Therapy For Uveal Melanoma Research Articles

The effect of intra- and inter-fractional motion on target coverage and margins in proton therapy for uveal melanoma

Introduction.This study aims to assess the effective lateral margin requirements for target coverage in ocular proton therapy (OPT), considering the unique challenges posed by eye motion and hypofractionation. It specifically addresses the previously unaccounted-for uncertainty contribution of intra-fractional motion, in conjunction with setup uncertainties, on dosimetric determination of lateral margin requirements.Method.The methodology integrates dose calculations from the in-house developed treatment planning system OCULARIS with measured intra-fractional motion, patient models from EyePlan and Monte Carlo (MC) sampling of setup uncertainties. The study is conducted on 16 uveal melanoma patients previously treated in the OPTIS2 treatment room at the Paul Scherrer Institute (PSI).Result.The retrospective simulation analysis highlights a significant impact of non-systematic factors on lateral margin requirements in OPT. Simulations indicate that reducing the 2.5 mm clinical lateral margin, represented by a 2.1 mm margin in this work, would have resulted in inadequate target coverage for two patients, revealing a greater impact of non-systematic factors on lateral margin requirements.Conclusions.This work characterizes intra-fractional motion in 16 OPT patients and identifies limitations of clinical margin selection protocols for OPT applications. A novel framework was introduced to assess margin sufficiency for target coverage. The findings suggest that prior research underestimated non-systematic factors and overestimated systematic contributions to lateral margin components. This re-evaluation highlights the critical need to prioritize the management of non-systematic uncertainty contributions in OPT.

Proton Therapy in Uveal Melanoma

Background/Objectives: Uveal melanoma is the most common primary intraocular malignancy in adults. Treatment options for localized, early-stage disease include enucleation, brachytherapy, and proton beam therapy. This review aims to evaluate the role of proton therapy in the definitive management of uveal melanoma, focusing on its physics, radiobiology, treatment techniques, and associated outcomes. Methods: This narrative review synthesizes current literature on proton therapy for uveal melanoma, emphasizing case selection, treatment efficacy, and side effects. Results: Proton therapy offers significant advantages for thicker uveal melanomas (over 8 mm) due to its unique physical properties, including a rapid dose fall-off that protects critical structures like the retina and optic nerve. Proton therapy may have benefits in tumor control for ocular melanomas given its increased relative biological effectiveness relative to photon therapy for these typically more radioresistant melanomas. Proton therapy may also hold special value for uveal melanomas in close proximity to the optic nerve, as patients are at high risk of visual toxicities with brachytherapy. The review discusses the efficacy of proton therapy across small, medium, and large tumors, along with strategies for improving patient survival through combined systemic therapy. Additionally, the potential of ocular reirradiation with proton therapy is addressed. Conclusions: Proton therapy is an effective treatment for uveal melanoma. It offers advantages over brachytherapy for large tumors, tumors that are close to the optic nerve or insertion of extra-ocular muscles.

Local anesthetic tetracaine hydrochloride induces pyroptosis via caspase-3/gasdermin E in uveal melanoma

BackgroundEvasion 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. MethodsWe 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. ResultsTTC 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. ConclusionsThis 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.

A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma.

Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small-molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases. We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients and an initial evaluation of efficacy after 13 patients. From April 2018 to April 2019, 13 patients were enrolled. Patients were predominantly female (69%) with a median age of 64 years (34-76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months. ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition. Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy.

Novel frameless LINAC radiosurgery solution for uveal melanoma.

Radiation treatment has replaced enucleation as an organ-preservation treatment for patients with uveal melanoma (UM). We developed a novel non-invasive, frameless LINAC based solution for fractionated stereotactic radiosurgery (fSRS) treatment. We designed and constructed the a stereotactic ocular localization box that can be attached and indexed to a stereotactic LINAC tabletop. It contains adjustable LED lights as a gaze focus point and CCD camera for monitoring of the patient's eye position. The device also has 6 infrared spheres compatible with the ExacTRAC IGRT system. Treatment plans were developed using iPLAN Dose version 4.5, with conformal dynamic arcs and 6MV photon beam in flattening filter free mode, dosed to 50Gy in 5 fractions. During treatment, patients were instructed to stare at the light when a radiation beam is prepared and ready for delivery. Eye movement was tracked throughout treatment. Residual setup errors were recorded for evaluation. The stereotactic ocular localization box was 3D-printed with polylactic acid material and attached to the stereotactic LINAC tabletop. 10 patients were treated to evaluate the feasibility, tolerability and setup accuracy. Median treatment time for each arc is 17.3 ± 2.4 seconds (range: 13.8-23.4). After ExacTRAC setup, the residual setup errors are -0.1 ± 0.3mm laterally, -0.1 ± 0.3mm longitudinally, and 0 ± 0.2mm vertically. The residue rotational errors are -0.1 ± 0.3 degree pitch, 0.1 ± 0.2 degree roll, and 0 ± 0.2 degree couch rotation. All patients received treatment successfully. We successfully developed a novel non-invasive frameless mask-based LINAC solution for SRS for uveal melanoma, or other ocular tumors. It is well tolerated with high set up accuracy. Future directions for this localization box would include a multi-center trial to assess the efficacy and reproducibility in the fabrication and execution of such a solution for UM therapy.

Abstract 671: G-protein coupled receptor (GPCR) screening library identifies sertindole, an antipsychotic, as potential therapeutic option to target GNAQ mutation Q209L in uveal melanoma

Abstract Background: Uveal melanoma is a rare but aggressive intraocular malignancy with limited therapeutic options. A hallmark genetic alteration associated with uveal melanoma is the mutation of the GNAQ gene, particularly the Q209L substitution in the Gαq protein, which contributes to oncogenic signaling and tumor progression. The GNAQ gene encodes for a Gαq protein that plays a critical role in signal transduction pathways involving G protein-coupled receptors (GPCRs). The Q209L substitution results in a gain-of-function mutation, leading to the chronic activation of downstream signaling pathways. This persistent signaling activity contributes to the uncontrolled growth of uveal melanoma cells. As G protein-coupled receptors (GPCRs) play a crucial role in this process, screening libraries of GPCR inhibitors has been explored as a potential therapeutic avenue. These libraries comprise a vast array of compounds with the potential to block or modulate GPCR activity. Identifying specific inhibitors that can effectively interfere with the oncogenic signaling cascades triggered by the mutated Gαq protein is a critical step in developing targeted therapies for uveal melanoma. Methods: GPCR library high throughput screening employed isogenic cell lines expressing wild type or mutant (Q209L) GNAQ. This process utilized IP-One assays to identify compounds affecting Gq-coupled receptors by detecting inositol monophosphate accumulation. Subsequently, promising hits were evaluated for their impact on inhibiting the growth and proliferation of uveal melanoma cells. Further analysis involved Western blotting to assess their potential in promoting autophagy and apoptosis, inhibiting downstream signaling pathways, and a migration assay. Finally, ROS generation was assessed using flow cytometry. Results: Using isogenic cell lines expressing GNAQ gene wild type and the Q209L mutant, a high-throughput screening of GPCR libraries identified sertindole among 5 hits. Sertindole showed a dose-dependent inhibition of Q209L-mutated uveal melanoma cells, significantly reducing cell viability, proliferation, and migration. It also suppressed key signaling pathways, including the critical MAPK pathway, and activated autophagy and apoptosis, likely via ROS generation. These findings suggest sertindole's multifaceted approach in suppressing cancer in uveal melanoma. Conclusion: Our study highlights the potential therapeutic value of sertindole in GNAQ Q209L-mutated uveal melanoma. Further research is needed to evaluate the efficacy of sertindole in preclinical mouse models of uveal melanoma. Citation Format: Shelby Rheinschmidt, Taylor Bargenquast, Sydney Adamson, Trason Thode, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Harini Tulasi, Brian Durbin, Justin Moser, Mohan Kaadige, Raffaella Soldi, Sunil Sharma. G-protein coupled receptor (GPCR) screening library identifies sertindole, an antipsychotic, as potential therapeutic option to target GNAQ mutation Q209L in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 671.

Результаты применения анти-VEGF-терапии пациентам с лучевой ретинопатией при увеальной меланоме

Relevance. Radiation retinopathy (RR) in the form of macular edema (ME) is a predictable complication of radiation therapy (RT) in uveal melanoma (UM). ME is the main reason for the decrease in visual acuity (VA) after RT. By reducing visual acuity, ME reduces the quality of life of such patients. To date, there is no standardized algorithm for the treatment of this pathology. In foreign literature, anti-vascular endothelium growth factor (anti-VEGF) are proposed as a solution to the problem, but even here their use is limited by the lack of experience of their introduction in domestic literature, the mode of administration and indications. Purpose. To present results of anti-VEGF treatment in patients with ME against the background of radiation treatment of UM. Material and methods. For the period from 2018 to 2023, at S. Fyodorov Eye Microsurgery Federal State Institution, Moscow, anti-VEGF injection was performed in 70 patients (70 eyes) with ME, which developed against the background of radiation therapy of UM. Of these, 24 (34%) patients were men, 46 (66%) were women. The average age of patients was 54 years (from 14 to 89 years). The average maximum corrected visual acuity (VA) when MO was diagnosed was 0,37 (from 0.001 to 1.0). According to optical coherence tomography, the average value of central macular thickness (CMT) at the time of diagnosis of ME was 411 microns (from 165 to 918), the average value of volume cube (VC) – 11.5 (range from 8 to 15.9). Results. The average VA after anti-VEGF treatment was 0.43 (from 0.001 to 1.0). Based on the data of changes in VA, 22 (32%) patients had stabilization of the process, 30 (43%) showed improvement, 18 (25%) – deterioration. According to optical coherence tomography, the average CMT value after anti-VEGF was 298 microns (from 57 to 688; p<0.001), and the average VC value was 10 (from 3.6 to 13.1;, p<0.001). Conclusion. The first experience of using anti-VEGF in our country has shown its effectiveness in reducing the height of macular edema and improving visual functions, which makes their use in radiation retinopathy expedient. Key words: uveal melanoma, radiation retinopathy, macular edema, anti-vascular endothelial growth factor

Clinical Outcomes in AYAs (Adolescents and Young Adults) Treated with Proton Therapy for Uveal Melanoma: A Comparative Matching Study with Elder Adults.

The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15-39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general.

Multi-omics approaches identify novel prognostic biomarkers of autophagy in uveal melanoma.

Uveal melanoma (UVM) is a rare yet malignant ocular tumor that metastases in approximately half of all patients, with the majority of those developing metastasis typically succumbing to the disease within a year. Hitherto, no effective treatment for UVM has been identified. Autophagy is a cellular mechanism that has been suggested as an emerging regulatory process for cancer-targeted therapy. Thus, identifying novel prognostic biomarkers of autophagy may help improve future treatment. Consensus clustering and similarity network fusion approaches were performed for classifying UVM patient subgroups. Weighted correlation network analysis was performed for gene module screening and network construction. Gene set variation analysis was used to evaluate the autophagy activity of the UVM subgroups. Kaplan-Meier survival curves (Log-rank test) were performed to analyze patient prognosis. Gene set cancer analysis was used to estimate the level of immune cell infiltration. In this study, we employed multi-omics approaches to classify UVM patient subgroups by molecular and clinical characteristics, ultimately identifying HTR2B, EEF1A2, FEZ1, GRID1, HAP1, and SPHK1 as potential prognostic biomarkers of autophagy in UVM. High expression levels of these markers were associated with poorer patient prognosis and led to reshaping the tumor microenvironment (TME) that promotes tumor progression. We identified six novel potential prognostic biomarkers in UVM, all of which are associated with autophagy and TME. These findings will shed new light on UVM therapy with inhibitors targeting these biomarkers expected to regulate autophagy and reshape the TME, significantly improving UVM treatment outcomes.

When Is the Optimum Radiological Response to Proton Beam Therapy in Uveal Melanoma?

Introduction: Proton beam therapy (PBT) is an effective treatment option for uveal melanomas. Following treatment, it may take many months for the tumour to respond and it may initially enlarge. We reviewed our PBT patients to determine when they showed a radiological response to treatment. Methods: Patients undergoing PBT for ciliary body or choroidal melanomas between 2008 and 2018 were included. Data were collected on patient demographics, treatments before and after PBT and survival. All ultrasound investigations prior and since PBT were reviewed and tumour volume calculated using a validated formula for a half-ellipsoid shape. Results: 193 patients were analysed, 169 with choroidal and 24 with ciliary body melanomas. 31.6% patients had other treatment prior to PBT. At a mean of 8 months post-PBT, 64.7% of patients had a reduced tumour volume with 20.2% having larger tumours. At a mean of 15 months post-treatment, these figures were 67.8% and 10.3%. 18.1% of patients had an enucleation during the study period. The earliest responses were seen at 2 months, the latest at 32 months post-treatment. 5-year melanoma-specific survival was 82.3%. Conclusions: In our study, by 6 months post-PBT, a majority of patients show a reduction in tumour volume. Of those that do not, many respond in the next 6 months and a response may be seen up to 32 months after treatment. Patients may need to be monitored for up to 32 months to see a final response to PBT treatment.

Deterioration of Visual Acuity after Brachytherapy and Proton Therapy of Uveal Melanoma, and Methods of Counteracting This Complication Based on Recent Publications.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The eyeball is the most common extracutaneous location of melanoma. UM is a huge threat to a patient's life. It metastasizes distantly via blood vessels, but it can also spread locally and infiltrate extraocular structures. The treatment uses surgical methods, which include, among others, enucleation and conservative methods, such as brachytherapy (BT), proton therapy (PT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS), transpupillary thermotherapy (TTT) and photodynamic therapy. The key advantage of radiotherapy, which is currently used in most patients, is the preservation of the eyeball with the risk of metastasis and mortality comparable to that of enucleation. Unfortunately, radiotherapy very often leads to a significant deterioration in visual acuity (VA) as a result of radiation complications. This article is a review of the latest research on ruthenium-106 (Ru-106) brachytherapy, iodine-125 (I-125) brachytherapy and proton therapy of uveal melanoma that took into account the deterioration of eye function after therapy, and also the latest studies presenting the new concepts of modifications to the applied treatments in order to reduce radiation complications and maintain better visual acuity in treated patients.

Overview of late complications of radiation therapy in uveal melanoma

Overview of late complications of radiation therapy in uveal melanoma

MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma

PurposeMRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound.MethodsTwenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline.ResultsPre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10−3mm2/s increase 12 months after treatment (p = 0.15).ConclusionMR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

Development of Uveal Melanoma-Specific Aptamer for Potential Biomarker Discovery and Targeted Drug Delivery.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. However, challenges in early diagnosis, high risk of liver metastasis, and lack of effective targeted therapy lead to poor prognosis and high mortality of UM. Therefore, generating an effective molecular tool for UM diagnosis and targeted treatment is of great significance. In this study, a UM-specific DNA aptamer, PZ-1, was successfully developed, which could specifically distinguish molecular differences between UM cells and noncancerous cells with nanomolar-range affinity and presented excellent recognition ability for UM in vivo and clinical UM tissues. Subsequently, the binding target of PZ-1 on UM cells was identified as JUP (junction plakoglobin) protein, which held great potential as a biomarker and therapeutic target for UM. Meanwhile, the strong stability and internalization capacity of PZ-1 were also determined, and a UM-specific aptamer-guided "nanoship" was engineered to load and selectively release doxorubicin (Dox) to targeted UM cells, with lower toxicity to nontumor cells. Taken together, the UM-specific aptamer PZ-1 could serve as a molecular tool to discover the potential biomarker for UM and to achieve the targeted therapy of UM.

Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma.

Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway, geranyl-geranylation, and subcellular localisation of the Rho-GTPase. We investigated drugs that affect the YAP/TAZ pathway, valproic acid, verteporfin and statins, in combination with MEK-inhibitor trametinib. We established IC50 values of the individual drugs and monitored the effects of their combinations in terms of proliferation. We selected trametinib and cerivastatin for evaluation of cell cycle and apoptosis. Synergism was detected using isobologram and Chou-Talalay analyses. The most synergistic combination was tested in vivo. Synergistic concentrations of trametinib and cerivastatin induced a massive arrest of proliferation and cell cycle and enhanced apoptosis, particularly in the monosomic, BAP1-mutated UPMM3 cell line. The combined treatment reduced ERK and AKT phosphorylation, increased the inactive, cytoplasmatic form of YAP and significantly impaired the growth of UM cells with monosomy of chromosome 3 in NSG mice. Statins can potentiate the efficacy of MEK inhibitors in the therapy of UM.

Depression and anxiety in patients with uveal melanoma undergoing curative proton treatment-A prospective study.

We prospectively addressed whether patient characteristics, oncological outcomes, or metastatic risk impacted depression and anxiety in patients undergoing curative proton treatment for uveal melanoma (UM). We assessed patient-reported outcomes regarding anxiety (GAD-7) before and 2 years after proton therapy and depression (PHQ-9) before, 1, and 2 years after proton therapy. We performed descriptive statistics and used linear mixed effect modeling to analyze how the oncological outcome and baseline characteristics impacted anxiety and depression scores. Of 130 (65 female) patients included, six developed metastatic disease and three died during the 2-year follow-up. The mean anxiety declined from 5.86 (SE=0.56) at baseline to 3.74 (SE=0.46) at 2 years (β=2.11; SE=0.6; p < .001). Depressive symptoms decreased moderately from 4.36 (SE=0.37) at baseline to 3.67 (SE=0.38) 2 years later. Patients with unfavorable metastatic risk or disease progression had elevated anxiety and depression scores. Although female patients reported overall higher anxiety scores, both sexes recovered substantially and to a similar extent during the 2-year follow-up (β=2.35; SE 0.87; p=.007 vs. β=1.88; SE=0.60; p=.002). A trend for prolonged depressive symptoms was observed in patients living alone compared to patients living with family members 1 year after the treatment (M=5.04 [SE=0.85] vs. M=3.73 [SE=0.31], β=1.32; SE=0.92; p=.152). Patients with high baseline anxiety levels showed initially more severe depressive symptoms, which improved significantly during follow-up (β=1.65; SE=0.68; p=.017). Most patients undergoing proton therapy for UM experienced mild, transient depressive symptoms and anxiety. Patients with high pre-treatment anxiety, unfavorable prognoses, and patients living alone may be more vulnerable to prolonged depressive symptoms. To these patients a more tailored support could be offered at an early stage of the disease.

Inter-Observer Variability in MR-Based Target Volume Delineation of Uveal Melanoma

Several efforts are being undertaken toward MRI-based treatment planning for ocular proton therapy for uveal melanoma (UM). The interobserver variability of the gross target volume (GTV) on magnetic resonance imaging (MRI) is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the interobserver variation in GTV delineation of UM on MRI. Six observers delineated the GTV in 10 different patients using the Big Brother contouring software. Patients were scanned at 3T MRI with a surface coil, and tumors were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2-weighted scans with an isotropic acquisition resolution of 0.8 mm. Volume difference and overall local variation (median standard deviation of the distance between the delineated contours and the median contour) were analyzed for each GTV. Additionally, the local variation was analyzed for 4 interfaces: sclera, vitreous, retinal detachment, and tumor-choroid interface. The average GTV was significantly larger on T1gd (0.57cm3) compared with T2 (0.51cm3, P=.01). A not significant higher interobserver variation was found on T1gd (0.41 mm) compared with T2 (0.35 mm). The largest variations were found at the tumor-choroid interface due to peritumoral enhancement (T1gd, 0.62 mm; T2, 0.52 mm). As a result, a larger part of this tumor-choroid interface appeared to be included on T1gd-based GTVs compared with T2, explaining the smaller volumes on T2. The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm, enabling small treatment margins. We recommend delineation based on the T1gd-weighted scans, as choroidal tumor extensions might be missed.

MR‐based follow‐up after brachytherapy and proton beam therapy in uveal melanoma

AbstractPurpose: Comparison of Magnetic Resonance Imaging (MRI) with conventional ultrasound for the follow‐up in Uveal Melanoma (UM) patients treated with brachytherapy or proton beam therapy (PBT).Methods: 26 UM patients were scanned before, 3, 6 and 12 months after ruthenium brachytherapy (n = 13) or PBT (n = 13) at 3Tesla MRI. Tumour prominence measurements were compared between MRI and ultrasound. On Perfusion weighted MR‐imaging (PWI), the relative enhancement and outflow at 2 min after peak were assessed. Treatment response was defined as a reduction of ≥0.6 mm prominence and/or ≥5% perfusion outflow was achieved.Results: Pretreatment prominences were comparable on MR and ultrasound (mean absolute difference 0.49 ± 0.46 mm), larger differences were observed at 3 and 6 months post treatment (0.88 ± 0.86 mm and 0.74 ± 0.72 mm, respectively). At 12 months post treatment, the difference was reduced to 0.55 ± 0.33 mm. Pretreatment, 76% of the UM showed a washout perfusion curve. The pretreatment average enhancement and outflow were 98% (SD:49%) and 31% (SD: 25%) respectively. At 3 months post treatment tumours showed 41% less outflow on average with more favourable perfusion curves (e.g. 68% showed a persistent or plateau curve). At 6 and 12 months post treatment, tumours continued to show less outflow (respectively, −47% and −38%) and more favourable perfusion curves (respectively, 79% and 76% with either persistent or plateau curves). These, generally favourable, perfusion changes were also observed when no reduction in prominence was yet apparent, which is why treatment response was more frequently detected on MRI as opposed to ultrasound. For example, at 3 months post treatment &gt;80% of patients were already detected on MRI versus 46% on ultrasound.Conclusions: MRI is beneficial for the follow‐up of UM patients, especially for PBT treated patients as these generally take longer before a reduction in prominence can be observed.

Inter‐Observer variability in MRI‐based target volume delineation of uveal melanoma

AbstractPurpose: Several efforts are being undertaken towards MRI‐based treatment planning for ocular proton therapy for uveal melanoma (UM). The inter‐observer variability of the gross target volume (GTV) on MRI is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the inter‐observer variation in tumour delineation of UM on MRI.Methods: Six observers delineated the tumour in 10 different UM patients using the Big Brother contouring software. Patients were scanned at 3 T MRI with a surface coil and tumours were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2‐weighted scans with a resolution of 0.8 mm isotropic for the acquisition voxels (1). Volume difference and overall local variation were analysed for each patient. Additionally the local variation was analysed for four interfaces: sclera, vitreous, retinal detachment, and tumour‐choroid interface.Results: The average tumour contour was significantly larger on T1gd (0.57 cm3) compared to T2 (0.51cm3, p = 0.01). A not significant higher interobserver variation was found on T1gd (0.4 1 mm) compared to T2 (0.35 mm). The largest variations were found at the tumour‐choroid interface, due to peritumoral enhancement (T1gd: 0.62 mm and T2: 0.5 2 mm). As a result, a larger part of this tumour‐choroid interface appeared to be included on T1gd based GTVs compared to T2, explaining the smaller volumes on T2.Conclusions: The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm. We recommend to delineate based on the T1gd‐weighted scans, as choroidal tumour extensions might be missed.Reference1. Ferreira, et al. MR imaging characteristics of uveal melanoma with histopathological validation. Neuroradiology. 2022; 64:171. doi: 10.1007/s00234‐021‐02825‐5.

Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.