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Purpose: The aim of our study is to evaluate local tumour control rates, radiation side-effects, visual preservation and disease-free survival (DFS) of uveal melanoma (UM) patients treated with fractionated stereotactic radiotherapy (fSRT). Methods: A retrospective study of UM patients, who were treated with fSRT (N = 189), was performed by the Rotterdam Ocular Melanoma Study group (ROMS), the Netherlands, between 1999 and 2014 with a follow-up of at least 5 years. Results: The 1-, 3-, 5-, 10- and 15-year local tumour control rates were as follows: 99.4%, 92.8%, 92.2%, 89.3% and 89.3%, respectively. Cataract (67.8%) was the most common side-effect of fSRT followed by retinopathy (35.1%), maculopathy (23.8%), vitreous haemorrhage (20.1%), neovascular glaucoma (NVG) (20.0%) and optic neuropathy (12.4%). Patients with anterior located UMs developed cataract more frequently (p = 0.047, multivariable analysis). By multivariable analysis, significant factors for secondary enucleation were tumour recurrence (p

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

Ocular melanoma (OM) is a rare noncutaneous malignancy and consists of 2 different subtypes based on the anatomic location in the eye: uveal melanoma and conjunctival melanoma. Like cutaneous melanoma, OM benefits from nuclear medicine and molecular imaging in nodal staging and clinical management. Through the illustration of 2 distinctive cases, we aim to demonstrate the complementary roles of standard lymphoscintigraphy, advanced SPECT/CT, 18F-FDG PET/CT, and 18F-FDG PET/MRI in accurate nodal staging and surveillance of OM. We also review the epidemiology, existing staging guidelines, and management of uveal melanoma and conjunctival melanoma.

Purpose: To compare the adverse side effects of fractionated stereotactic photon beam radiotherapy (fSRT) with proton beam radiotherapy (PBR) in patients with uveal melanoma (UM). Methods: 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. Results: 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. Conclusions: Both treatments have excellent local tumour control. In matched groups, vitreous haemorrhage was the only adverse side effect showing a significant difference between groups.

Though being usually a cutaneous tumor, melanomas can occur in several extracutaneous sites. Primary mucosal melanomas are rare, and primary gastric mucosal melanomas are considered extremely rare. Compared with cutaneous and ocular melanoma, mucosal melanomas have the lowest five-year survival. High level of suspicion of such rare condition may be the only way for early detection, diagnosis and chance for successful management of similar cases. In the present report, a case of a primary gastric melanoma in a 73-year-old man is described, along with a short review of the literature

Purpose A retrospective evaluation of effectiveness of brachytherapy or enucleation in treatment of rare form of uveal melanoma: ring melanoma. Material and methods Analysis comprised 49 patients treated from 2000 to 2019 for ring melanoma involving ciliary body. In 15 patients, primary treatment consisted of brachytherapy (106Ru or 125I), whereas in 34 patients, eyeballs were enucleated. The evaluation concerned differences between analyzed groups relating to the clinical and histopathological features as well as overall survival, cancer-specific overall survival, and disease-free survival. Results No significant differences between the analyzed groups were found with regards to clinical and histopathological features, apart from intra-ocular pressure (increased in the enucleation group). Kaplan-Meier analysis did not reveal any significant differences between the group treated with enucleation and the group undergoing brachytherapy, both with regards to overall survival (p = 0.325) and cancer-specific overall survival (p = 0.477). A significant difference was observed in disease-free survival (p = 0.009), which was significantly shorter in the group undergoing brachytherapy. In the analysis of parameters of the applied brachytherapy, no significant differences between patients with and without local recurrence were found. Mean observation period was 350.8 weeks (range, 24-996 weeks, SD = 231.6). A local recurrence occurred in 11 (22.4%) patients, including 3 (6.1%) in enucleation and 8 (16.3%) after brachytherapy groups. Metastasis developed in 11 (22.4%) cases after a mean follow-up of 133 weeks (33.25 months), range 3-655 weeks. Conclusions Preliminary observations may suggest that brachytherapy in this rare form of uveal melanoma, such as ring melanoma involving the ciliary body, may be taken into consideration as a useful alternative to enucleation. However, the confirmation of such an approach requires a larger patients' group to be gathered, and also a longer follow-up period. This is especially important in patients with a good baseline visual acuity in the affected eye, or when the neoplasm is present in the remaining eye with vision.

Background: Uveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM. Summary: This review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms “uveal melanoma” and “ocular melanoma,” excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM. Key Messages: There is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design.

Purpose Radiation side effects and visual outcome for uveal melanoma patients managed with plaque radiotherapy are dependent on the radiation dose administered to the tumor and nearby healthy tissues. We have developed an open-source software tool, EyeDose, to simplify and standardize tumor and critical structure dose reporting for Collaborative Ocular Melanoma Study eye plaques. Methods and Materials EyeDose is a MATLAB-based program that calculates point dose and volume dose metrics for standard models of the tumor and critical ocular structures. It uses published three-dimensional dose distributions for eye plaques, calculated with Monte Carlo methods, which are oriented with respect to the eye using the tumor's position on a fundus diagram. A standard model for the ocular structures was created using published measurements and patient CT scans. EyeDose reports radiation statistics for the fovea, optic disc, lens, lacrimal gland, retina, and tumor. The dosimetric margin for implant placement uncertainty is also calculated. Results EyeDose calculations were validated against previously published Monte Carlo results for eight different tumor positions, including the dose to the fovea, optic disc, lacrimal gland, lens, and along the central axis. EyeDose accepts a spreadsheet input for rapidly processing large retrospective patient data sets, with an average run time of Conclusions EyeDose calculates radiation statistics for Collaborative Ocular Melanoma Study eye plaque patients with Monte Carlo accuracy and without a treatment planning system. EyeDose streamlines data collection for large retrospective studies and can also be used prospectively to assess plaque applicability.

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.

Uveal melanoma is a rare cancer in adults, but its treatment is one of the clinical unmet needs in the melanoma field. Metastatic disease develops in approximately 50% of patients and is associated with poor survival due to the lack of effective treatment options. It provides a paradigm for cancers that show evidence of aberrant G protein–coupled receptor signaling, tumor dormancy, and liver-selective metastatic tropism and are associated with the loss of the BAP1 tumor suppressor. At the Melanoma Research Foundation CURE OM Science Meeting at the Society for Melanoma Research Meeting held in Utah on November 20, 2019, clinicians and researchers presented findings from their studies according to three themes within uveal melanoma: (i) ongoing clinical trials, (ii) molecular determinants, and (iii) novel targets that could be translated into clinical trials. This meeting underscored the high interest in the uveal melanoma research field and the unmet need for effective treatment strategies for late-stage disease. Findings from ongoing clinical trials are promising, and multiple studies show how novel combinatorial strategies increase response rates. Novel targets and tumor vulnerabilities identified bioinformatically or through high-throughput screens also reveal new opportunities to target uveal melanoma. The future directions pursued by the uveal melanoma research field will likely have an impact on other cancer types that harbor similar genetic alterations and/or show similar biological properties.

Purpose Brachytherapy with iodine-125 (125I) has been extensively used as a conservative treatment for uveal melanoma (UM). Surgical technique for correct placement of episcleral radioactive plaques (ERP) in UM cases with posterior choroidal location and/or small size can be difficult and inaccurate. In this study, the correct positioning of plaques was assessed by intra-operative ultrasound control. Material and methods This was a longitudinal, retrospective study of consecutive 20 patients with UM (small-medium size and/or posterior location) who received 125I brachytherapy. Location of plaques was adjusted by intra-operative ocular ultrasonography control. To perform ocular intra-operative ultrasonography, a 10 MHz probe was used to longitudinal and transverse bases in corresponding dummy plaques. Results The study included 8 males and 12 females, with a mean age of 66.3 years (SD = 14.53), 5 right eyes (RE) and 15 left eyes (LE). In ultrasound examination, 4 UMs were of mushroom morphology and the rest nodular. Means of the size of UM by ultrasound were (mm): Lb: 10.60 (SD = 2.24) × Tb: 9.88 (SD = 1.54) × H: 4.02 (SD = 1.44) (3 cases corresponding to small size of collaborative ocular melanoma study (COMS), and 17 cases to medium). The plaques used were between 14 and 20 mm in diameter, with an average distance between the edge of greater base of the tumor and the edge of plate of 2.44 mm (SD = 0.34). It was necessary to surgically reposition the plaque in 4 cases (20%). Conclusions Intra-operative ultrasound control improves the accuracy of radioactive plaque placement for the treatment of medium-small UMs in posterior location. Probably, this technique should be applied in all cases of brachytherapy, regardless of the isotope chosen and the location of tumor mass, in order to perfectly adjust therapeutic position.

Purpose Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor. The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib. This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study. In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28–255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events. Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells. ClinicalTrials.gov, NCT00982865

Purpose There is no current randomized data comparing the efficacy of brachytherapy and enucleation for patients with larger sized tumors. The purpose of the present study was to use a large, contemporary database to determine current practice patterns and compare survival outcomes between different management options for patients with choroidal melanoma of various sizes. Material and methods The National Cancer Database was queried (2004-2014) for histologically-confirmed choroidal melanoma for patients treated with brachytherapy versus enucleation. Chi-square test was used to compare categorized demographic and clinical variables in both arms. Kaplan-Meier analysis evaluated overall survival (OS). Cox proportional hazards assessment determined variables associated with OS. Patients were divided into cohorts representing small, medium, and large tumors. Propensity scores matching (PSM) was utilized to compare more similar cohorts. Results A total of 7,096 patients met the selection criteria; 5,501 (78%) patients received brachytherapy and 1,595 (22%) patients were treated with enucleation. After PSM, 5-yr OS for small tumors was 87% vs. 64%, for medium tumors was 77% vs. 57%, and for large tumors was 68% vs. 46% for brachytherapy and enucleation, respectively (p < 0.001). Following PSM, multivariate Cox regression found older age (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.51-2.06), more comorbidities (HR = 1.46, 95% CI = 1.25-1.70), extraocular extension (EOE) (HR = 1.25, 95% CI = 1.06-1.48), ciliary body invasion (CBI) (HR = 1.20, 95% CI = 1.02-1.40), and larger size (HR = 1.52, 95% CI = 1.40-1.66) were negative prognosticators of survival. Brachytherapy was a positive prognosticator of survival (HR = 0.45, 95% CI = 0.40-0.51). Conclusions Patients selected for brachytherapy had improved survival compared to enucleation in all size cohorts. EOE and CBI are significantly higher in the enucleation cohort and are important negative prognosticators for survival selected against patients having brachytherapy. Brachytherapy is a reasonable treatment option for certain patients with large size tumors.

The height of the adult individual is a balance of the expression of some genetic factors (especially the Y-M 170 haplotype of the Y chromosome) and the environment (nutrition and morbidity during childhood). Higher height is associated with a low risk of developing coronary heart disease, hypertension, gastroesophageal reflux, diaphragmatic hernia, but with a higher risk for atrial fibrillation, venous thromboembolism, intervertebral disc pathology, vasculitis and cancer. The research consisted of a retrospective observational study on patients who received immunotherapy (IT) with nivolumab for cutaneous and ocular melanoma neoplasms. We intended to highlight the associations between the duration of immunotherapy and sex profiles, age, anthropometric data (height, weight). Even though the number of available cases was relatively small (42), an inverse association between the body mass index of the subjects and the duration of immunotherapy could be proved, a more expressed association in case of male patients.

Background: Treatment planning for I-125 plaque therapy for uveal melanoma has advanced significantly since the Collaborative Ocular Melanoma Study trial, with more widely available image-guided planning and improved dosimetry. Objective: We evaluated real-world practice patterns for I-125 plaque brachytherapy in the United States by studying practice patterns at centers that comprise the Ocular Oncology Study Consortium (OOSC). Methods: The OOSC database and responses to a treatment practice survey were evaluated. The database contains treatment information from 9 institutions. Patients included in the database were treated between 2010 and 2014. The survey was conducted in 2018 and current treatment planning methods and prescriptions were queried. Results: Examination of the OOSC database revealed that average doses to critical structures were highly consistent, with the exception of one institution. Survey responses indicated that most centers followed published guidelines regarding dose and prescription point. Dose rate ranged from 51 to 118 cGy/h. As of 2018, most institutions use pre-loaded plaques and fundus photographs and/or computed tomography or magnetic resonance imaging in planning. Conclusions: While there were differences in dosimetric practices, overall agreement in plaque brachytherapy practices was high among OOSC institutions. Clinical margins and planning systems were similar among institutions, while prescription dose, dose rates, and dosimetry varied.

Simple Summary Although uncommonly encountered, ocular melanoma may threaten the vision and even the life of a patient. The clinical feature and long-term results of ocular melanoma have rarely been described in the Asian population, as it has a low incidence for non-Caucasians. Therefore, we investigated the epidemiology, clinical manifestation, treatment strategy, and long-term outcome of ocular melanoma in a tertiary referral center in Taiwan. Abstract Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13–58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

Melanomas are the most common cancer of the eye in canines, felines and humans. The treatment approaches vary, since no gold standard exists. Therefore, this systematic review aimed to compare the treatment modalities in ocular melanoma in rabbits. Medline/PubMed, Cochrane Library, Web of Science and Embase were searched for articles published until 21 April 2021 in English, Portuguese or Spanish, reporting animal studies evaluating photodynamic therapy (PDT), laser, radiotherapy or surgical excision. Twenty-seven articles were included for the qualitative synthesis, with publication dates from 1970 to 2018. Of the selected studies, 19 used PDT, six used radiotherapy and two used laser as treatment. No studies regarding surgical therapy that met the inclusion criteria were obtained. The tumour therapy results were evaluated in a heterogeneous manner for different periods and various methods, including microscopy, angiographic, histological examination, fundoscopy, ultrasound exam and electroretinogram. The treatment modalities analysed successfully treated the ocular melanoma, with tumour necrosis being commonly observed. Despite the therapeutic efficacy shown, side effects have been reported for all the therapies. The studies showed high heterogeneity, and therefore, in the future, new studies should be carried out to increase knowledge about ocular melanoma treatment. The analysed therapies can be used successfully in the treatment of ocular melanoma, with more conservative options such as PDT presenting great potential.

Srijan Valasapalli,1 Achuta Kumar Guddati2 1Department of Medicine, Carle Foundation Hospital, Urbana, IL, 61801, USA; 2Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA, 30909, USACorrespondence: Achuta Kumar GuddatiDivision of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA, 30909, USATel +1 312-404-8928Email aguddati@augusta.eduBackground: Ocular and orbit melanoma is a rare subtype of melanoma for which outcomes have not been adequately reported. We have analyzed the incidence-based mortality trends of ocular and orbit melanoma over 15 years in USA. Most ocular melanomas originate from the uvea and, to a lesser extent, from the conjunctiva. Primary orbital melanoma is exceedingly rare.Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried to find the incidence-based mortality for all patients diagnosed with ocular and orbit melanoma for the years 2000 to 2018. Results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan Native, and Asian/Pacific Islanders). A paired t-test was used to determine the statistically significant difference between various subgroups (p < 0.05).Results: Incidence-based mortality has been the highest in Caucasian/White patients from 2000 to 2018, followed by African American/Black and Asian/Pacific Islander patients. American Indian/Alaskan native patients appear to have the least mortality. There was a statistically significant difference (p< 0.05) in mortality between Caucasian/White patients from 2000 to 2018, and African American/Black and Asian/Pacific Islander patients. The sample size for African American/Black and American Indian/Alaskan native patients was too low to discern a meaningful trend in mortality. Overall, it appears that Caucasian males and females have a far higher and worsening incidence-based mortality compared to other races.Conclusion: Ocular melanoma and orbit melanoma are rare entities that are predominantly seen in Caucasian/White patients. This study shows that incidence-based mortality has been worsening for these patients in the past two decades. These entities have a poor prognosis and have not been studied extensively in immunotherapy trials. There is a need for new clinical trials to help improve mortality rates.Keywords: ocular melanoma, mortality, trend, incidence

Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%, Fisher’s exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.

Purposes: We analyzed patient, tumor and dosimetric characteristics of subjects in a Spanish population diagnosed with uveal melanoma treated with iodine 125 (I125) episcleral brachytherapy, who presented with post-treatment loss of useful visual acuity and global evolution of visual acuity. Methods: A single historic observational cohort study was undertaken. Patients with uveal melanoma were recruited between September 1995 and June 2015. Clinical, tumor and dosimetric data collection and visual acuity evaluations were performed under everyday practice conditions based on a useful visual acuity >0.1 on the decimal scale. The baseline analysis was performed using descriptive and survival analyses according to Kaplan-Meier curves. Results: A total of 286 of the 665 patients diagnosed with uveal melanoma received episcleral brachytherapy, and 198 were included in the study. The mean follow-up time was 75.3 months (95% CI = 68.0-82.6). Patients with post-treatment useful visual acuity loss (n=94, 47%) presented the following characteristics: visual symptoms (n=80, p-value = 0.001); iris color (brown n=33, hazel green n=49, p-value = 0.047); Collaborative Ocular Melanoma Study size (medium n=80, p-value = 0.159); tumor, node, metastasis stage (T2: n=38, T3: n=38, p=0.012); shape (nodular n=67, mushroom-shaped n=26, p=0.001); posterior pole involvement (n=47, p=0.04); recurrence (n=10, p=0.001); and dose administered in the fovea, optic nerve and center of the eye (p

Purpose The purpose of this study is to compare optic disc dose (ODD) between 125I and 103Pd Collaborative Ocular Melanoma Study (COMS) plaques in ocular brachytherapy. Methods A previously validated in-house brachytherapy dose calculation program was used for ODD calculations. ODD was calculated as a function of tumor margin-to-optic disc distance (DT) up to 5 mm for various tumor basal dimensions (BDs), for a prescription depth of 5 mm, and for standard and notched COMS plaques loaded with 125I (model: IAI-125A) and 103Pd (model: IAPd-103A) seeds. ODD calculations were repeated for prescription depths from 2 mm to 10 mm in 1 mm intervals. A prescribed dose of 85 Gy (irradiation time: 120 hours) was normalized to each prescription depth. Dose conversion factors (DCFs) for each prescription depth were calculated by taking a ratio of [total reference air kerma (TRAK) per seed]prescription depth to [TRAK per seed]5 mm. ODD reduction by notched COMS plaques was calculated for each prescription depth by subtracting ODD for notched COMS plaques from ODD for standard COMS plaques. Results Trends of ODD as a function of DT for various BDs are similar between the two seed types in both standard and notched COMS plaques. However, due to the energy difference, there exists a transition distance (dt) for each BD in each plaque at which ODD for 125I COMS plaques equals that for 103Pd COMS plaques. For small BDs, at DT dt, the opposite is observed. For the largest 1-3 BD(s), contrarily, dt occurs within the tumor, and thus, ODD for 125I COMS plaquesis always higher. Trends of ODD reduction by notched COMS plaques as a function of DT for various BDs are the same for the two seed types except that maximum ODD reduction by 103Pd COMS notched plaques is larger. DCF increases with increasing prescription depth for both seed types. Conclusions There exist ODD differences between 125I and 103Pd COMS plaques and the differences depend on DT, BD, plaque size, and prescription depth.

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.

Supplemental Digital Content is available in the text., No data exist regarding whether any first-line treatment for metastatic uveal melanoma provides overall survival (OS) benefit, if staged and compared to best supportive care (BSC). We analyzed OS in a nationwide, consecutive cohort diagnosed with metastatic uveal melanoma between January 1999 and December 2016. The Helsinki University Hospital Working Formulation was used to assign patients to stage IVa, IVb and IVc, corresponding to predicted median OS ≥12

Uveal melanoma (UM) is the most frequent intraocular malignancy in adults, affecting the iris, choroid, and ciliary bodies [...]

Purpose To develop a treatment planning platform for episcleral Collaborative Ocular Melanoma Study plaque therapy in an established treatment planning software and to improve an existing quality assurance (QA) process for nonuniformly loaded plaques that measures air kerma strengths (AKSs) and loading profile. Materials and Methods Treatment planning is performed in Pinnacle using scripts that let the planner choose plaque size and notching. Scripts load seed positions for each plaque and five source groups corresponding to available stock seeds that can be placed into each seed position. Contours are loaded that display the model eye and the plaque itself. Plaque QA is performed using a modification of our previous pinhole apparatus by replacing x-ray film exposure with an optical camera and scintillating film system. The captured image is processed to remove background and to correct the intensity of seeds on the plaque periphery. Measured total optical counts provide an estimate of total plaque AKS. Results Treatment planning of eye plaques using Pinnacle, in conjunction with our stock inventory of seeds, is established as standard practice at our center. Planned plaques can vary from uniformly loaded to asymmetrically loaded notched plaques. Using the optical camera system for assessment of the seed loadings has decreased QA time from 40 min/plaque to 10 min/plaque. Total AKS of each plaque can be measured using the optical camera with an accuracy of 10%. Conclusions Treatment planning is performed on a Health Canada–approved software that accommodates nonuniform plaque loading. Optical imaging of the plaque provides absolute total AKS and the relative seed arrangement in the plaque.

While the most compelling levels of evidence for the use of Yttrium-90 (90Y) radioembolization are in patients with hepatocellular carcinoma and hepatic metastases from colorectal cancer, a growing body of literature supports its use in other primary and secondary hepatic malignancies. This includes intrahepatic cholangiocarcinoma, as well as hepatic metastases from neuroendocrine cancer, ocular melanoma, and breast cancer. While is it not feasible to conduct prospective, randomized trials for radioembolization in the setting of these malignancies due to the low overall prevalence of liver-only disease, numerous single-arm studies in the last several years make a compelling argument for its use in select situations. This clinical update summarizes those findings.

The diagnosis of iris melanoma can be difficult, with no established diagnostic criteria currently available. Careful monitoring of patients with suspicious iris lesions is one approach to managing these tumors. We determined the risk of malignant transformation and melanoma-related mortality in patients under observation to evaluate the validity of this management approach. This was a retrospective chart review of patients with suspicious iris lesions diagnosed at Massachusetts Eye and Ear Infirmary (MEE) between 1975 and 2014. All patients with an initial diagnosis of suspicious iris lesion followed and/or treated after malignant transformation at the MEE in this 39-year period were included in the cohort. Rates of malignant transformation and melanoma-related mortality were calculated. Treatment outcomes after proton beam irradiation were evaluated in patients who developed iris melanomas during observation. Two hundred thirty-four patients had a diagnosis of suspicious iris lesion (median follow-up, 5.8 years). Malignant transformation occurred in 16 (6.8%) patients with suspicious lesions during the observation period (median follow-up, 9.9 years). All patients diagnosed with iris melanomas were treated with proton beam irradiation (PBI). Complications after treatment included cataract (18.8%), secondary glaucoma (6.3%), and neovascular glaucoma (12.5%). Two of 16 patients (12.5%) who developed iris melanomas died of metastatic melanoma 32.6 months and 10 years after treatment with PBI. Both cases had been followed regularly to monitor for malignant transformation of their suspicious lesions (8.2 years and 3.2 years before melanoma diagnosis, respectively). These data suggest that suspicious iris lesions have low malignant potential, and a conservative approach to the management of these lesions is appropriate. Survival does not appear to be compromised with an observational approach, and there is potential for preservation of good visual function because vision-threatening treatments can be avoided.

This study describes non-invasive photoacoustic imaging to detect and monitor the growth of conjunctival melanomas in vivo. Conjunctival melanomas were induced by injection of melanotic B16F10 cells into the subconjunctival space in syngeneic albino C57BL/6 mice. Non-invasive in vivo photoacoustic tomography was performed before, and after tumor induction up to 2 weeks. Spectral unmixing was performed to determine the location and to assess the distribution of melanin. The melanin photoacoustic signal intensity was quantified from the tumor-bearing and control eyes at all timepoints. For postmortem validation, total tumor and melanotic tumor volumes were measured using H&E stained tumor sections and were compared to in vivo photoacoustic imaging measurements. Photoacoustic imaging non-invasively detected eyes bearing conjunctival tumors of varying sizes. The melanin signal was detected as early as immediately following injection of melanotic tumor cells. Changes in tumor size over time were assessed with changes in the volume and intensity of the melanin signal. Four growing tumors and one regressing tumor were observed. Three tumors without significant change in signal intensity over time were observed, showing variable growth. Photoacoustic melanin signal on the last day of in vivo imaging correlated with postmortem total tumor volume (R2 = 0.81) and melanotic tumor volume (R2 = 0.80). The results of our study show that actively growing conjunctival melanomas can be quantified in a non-invasive manner using in vivo photoacoustic tomography. The photoacoustic melanin signal intensity correlated with total and melanotic tumor volume. This novel in vivo imaging platform may help to assess new treatment modalities to manage ocular tumors.

Plaque brachytherapy is a well-accepted modality to manage selected cases of ocular melanoma. Although this modality provides validated oncologic and quality of life benefits, severe complications and adverse events can occur. This article reviews complications and adverse events of plaque brachytherapy, including scleral necrosis, strabismus, cataract, glaucoma, and retinopathies as well as management of these conditions. For practicing oncologists and ophthalmologists, these complications are important to understand, identify, and treat. Additionally, an understanding of common complications of brachytherapy should influence the decision of pursuing it as a treatment option.

Potential environmental sources of oxidative damage to the lens and retina are cigarette smoke and sunlight exposure. Ultraviolet radiation, specifically UV-B in the range 290 to 320 nm, has been implicated in the development of age-related cataract. Research in laboratory animals and with cadaver lenses has shown that UVB is absorbed by the lens and that cataract can be induced by the introduction of UV-B radiation. Investigators from the Chesapeake Bay Watermen Study revealed that recent sunlight exposure was strongly related to geographic atrophy, suggesting that the normal mechanisms of retinal photooxidative repair may decrease with age. The role of solar UV radiation in the development of climatic droplet keratopathy, ocular melanoma, pinguecela and carcinoma in situ was reviewed recently by a WHO task group. The epidemiologic data support a role for sunlight in the development of cataract and pterygium, and possibly AMD, but more data are needed.

Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor because compared to other cancers it usually presents a well-expressed lymphoid infiltration. The aim of this paper is to perform a multidisciplinary comprehensive review of the evidence available about the combination of radiotherapy and immunotherapy for melanoma. Radiation, in fact, can increase tumor antigens visibility and promote priming of T cells but can also exert immunosuppressive action on tumor microenvironment. Combining radiotherapy with immunotherapy provides an opportunity to increase immunostimulatory potential of radiation. We therefore provide the latest clinical evidence about radiobiological rationale, radiotherapy techniques, timing, and role both in advanced and systemic disease (with a special focus on ocular melanoma and brain, liver, and bone metastases) with a particular attention also in geriatric patients. The combination of immunotherapy and radiotherapy seems to be a safe therapeutic option, supported by a clear biological rationale, even though the available data confirm that radiotherapy is employed more for metastatic than for non-metastatic disease. Such a combination shows promising results in terms of survival outcomes; however, further studies, hopefully prospective, are needed to confirm such evidence.

Iris melanocytic tumours, are the most dangerous tumours in the eye , commonly known as eye tumours. This includes freckle, nevus, melanocytoma, Lisch nodule, and melanoma. The detection of eye tumour is very difficult in early stages. Many research works are being carried out to detect eye diseases. But few research works in the eye tumour were published. Most of the system needs specific data acquisition devices to capture the region. This is very expensive. To diagnose eye melanoma, doctors recommend PET - CT, eye ultrasound, angiogram, optical coherence tomography, etc. Here, a new approach is presented to detect the eye tumour from eye images using deep learning technique. The deep network model created with modified LeNet architecture. The model created with the segmented eyeball images. Hough circle transformation could predict the eyeball and iris regions. As the deep learning technique needs more data for training, the number of image data has been increased with image augmentation method. Successful testing of this method with an accuracy of 95% shows that this method can be implemented in real time applications.

Uveal melanoma (UM) and conjunctival melanoma (CM) are ocular malignancies that give rise to life-threatening metastases. Although local disease can often be treated successfully, it is often associated with significant vision impairment and treatments are often not effective against metastatic disease. Novel treatment modalities that preserve vision may enable elimination of small tumors and may prevent subsequent metastatic spread. Very few mouse models of metastatic CM and UM are available for research and for development of novel therapies. One of the challenges is to follow tumor growth in-vivo and to determine the right size for treatment, mainly of the posterior, choroidal melanoma. Hence, the purpose of this study was to establish a simple, noninvasive imaging tool that will simplify visualization and tumor follow-up in mouse models of CM and UM. Tumors were induced by inoculation of murine B16LS9 cells into the sub-conjunctival or the choroidal space of a C57BL/6 mouse eye under a surgical microscope. Five to ten days following injection, tumor size was assessed by Phoenix MicronIV™ image-guided Optical Coherence Tomography (OCT) imaging, which included a real-time camera view and OCT scan of the conjunctiva and the retina. In addition, tumor size was evaluated by ultrasound and histopathological examination of eye sections. Tumor growth was observed 5-9 days following sub-conjunctival or sub-retinal injection of seven-thousand or seventy-thousand cells, respectively. A clear tumor mass was detected at these regions using the MicronIV™ imaging system camera and OCT scans. Histology of eye sections confirmed the presence of tumor tissue. OCT allowed an accurate measurement of tumor size in the UM model and a qualitative assessment of tumor size in the CM model. Moreover, OCT enabled assessing the success rate of the choroidal tumor induction and importantly, predicted final tumor size already on the day of cell inoculation. In conclusion, by using a simple, non-invasive imaging tool, we were able to follow intraocular tumor growth of both CM and UM, and to define, already at the time of cell inoculation, a grading scale to evaluate tumor size. This tool may be utilized for evaluation of new mouse models for CM and UM, as well as for testing new therapies for these diseases.

BACKGROUND Isolated pancreatic metastasis from melanoma is extremely uncommon and accounts for approximately only 2% of visceral disseminations of melanoma.1-3 Interestingly, pancreatic localizations disproportionately derive from primary ocular melanoma.1,2 Despite the currently available evidence on this argument being scarce, the survival outcomes of patients receiving resection for visceral melanoma metastases are reported to be superior than those managed by non-surgical modalities.4,5 CASE PRESENTATION: A 59-year-old female with a history of uveal melanoma presented with surveillance-detected metastatic disease confined to the pancreas. Computed tomography demonstrated one lesion located in the body of the pancreas and one further lesion in the head. The presented video illustrates the details of an extended, ultrasound-guided, robotic distal pancreatectomy. DISCUSSION Metastatic ocular melanoma has a highly variable natural history, which ranges from a fulminant course to prolonged stable disease.6 In contrast to cutaneous melanoma derivation, metastases mostly occur via hematogenous spread, in the absence of lymphatic drainage of the eye.6,7 Liver is the most common site of secondary localization and is not involved by metastatic disease in

ObjectiveTo analyse ocular and systemic findings of patients presenting with systemic metastasis.Methods and analysisIt is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases.ResultsOf 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1–T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category.ConclusionsThough higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.

Since the Collaborative Ocular Melanoma Study (COMS) reported similar mortality rates between enucleation and plaque brachytherapy for patients with medium-sized choroidal melanoma, radiation plaques have become the standard method of treatment for uveal melanoma. However, enucleation remains a valid primary treatment technique in some cases of melanoma with specific surgical indications, risks, and benefits. Today, most physicians evaluate the size and location of the tumor, the presence of extrascleral extensions, feasibility of vision retention, and patient preference when deciding between surgical options, although controversy remains regarding the best treatment course for small- and large-sized tumors. In recent years, genetic profiling has also become an important factor in deciding metastatic risk in uveal melanoma, and fine needle aspiration biopsy is now an important step in assessing melanoma prognosis.

Radiotherapy has an established role in multiple settings in the treatment of uveal melanoma, initially emerging as an effective treatment option that can spare both globe and visual function. Delivery modalities include eye plaque brachytherapy, proton/particle beam therapy, and photon-based treatments. This section reviews the indications for radiotherapy, compares different radiotherapy modalities, and discusses outcome measures following radiotherapy for uveal melanoma. Local recurrence in uveal melanoma is associated with distant metastasis and mortality. Thus, an understanding of the different radiotherapy modalities and factors to optimize local control has impactful ramifications.

Plaque brachytherapy and other radiation treatments have become an increasingly popular option for primary treatment of uveal melanoma since the publication of results from the Collaborative Ocular Melanoma Study. Radiation therapy, however, can cause direct or indirect damage to important ocular structures outside of the tumor, especially to the lens, retina, and optic nerve. Recent advancements in plaque brachytherapy technology have allowed for the reduction of iatrogenic injury, though some radiation damage is still unavoidable and follow-up treatment options are limited. Before treating with plaque brachytherapy or other radiation options, physicians must evaluate tumor- and patient-level risk factors for extensive radiation damage and discuss the risks and benefits of such a treatment with patients. In the years following radiation therapy for uveal melanoma, patients should also be followed closely by an ophthalmologist to assess for the delayed onset of radiation damage.

Author(s): Spungen, Hannah; Weingrow, Daniel | Abstract: Case Presentation: A 41-year-old man presented to the emergency department with five months of progressive monocular vision loss in his right eye, which he described as a gradually descending and enlarging black spot. He had no light perception in his right eye with elevated intraocular pressure and an afferent pupillary defect, while his left eye visual acuity and pupillary exam was normal. Point-of-care ultrasound demonstrated a hyperechoic, pedunculated mass in the posterior chamber of his right eye, consistent with a diagnosis of ocular melanoma. Ophthalmology scheduled the patient for an elective, right eye enucleation the following week, after which a diagnosis of uveal melanoma (UM) was confirmed on histopathology.Discussion: Uveal melanoma is an uncommon diagnosis that requires prompt intervention and surveillance due to the possibility of distant metastases arising in up to 50% of patients. Emergency department diagnosis of UM may be confounded by features of other intraocular pathology, such as increased ocular pressure or the finding of retinal detachment on fundoscopy. When emergency providers encounter glaucoma or retinal detachment on physical exam, point-of-care ultrasonography represents a key adjunct in the timely diagnosis and referral of this potentially vision- and life-threatening malignancy.

In contrast to cutaneous melanoma, there are no uniform guidelines regarding surveillance of ocular (uveal, conjunctival) melanomas. A consented standard operating procedure (SOP) by the "Netzwerk onkologische Spitzenzentren" Germany only exists for conjunctival melanoma but not for uveal melanoma. Surveillance is partially based on German S3-guidelines for cutaneous melanoma and is carried out by oncologic centres in a multidisciplinary approach. This study aims to evaluate patients' adherence to surveillance programs and whether surveillance recommendations (examinations, intervals) can be realised.Retrospective analysis of all ocular melanoma patients overseen at the University Hospital of Cologne between 2008 and 2019. The study evaluates rates of successful patient integration into a standardized surveillance program and patients' surveillance adherence, subject to age, gender, primary therapy and tumour entity, respectively.99 patients were included (56 female, 43 male), 83 of which had uveal melanomas and 16 conjunctival melanomas. Mean follow-up was 59 months. 81% of patients were integrated into a surveillance program. Surveillance was performed according to published recommendations in 78%. 13% of patients dropped out of the surveillance program after a mean period of 38 months.Our data show a growing number of patients in standardized surveillance. However, there are still gaps. There is a need for guidelines specifically designed for ocular melanomas, allowing centres to offer patients an individualized approach.Im Gegensatz zum Hautmelanom existieren keine einheitlichen Leitlinien für die Nachsorge bei okulären Melanomen (Aderhaut- und Bindehautmelanome). Lediglich für das Bindehautmelanom gibt es eine konsentierte Standard Operating Procedure (SOP) im Netzwerk onkologischer Spitzenzentren Deutschlands. Die Nachsorge erfolgt i. d. R. in Zentren und dort dann multidisziplinär, teilweise in Anlehnung an die S3-Leitlinie des Hautmelanoms. Ziel dieses Beitrags ist es, die Umsetzung von Nachsorgeempfehlungen (Diagnostik, Intervalle) sowie die Nachsorgeadhärenz okulärer Melanompatienten zu prüfen.Deskriptive, retrospektive Analyse aller Patienten mit Bindehaut- und Aderhautmelanom, die in den Jahren 2008 bis 2019 an der Universitätsklinik Köln betreut wurden. Bestimmt wurde die Rate an erfolgreicher Anbindung an ein strukturiertes Nachsorgeprogramm sowie die Nachsorgeadhärenz, jeweils in Abhängigkeit von Patientenalter, Primärtherapie und Tumorentität.Es wurden 99 Patienten (56 weiblich, 43 männlich) eingeschlossen, darunter 83 Aderhaut- und 16 Bindehautmelanome. Das mittlere Follow-up waren 59 Monate. Eine Anbindung an die interdisziplinäre Nachsorge erfolgte in 81% der Fälle. 78% der Fälle wurden entsprechend den jeweiligen Empfehlungen versorgt. Zu einem Ausscheiden aus dem Nachsorgeprogramm kam es in 13% der Fälle, durchschnittlich nach 38 Monaten.Die Daten zeigen einen zunehmenden Anteil an standardisiert nachkontrollierten Patienten, jedoch noch keine flächendeckende Nachsorge. Es besteht der Bedarf nach Leitlinien, die den okulären Tumorentitäten gerecht werden, um Patienten ein individualisiertes Vorgehen anbieten zu können.

Approximately 5% of all melanoma tumors arise in ocular tissue. Most ocular melanoma (85%) is uveal (iris, ciliary body or choroid) in origin and it is the most common intraocular malignant tumor. Tumors arise from the pigment cells (melanocytes).

Orbital tumors are rare lesions comprising 0.1% of all tumors and less than 20% of all ocular diseases. These lesions in children and adults differ significantly in their incidence, tumor type, and treatment management. Although surgery and systemic therapies are commonly used in the management of these diseases, radiation therapy has become a widely used treatment for both benign and malignant tumors of the orbit. Radiotherapy is used as a definitive treatment to provide local control while avoiding morbidity associated with surgery for some tumors while it is used as an adjuvant treatment following surgical resection for others. For many tumors, radiation provides excellent tumor control with preservation of visual function. This article is dedicated for presenting the most common applications of orbital radiotherapy. A brief overview of the commonly available radiation therapy modalities is given. Dose constraint goals are reviewed and acute and long-term side effects are discussed. Orbital tumors covered in this article include optic glioma, ocular melanoma, retinoblastoma, orbital rhabdomyosarcoma, orbital lymphoma, and lacrimal gland tumors. Background information, indications for radiotherapy, and goals of treatment for each case example are described.

Ocular melanomas are uncommon cancers in Southeast Asia unlike in the West. We conducted a retrospective review of patients (n = 44) with histologically-proven ocular melanoma within a multi-ethnic Asian cohort from Singapore. Clinicopathological features and relapse patterns were examined, and survival outcomes of interest included recurrence-free survival (RFS) and overall survival (OS). Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional regression. The study cohort included 18 male and 26 female patients, with a median age of 52 years (range 8–78). Median follow-up was 154 months. For uveal melanomas (n = 29), the 5-year RFS and OS was 56.8% and 76.6%, respectively; whilst for conjunctival melanomas (n = 15), the 5-year RFS and OS was 30.1% and 68.8%, respectively. Fifteen patients (38.5%) eventually developed metastasis, following which the median survival was only 17 months. Multivariate analysis demonstrated that higher T stage was a significant independent predictor for both OS (HR 8.69, 95% CI 1.03 to 73.09, p = 0.047) and RFS (HR 11.62, 95% CI 2.45 to 55.00, p = 0.002). Smoking history was independently predictive of better RFS (HR 0.08, 95% CI 0.01 to 0.78, p = 0.030). In conclusion, our study demonstrates the poor ocular melanoma outcomes in Southeast Asians, highlighting the necessity for urgent research in this area of unmet clinical need.

Purpose To describe the first series of six young uveal melanoma (UM) patients with oral isotretinoin and/or topical retinoid therapy prior to diagnosis. Observations The case series is based on clinical observations at our UM quaternary referral center. Six UM patient cases are reported, ages 16–44 years old. All had been using either oral (isotretinoin) and/or topical (tretinoin or tazarotene) retinoid treatment (3 months–~10 years) prior to or at the time of diagnosis (3 of 6 cases). All patients had ocular complaints on presentation, and the onset of certain symptoms corresponded with the course of retinoids. Other potential risk factors or relevant history included Caucasian background, cone-rod dystrophy and active smoker status (Case 2), family history of UM and pregnancy at time of diagnosis (Case 3), past smoking and possible secondary Chernobyl exposure as a baby (Case 5). All patients were treated with proton beam radiotherapy and currently have no sign of recurrent or metastatic disease. Conclusions and importance Retinoid therapy has been linked to various benign and/or reversible effects on the anterior and posterior eye, though pathophysiology remains not well understood. Uveal melanoma (UM) is a rare cancer diagnosis in young adults. We report here the first case series of young UM patients with a history of retinoid use and ocular complaints. No causal link is claimed and further systematic epidemiologic and biologic study of retinoid therapy and ocular impact may provide additional relevant data, particularly in young ocular melanoma patients.

Background Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver. Methods Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6–8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. Results Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6–69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively. Conclusions M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.

Purpose Investigate the involvement of vascular endothelial growth factor receptor 1 (VEGFR1) in vasculogenic mimicry (VM) formation in ocular melanoma, as well as whether or not VEGFR1-targeted contrast-enhanced ultrasound (CEUS) can evaluate and quantify VM perfusion and function in the ocular melanoma model. Methods The expression of VEGFR1 was examined using immunofluorescence, western blot, and quantitative polymerase chain reaction. VM networks were analyzed with tube formation and periodic acid Schiff staining. Targeted microbubbles (MBs) were constructed and used for targeted CEUS imaging in vivo. Comparisons were made in perfusion parameters of tumors between targeted and non-targeted CEUS imaging. Results VEGFR1 was highly expressed, and knockdown of VEGFR1 significantly decreased VM protein expression and disrupted VM formation in MUM-2B melanoma. VEGFR1-targeted MBs specifically bind to MUM-2B cell surfaces. CEUS with VEGFR1-targeted MBs showed significant imaging enhancement throughout the entire perfusion phase compared with CEUS with IgG MBs. VEGFR1-targeted imaging was able to detect a decrease in maximum intensity and mean transit time in VEGFR1 knockdown melanoma compared with control melanoma. The pathological VM patterns were consistent with VEGFR1-targeted CEUS findings. Conclusions VEGFR1 was responsible for VM network formation and was required for efficient choroidal melanoma tumor growth. This study shows that VEGFR1-targeted CEUS can track VM levels in animal models of ocular melanoma at morphological levels in vivo. This experiment is noninvasive and reproducible and indicates the possibility of real-time in vivo imaging technology for VM evaluation. Translational relevance Based on our study results, VEGFR1 could prove to be a promising treatment that targets VM formation in choroidal melanoma. Our findings also suggest the potential use of VEGFR1-targeted CEUS for quantitative monitoring of VM processes at the molecular level in the future.