1c7a haplogroup, whereas 92.1 cells had mtDNA H31a haplogroup. mtDNA copy numbers were significantly higher in primary cell lines. The metastatic UM cells showed down-regulation of POLG, TFAM, NRF-1 and SIRT1 compared to their primary MEL270 cells. PGC-1α was downregulated in 92.1 and upregulated in MEL270, OMM2.3 and OMM2.5. Conclusions: Our finding suggests that within metastatic cells, the heteroplasmic SNPs, copy numbers and mitochondrial biogenesis genes are modulated differentially compared to their primary UM cells. Therefore, investigating pathogenic mtDNA variants associated with cancer metabolic susceptibility may provide future therapeutic strategies in metastatic UM. Uveal melanoma (UM) is the most common primary intraocular tumor in adults and newer strategies are needed to treat metastatic UM tumors. This is the first study showing the mitochondrial (mt) DNA variations and identification of mtDNA haplogroup in UM cell lines. The entire mtDNA genome sequencing showed differences in heteroplasmic SNPs in primary (92.1 and MEL270) and metastatic cell lines (OMM2.3 and OMM2.5 derived from liver metastasis of the primary MEL270 patient). Our work demonstrates the modulation in mitochondrial biogenesis genes and variable levels of mtDNA copy number indicating mtDNA as a potential future therapeutic target in metastatic UM. [ABSTRACT FROM AUTHOR]

To determine the response rate of choroidal melanoma following primary photodynamic therapy, we conducted a meta-analysis of published studies. A total of 7 studies reporting photodynamic therapy as primary treatment of choroidal melanoma in 162 patients with a mean tumor height of 2.8 mm (1.4 to 4.2) were identified. Forty-six percent of tumors were amelanotic, 48% were fully pigmented, and 6% had partial pigmentation. The photodynamic therapy parameters in all studies included 10-minute intravenous infusion of verteporfin (6 mg/m2), but varied in number of sessions (1 to 3), fluence (1× to 19×), and number of spots (single or multiple). The response was defined as tumor regression (partial or total) or lack of growth after initial treatment. The response to photodynamic therapy was predominantly observed as regression (126 [78%]). Overall response rate was 80% (mean) with a wide range among studies (58%–100%) over a period of 50 months (mean) with variable follow-up (range, 1–156 months). None of the studies reported progression- or recurrence-free survival; however, the recurrence rate was not related to the follow-up duration. Favorable prognostic factors were smaller size and lack of pigmentation. The overall response rate of 80% suggests that photodynamic therapy may be an effective primary treatment for small choroidal melanoma, especially in cases without pigmentation. Artifacts in study design (inclusion criteria and outcome measure) may have contributed to the variable observed response rate. Further studies with uniform inclusion criteria, standardized treatment parameters, well-defined outcome measures, and long follow-up are needed. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common primary ocular tumor in the adult population. Even though these primary tumors are successfully treated in 90% of cases, almost 50% of patients ultimately develop metastasis, mainly in the liver, via hematological dissemination, with a median survival spanning from 6 to 12 months after diagnosis. In this context, chemotherapy regimens and molecular targeted therapies have demonstrated poor response rates and failed to improve survival. Among the multiple reasons for therapy failure, the presence of cancer stem-like cells (CSCs) represents the main cause of resistance to anticancer therapies. In the last few years, the existence of CSCs in UM has been demonstrated both in preclinical and clinical studies, and new molecular pathways and mechanisms have been described for this subpopulation of UM cells. Here, we will discuss the state of the art of CSC biology and their potential exploitation as therapeutic target in UM. [ABSTRACT FROM AUTHOR]

[Display omitted] • Green synthesis of silver nanoparticles mediated by Curcuma longa extract. • Curcuma longa extract act as a reducing and stabilizing agent without any toxic regents. • Ag NPs/C. longa nanocatalyst was used to reduction of organic pollutants. • Ag NPs/C. longa nanocatalyst shown good antioxidant and anti-cancer effects. The creation of cutting-edge technology for the effective method of treating wastewater that contains hazardous organic contaminants is crucial on a global scale. The use of nanocatalysts based on noble metals and sodium borohydride as a reduction agent has become common practice in recent years to remove organic pollutants from aqueous media. This paper describes a simple method for synthesizing silver nanoparticles as a hopeful nanocatalyst for organic pollution reduction. A silver salt precursor (AgNO 3) was reduced using Curcuma longa extract without the use of the materials such as reducing or capping agents. XRD, FESEM-EDS, TEM, UV–Vis spectroscopy, and FTIR were applied to characterize the Ag NPs/C. longa nanocatalyst. In the water solvent and ambient temperature, the performance of nanocatalyst was evaluated during the reaction reduction of 4-nitrophenol, and toxic dyes such as methylene blue (cationic dye), and methyl orange (anionic dye). In addition to reducing 4-nitrophenol and dyes, the nanocatalyst demonstrated good catalytic performance. For the reduction of these compounds, the estimated pseudo-first-order rate constants were 0.05, 0.047, and 0.037 s−1, respectively. Five successive cycles of this nanocatalyst did not significantly decrease its catalytic activity. A study has demonstrated that Ag NPs/C. longa nanocatalyst have the potential to reduce harmful pollutants from wastewater chemically, as well as they are an ideal catalyst for environmental applications because of their environmentally friendly synthesis and reusability. The in vitro anticancer effects of biologically synthesized Ag NPs/C. longa nanocatalyst against uveal melanoma cell was reported. The IC 50 of the Ag NPs/C. longa nanocatalyst was 106 µg/mL against MUM2B. The highest antioxidant effect was shown at 1000 μg/ml and above 100 % and the IC 50 was 157 µg/mL. Analysis of expression level of some genes (PIK3, AKT, and mTOR) involved in the mTOR pathway and Bax, Bcl2, and Caspase-3 observing that Ag NPs/C. longa nanocatalysts control MUM2B cell apoptosis and proliferation via the PI3K-Akt-mTOR signaling pathway regulation. Ag NPs/C. longa nanocatalysts induced the cell cycle inhibition and apoptosis in the mTOR pathway. [ABSTRACT FROM AUTHOR]

In recent years, advances in melanoma treatment have renewed patient hope. This comprehensive review emphasizes the evolving treatment landscape, particularly highlighting first-line strategies and the interplay between immune-checkpoint inhibitors (ICIs) and targeted therapies. Ipilimumab plus nivolumab has achieved the best median overall survival, exceeding 70 months. However, the introduction of new ICIs, like relatlimab, has added complexity to first-line therapy decisions. Our aim is to guide clinicians in making personalized treatment decisions. Various features, including brain metastases, PD-L1 expression, BRAF mutation, performance status, and prior adjuvant therapy, significantly impact the direction of advanced melanoma treatment. We also provide the latest insights into the treatment of rare melanoma subtypes, such as uveal melanoma, where tebentafusp has shown promising improvements in overall survival for metastatic uveal melanoma patients. This review provides invaluable insights for clinicians, enabling informed treatment choices and deepening our understanding of the multifaceted challenges associated with advanced melanoma management. [Display omitted] • Ipilimumab/nivolumab is the regimen of choice, achieving a mOS of over 70 months. • New ICIs, like relatlimab, add complexity to first-line therapy decisions. • Brain metastases, PD-L1, BRAF, PS, prior adjuvant, guide advanced melanoma treatment • Tebentafusp improved OS for metastatic uveal melanoma patients [ABSTRACT FROM AUTHOR]

Uveal melanoma is the most common primary ocular tumor owing to its highly invasive and metastatic characteristics. Currently, standard clinical treatment has an unsatisfied curative effect due to the lack of an effective approach to inhibit the tumor metastasis. Therefore, it is necessary to develop a new strategy that can both restraint local tumors and suppress the ocular tumor metastasis. Herein, we developed ultrasound-responsive nanoparticles (FeP NPs) that can both hinder the growth of in situ ocular tumor and prevent the tumor metastasis through the ferroptosis-apoptosis combined-anticancer strategy. The FeP NPs were assembling by stimulating gallic acid-Fe (III) and paclitaxel, then could be internalized into tumor cells under the cooperative effect of ultrasound, which further activates the intracellular Fenton reaction and generates high reactive oxygen species levels, ultimately leading to mitochondrial damage, lipid per-oxidation, and apoptosis. The FeP NPs can efficiently inhibit the tumor growth in an orthotopic uveal melanoma model. More importantly, the level of the promoting-metastatic factor nerve growth factor receptor (NGFR) secreted by cancer cells is significantly reduced, further limits cancer metastasis to the cervical lymph node and finally inhibits lung metastasis of uveal melanoma. We believe that these designed ultrasound-enhanced nanoparticles possess potential clinical application for preventing the regeneration and metastasis of uveal melanoma. Ultrasound-Enhanced Nano catalyst were assembling by stimulating gallic acid-Fe (III) and paclitaxel, then could be internalized into tumor cells under the cooperative effect of ultrasound, which further activates the intracellular Fenton reaction and generates high reactive oxygen species levels, ultimately leading to mitochondrial damage, lipid per-oxidation, and apoptosis, further amplify the therapeutic effect of the ferroptosis and chemotherapy plus ultrasound therapy. [Display omitted] • FeP NPs, crafted from gallic acid-Fe and paclitaxel, boost ferroptosis and chemo-ultrasound efficacy in tumors. [ABSTRACT FROM AUTHOR]

To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors. Observational case series. Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas. Hematoxylin–eosin and PAX8 immunohistochemical stains were performed on all specimens. In appropriate cases, bleached preparations and other immunohistochemical stains, including AE1/AE3 cytokeratin, Lin28A, and CD45, were performed. Distribution of PAX8 expression in normal and neoplastic tissue. Strong nuclear PAX8 expression was observed in the normal corneal epithelium, iris sphincter pupillae muscle, iris pigment epithelium and dilator muscle complex, nonpigmented and pigmented epithelia of the ciliary body, lens epithelium, and a subset of retinal neurons. The normal retinal pigment epithelium and uveal melanocytes did not stain for PAX8. The ciliary body epithelial and neuroepithelial tumors (adenoma, adenocarcinoma, and medulloepithelioma) showed uniform strong nuclear PAX8 immunoreactivity. All melanocytic tumors (iris melanoma, ciliary–choroidal melanoma, and melanocytoma) and retinal pigment epithelial neoplasms showed negative results for PAX8. A subset of tumor-associated lymphocytes, most prominent in uveal melanoma, showed positive results for PAX8. The uniformity of the PAX8 staining was superior to the variable cytokeratin staining in the ciliary epithelial neoplasms and the variable Lin28A staining in malignant medulloepithelioma. The veracity of PAX8 staining was equally as robust on cytologic analysis and open-flap biopsy specimens of ciliary epithelial and iris epithelial neoplasms, melanocytoma, and melanoma. PAX8 has proven to be a very useful diagnostic marker in a select group of adult intraocular tumors, and we highly recommend its inclusion in diagnostic antibody panels of morphologically challenging intraocular neoplasms. [ABSTRACT FROM AUTHOR]

Radiation maculopathy and radiation-induced macular edema are common, sight-threatening complications after radiotherapy, especially that used for uveal melanoma. While many treatment and preventive strategies have been proposed, management of these conditions is still challenging. Initially, treatments were based on the use of retinal laser, but the outcomes were poor. Subsequently, management has shifted toward injection of intravitreal antivascular endothelial growth factor or corticosteroids. We reviewed current clinical evidence, which mostly relies on small sample-sized and retrospective studies, for the management of radiation maculopathy and, in particular, radiation-induced macular edema. At present, the first-line approach is usually intravitreal antivascular endothelial growth factor. Intravitreal dexamethasone implantation may be an option for those with suboptimal response or contraindications to antivascular endothelial growth factor agents. Possible preventive treatments that require future study are intravitreal bevacizumab and ranibizumab, peripheral laser photocoagulation, and subtenon triamcinolone acetonide. [ABSTRACT FROM AUTHOR]

• Uveal melanoma treated with stereotactic radiotherapy: 5-year tumour control 96.1%. • Uveal melanoma treated with proton beam radiotherapy: 5-year tumour control 96.1%. • Vitreous haemorrhages occur more after stereotactic radiotherapy than proton beam. • Larger tumours are a risk for maculopathy and enucleation. To compare the adverse side effects of fractionated stereotactic photon beam radiotherapy (fSRT) with proton beam radiotherapy (PBR) in patients with uveal melanoma (UM). A retrospective study investigating 306 UM patients treated with fSRT (N=153) by the Rotterdam Ocular Melanoma Study group (ROMS), The Netherlands, between 1999–2014 or with PBR (N=153) at the Royal Liverpool University Hospital and the Clatterbridge Cancer Centre, Bebington, United Kingdom, between 1993–2014. The tumours treated with fSRT were matched with tumours treated with PBR based on sex, left or right eye, TNM classification, posterior margin ≤ or > 3mm of the fovea and of the optic disc. The five-year actuarial rates of tumour recurrence were 4.5% for fSRT and 6.1% for PBR. For fSRT and PBR, the five-year actuarial rates of maculopathy were 14.9% and 12.4%, and for vitreous haemorrhage were 29.4% and 4.7%, respectively. Only vitreous haemorrhage (HR: 0.19, 95% CI: 0.07–0.56) was more common after fSRT compared to PBR. Overall, larger tumours were risk factors for maculopathy and secondary enucleation. Both treatments have excellent local tumour control. In matched groups, vitreous haemorrhage was the only adverse side effect showing a significant difference between groups. [ABSTRACT FROM AUTHOR]

• The potential and pitfalls of target volume definition in ocular proton therapy based on Magnetic Resonance Imaging (MRI) were investigated and compared to the conventional clinical method based on metallic clips implantation on 33 uveal melanoma patients. • In contrast to previous publications, an extensive description of discrepancies between the different modeling of the target volumes, together with a thorough investigation of the causes, is performed, as well as an investigation into the potential dosimetric consequences. • For two out of thirty-three (6%) patients the lesion was invisible in MRI. Significant discrepancies between MRI and clips-based eye models were observed for tumor volume definition, with the MRI volumes being, on average, smaller than the clips-based one. Our results demonstrate that, independent of observer, while the height of MRI-based tumor volume agrees with the ultrasound assessment used in the conventional approach, inconsistencies in the definition of the base of the tumor between models produce the largest discrepancy in tumor volume definition. • We observed a decrease of delineation discrepancies between radiation oncologists as a function of tumor size suggesting that, the bigger the lesion, the more visible it is on MRI images. • Although the proposed MRI protocol has the potential to improve the accuracy of the eye model, on its own, it cannot replace the current clinical standard for target volume definition. However, the situation could change with the introduction of complementary ophthalmological imaging into the MRI approach in a geometrically accurate fashion. Ocular proton therapy (OPT) for the treatment of uveal melanoma has a long and remarkably successful history. This is despite that, for the majority of patients treated, the definition of the eye anatomy is based on a simplified geometrical model embedded in the treatment planning system EyePlan. In this study, differences in anatomical and tumor structures from EyePlan, and those based on 1.5T magnetic resonance imaging (MRI) are assessed. Thirty-three uveal melanoma patients treated with OPT at our institution were subject to eye MRI. The target volumes were manually delineated on those images by two radiation oncologists. The resulting volumes were geometrically compared to the clinical standard. In addition, the dosimetric impact of using different models for treatment planning were evaluated. Two patients (6%) presented lesions too small to be visible on MRI. Target volumes identified on MRI scans were on average smaller than EyePlan with discrepancies arising mostly from the definition of the tumor base. Clip-to-tumor base distances measured on MRI models exhibited higher discrepancy to ophthalmological measurements than EyePlan. For 53% of cases, treatment plans optimized for lesions identified on MRI only, failed to achieve sufficient target coverage for EyePlan volumes. The analysis has shown that 1.5T MRI might be more susceptible to misses of flat tumor extension of the clinical target volume than the current clinical standard. Thus, a proper integration of ancillary imaging modalities, leading to a better characterization of the full lesion, is required. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common intraocular tumor in adults and has a high incidence of metastases. Possible treatments remain limited in UM with enucleation and radiation, leading to poor prognosis in this chemo-resistant carcinoma. Thus, urging demand for novel treatment is needed. We examined the antitumor efficacy of a new recombinant oncolytic herpes simplex virus type 1 (oHSV-1) armed with E.coli cytosine deaminase (CD). We determined the efficacy of the oncolytic virus in UM cell lines. In vivo experiments showed that oHSV-CD/5-fluorocytosine (5-FC) treatment reduce tumor volume and prolonged survival. We further demonstrated the molecular mechanisms of oHSV-CD/5-FC treatment. The oncolytic virus down-regulated IL-6 expression and thereby reversed the epithelial-mesenchymal transition (EMT) phenotype. Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) metabolism, was also down-regulated. Therefore, the efficacy of oHSV-CD/5-FC was synergistically enhanced by DPD down-regulation and EMT inhibition. This study provides solid evidence for the antitumor efficacy of oHSV-CD/5-FC treatment in vitro and in vivo. The molecular mechanisms of this treatment may bring a new therapeutic approach for future treatment of UM. [ABSTRACT FROM AUTHOR]

In cases of suspected intraocular malignancy, vitreous may be the preferred pathologic sample; however, cellularity may be insufficient for definitive cytopathological diagnosis. Ancillary methodology to study vitreous fluid aspiration for mutational analysis may assist in treatment decisions. Three individual patient vitreous humor samples were received in the laboratory for mutation testing. The samples were collected during standard of care and analyzed for routine cytopathology. In each case, cytopathology was inconclusive and mutational analyses to support diagnostic suspicions were clinically requested. Based on the clinically and pathologically suspected diagnoses, an appropriate massively parallel sequencing assay previously validated for clinical use was performed using DNA extracted from vitreous samples that had previously undergone various processing. Nucleic acid yield was assessed by fluorometric or spectrophotometric methods, with yield ranging from 2.7 to 86.5 ng. Library preparations were performed using standard laboratory protocols. Two of the cases were suspicious for melanoma and a 50-gene solid tumor panel was performed. The third case was worrisome for vitreoretinal lymphoma and a 49-gene myeloid panel was performed. In all cases, the molecular profiling assisted with the clinical assessment and/or management of each patient. • In this case series, the cytology of the vitreous was inconclusive and molecular profiling of the vitreous did identify variants that contributed to the clinical assessment of each patient. • In cases of inconclusive cytology, it may be possible to clarify the clinical picture using molecular profiling by massively parallel sequencing of vitreous. • In these cases, the molecular profiling assisted with diagnosis, patient management, and/or treatment. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available. To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs). We demonstrated that the Bcl-2/X L /W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect. We showed that inhibition of Bcl-2/X L /W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/X L /W and MDM2 co-inhibition as a promising strategy in UM. • We assessed the sensitivity of a panel of uveal melanoma (UM) cell lines to 30 drug combinations. • Bcl-2/XL/W inhibitor sensitised the UM cell lines to mTOR, MEK and MDM2 inhibitors. • Combined inhibition of Bcl-2/XL/W and MDM2 showed a synergistic trend in UM preclinical models. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Conventional methods of UM treatment are based on chemotherapy and radiotherapy, which have been able to control tumor growth in a limited way. But due to the inadequacy and many side effects of these treatments, many UM patients die during treatment, and approximately 50% of patients develop metastasis. Meanwhile, the 2-year survival rate of these patients from the time of metastasis is 8%. Since immunotherapy has the potential to be the most specific and efficient method in the treatment of tumors, it is considered an attractive and promising research field in the treatment of UM. This review highlights recent advances in UM immunotherapy and provides new immunological approaches on how to overcome the challenges of UM immunotherapy. [Display omitted] • Uveal melanoma has a very poor prognosis and more than 50% of patients experience metastasis. • Immunotherapy can be very successful in treating uveal melanoma by bypassing tumor-induced immunosuppressive mechanisms. • Finding strategies to overcome the challenges of uveal melanoma immunotherapy will help to find more effective treatments. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult population. Primary methods for treatment of UM involves surgery Proton Beam Therapy (PBT), Plaque Brachytherapy, phototherapy, and Charged Particle Radiation Therapy (CPT). It has been found that approximately 50 % of patients diagnosed with UM ultimately experience development of metastatic disease. Furthermore, it has been identified that majority of the patient experience metastasis in liver with a prevalence of 95 %. Management of metastatic UM (MUM) involves various therapeutic modalities, including systemic chemotherapy, molecular targeted therapy, immunotherapy and liver directed interventions. We outline gene mutation in UM and addresses various treatment modalities, including molecular targeted therapy, miRNA-based therapy, and immunotherapy. Additionally, inclusion of ongoing clinical trials aimed at developing novel therapeutic options for management of UM are also mentioned. [Display omitted] • Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult. • It has been identified that majority of patient experience metastasis in liver. • We outline gene mutation and addresses various treatment modalities in UM. • Ongoing clinical trials for management of UM are also discussed. [ABSTRACT FROM AUTHOR]

Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis. Although UM morphology and biology have been extensively studied, there are significant gaps in our understanding of the early stages of UM tumor evolution and effective treatment to prevent metastatic disease remain elusive. A better understanding of the mechanisms that enable UM cells to thrive and successfully metastasize is crucial to improve treatment efficacy and survival rates. For more than forty years, animal models have been used to investigate the biology of UM. This has led to a number of essential mechanisms and pathways involved in UM aetiology. These models have also been used to evaluate the effectiveness of various drugs and treatment protocols. Here, we provide an overview of the molecular mechanisms and pharmacological studies using mouse and zebrafish UM models. Finally, we highlight promising therapeutics and discuss future considerations using UM models such as optimal inoculation sites, use of BAP1 mut-cell lines and the rise of zebrafish models. [ABSTRACT FROM AUTHOR]

A new Collaborative Ocular Melanoma Study (COMS)-like 24 mm eye plaque was experimentally characterized using physical and dosimetric measurements in preparation for clinical usage. The new eye plaque will enable surgeons and radiation oncologists to accommodate patients who have larger ocular melanoma tumors. Physical measurement of the Modulay radius of curvature was performed using a FARO Edge, and the base thickness of the Silastic insert was measured with a depth gauge and Vernier caliper. Dosimetric measurements, using Gafchromic film, were used to determine the absolute dose as a function of the depth along the plaque's central axis, profiles as a function of polar angle, and basal coverage at the inner sclera. The measured results were compared with a theoretical model, which incorporated the plaque's heterogeneities using a modified TG-43 formalism. The Modulay radius of curvature measured 14.7 mm (specification = 14.55 mm). The Silastic base thickness measured 0.9 mm (specification = 1.0 mm). For a 24 mm plaque fully loaded with 1.27 U 125I model 2301 seeds, the dose rate at a prescription depth of 5 mm from the inner sclera was measured to be 36 cGy U−1 hr−1. The basal coverage for the same prescription depth was 17.9 mm. The experimental measurements were in close agreement with the theoretical predictions. The new 24 mm COMS-like plaque was experimentally validated for clinical use. Physical and dosimetric measurements for the 24 mm plaque agreed with nominal specifications and theoretical predictions. The 24 mm plaque provides greater basal coverage and lower surface doses than existing COMS plaques. [ABSTRACT FROM AUTHOR]

The purpose of the study was to determine dosimetric effects of performing concurrent I-125 Collaborative Ocular Melanoma Study plaque brachytherapy and vitrectomy with replacement using silicone oil, previously shown to be a means of shielding uninvolved parts of the eye. Monte Carlo simulations using MCNP6 were performed to compare the dosimetry with all eye materials assigned as water, and for the vitreous (excluding the tumor), composed of polydimethylsiloxane oil for three generic, one large tumor, and two patient geometry scenarios. Dose was scored at the tumor apex, along the sclera, and within a 3D grid encompassing the eye. The assessed patient cases included vitrectomies to treat intraocular pathologies; not to enhance attenuation/shielding. The doses along the sclera and for the entire eye were decreased when the silicone oil replaced the vitreal fluid, with a maximum decrease at the opposite sclera of 63%. Yet, absolute changes in dose to critical structures were often small and likely not clinically significant. The dose at the tumor apex was decreased by 3.1–9.4%. Dose was also decreased at the edges of the tumor because of decreased backscatter at the tumor-oil interface. Concurrent silicone vitrectomy was found to reduce total radiation dose to the eye. Based on current radiation retinopathy predictive models, the evaluation of the absolute doses revealed only a subset of patients in which a clinically significant difference in outcomes is expected. Furthermore, the presence of the silicone oil decreased dose to the tumor edges, indicating that the tumor could be underdosed if the oil is unaccounted for. [ABSTRACT FROM AUTHOR]