The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma.

OBJECTIVE: To describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients. DESIGN: Description of a clinical registry. PARTICIPANTS: Patients with uveal melanoma. METHODS: A panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries. RESULTS: The data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described. CONCLUSIONS: The FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.

The multifunctional human ocular melanocortin system.

Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.

Uveal melanoma (UM) is the principal type of intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease with very poor survival. There are few drugs available to treat the primary or metastatic UM. This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM. The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors. In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines. Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could be evaluated in future clinical trials.

Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations.

Purpose: Familial adenomatous polyposis (FAP) has an almost 100% colorectal cancer risk warranting early detection in gene carriers. This study presents congenital hypertrophy of the retinal pigment epithelium (CHRPE) as a highly specific phenotypical marker for FAP that can be used in screening at-risk individuals. Screening recommendations including morphological subclassification were formulated with supporting literature. Methods: A systematic literature review with a comprehensive search strategy was conducted using online databases. Manual searches of bibliographies and reference lists were also performed. Studies meeting inclusion criteria were graded with respect to their hierarchy of evidence and strength of recommendations according to the National Health and Medical Research Council (NHMRC) guidelines of Australia. Results: Almost 4500 participants were analysed across 28 included studies. The mean specificity of CHRPE as a phenotypical screening marker of FAP was 89% (standard deviation (SD); 14) with a mean sensitivity of 79% (SD; 8). The mean prevalence of CHRPE amongst FAP participants; at-risk participants were found to be 76% (SD; 24) and 37% (SD; 21) respectively. Bilateralism and multiple lesion number ≥3 are features highly specific for FAP. Conclusion: CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP. Clinical recognition further allows increased gene analysis efficiency. The absence of CHRPE alone cannot exclude FAP. Our screening recommendations provide guidance to clinicians on evidence based CHRPE assessment. We would advocate inclusion of ocular examinations as part of a three-pronged approach, along with endoscopy and genetic testing, for efficient, timely FAP assessment in at-risk individuals.

The multi-kinase inhibitor afatinib serves as a novel candidate for the treatment of human uveal melanoma.

PURPOSE: Uveal melanoma (UM) is the most common intraocular malignancy in adults with a poor prognosis and a high recurrence rate. Currently there is no effective treatment for UM. Multi-kinase inhibitors targeting dysregulated pro-tumorigenic signalling pathways have revolutionised anti-cancer treatment but, as yet, their efficacy in UM has not been established. Here, we identified the multi-kinase inhibitor afatinib as a highly effective agent that exerts anti-UM effects in in vitro, ex vivo and in vivo models. METHODS: We assessed the anti-cancer effects of afatinib using cell viability, cell death and cell cycle assays in in vitro and ex vivo UM models. The signaling pathways involved in the anti-UM effects of afatinib were evaluated by Western blotting. The in vivo activity of afatinib was evaluated in UM xenograft models using tumour mass measurement, PET scan, immunohistochemical staining and TUNEL assays. RESULTS: We found that afatinib reduced cell viability and activated apoptosis and cell cycle arrest in multiple established UM cell lines and in patient tumour-derived primary cell lines. Afatinib impaired cell migration and enhanced reproductive death in these UM cell models. Afatinib-induced cell death was accompanied by activation of STAT1 expression and downregulation of Bcl-xL and cyclin D1 expression, which control cell survival and cell cycle progression. Afatinib attenuated HER2-AKT/ERK/PI3K signalling in UM cell lines. Consistent with these observations, we found that afatinib suppressed tumour growth in UM xenografted mice. CONCLUSION: Our data indicate that afatinib activates UM cell death and targets the HER2-mediated cascade, which modulates STAT1-Bcl-xL/cyclin D1 signalling. Thus, targeting HER2 with agents like afatinib may be a novel therapeutic strategy to treat UM and to prevent metastasis.

The unfolded protein response and the biology of uveal melanoma.

Uveal melanoma (UM) is a highly metastatic ocular cancer that arises from the melanocytes of the uveal tract (the choroid, ciliary body and iris). Despite a growing understanding of UM biology, effective systemic treatments are currently lacking and the cancer has an extremely poor prognosis. Therefore, identifying novel agents that act by new tumorigenic mechanisms in UM is essential to address this unmet clinical need. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the organelle, and the unfolded protein response (UPR) is the cellular mechanism that is activated so that cells may adapt to the situation. Dysregulated UPR signalling has been detected in UM tumors and has been associated with an increase in immune evasion and metastatic activity. A number of established and novel oncology drugs act in part by modulating ER stress and the UPR. The induction of protein-folding stress and the UPR could be a novel approach for the development of new therapeutics in UM. Further studies are now warranted to understand the mechanisms and consequences of UPR signalling in UM.

The application of natural compounds in uveal melanoma drug discovery.

OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular tumour in adults. UM has a poor overall prognosis and ~50% of patients progress to metastatic disease that has a median survival of 5.2 months. There are currently no proven pharmacological treatments for primary or metastatic UM. Research efforts continue to seek new agents. Many natural compounds have shown promising anti-UM activity in in-vitro and/or in-vivo studies. This review summarises the current findings for natural compounds that may be potentially useful in treating UM. KEY FINDINGS: Literature suggests that natural compounds, such as pristimerin, picropodophyllin, oridonin, zeaxanthin, withaferin and FR-900359, may be promising candidate compounds to treat UM. Most of these compounds have demonstrated satisfactory efficacy in inhibiting in-vitro UM cell growth. SUMMARY: The evidence regarding the anti-UM effects of natural compounds is mainly limited to in-vitro studies; to date, only a small number of these agents have been evaluated in vivo. The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM.

Conservative resection and adjuvant plaque brachytherapy for early-stage conjunctival melanoma.

BACKGROUND: To describe the outcome of patients treated by conservative surgical excision followed by adjuvant plaque brachytherapy for early-stage primary or recurrent conjunctival melanoma. DESIGN: Retrospective, non-comparative, interventional case series. PARTICIPANTS: We reviewed 19 eyes in 19 consecutive patients presenting with biopsy proven conjunctival melanoma with pathologic stage pT1c or less. METHODS: Patients with primary or recurrent early-stage conjunctival melanoma were identified and treated using a conservative resection technique (tractional micro-dissection) involving avoidance of deep dissection and modest lateral clearance followed by adjuvant plaque brachytherapy. MAIN OUTCOME MEASURE: Local recurrence and ocular complications. RESULTS: Mean age was 55.2 years and male : female (8:11). Mean follow up was 43.1 months (range 30.1-54.3 months). All patients were treated by conservative resection followed by adjuvant Iodine-125 plaque brachytherapy. The treatment dose was 100 Gy to a depth of 1.5-3.0 mm. OUTCOMES: median visual acuity and intraocular pressure were unchanged after surgery. Six patients experienced corneal ulceration in the immediate postoperative period. No patients experienced recurrence at the treatment site or metastases. Three patients experienced new lesions distant from the treatment site. CONCLUSIONS: Conservative resection and adjuvant plaque brachytherapy is an effective and well-tolerated modality for the management of patients with early-stage conjunctival melanoma.

The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome.

The choroid within the human eye contains a rich milieu of cells including melanocytes. Human choroidal melanocytes (HCMs) absorb light, regulate free radical production, and were recently shown to modulate inflammation. This study aimed to identify key genes and pathways involved in the inflammatory response of HCMs through the use of RNA-seq. Primary HCMs were cultured from donor choroids, RNA was extracted from control and lipopolysaccharide (LPS)-treated HCMs, and mRNA was sequenced. Functional annotation and pathway analysis were performed using gene ontology and gene set enrichment analyses. Representative RNA-seq results were verified with RT-qPCR and protein measurements. We detected 100 differentially expressed genes including an array of CCL and CXCL cytokines and mediators of cell-cell and cell-matrix adhesion, such as ICAM1, CLDN1, CCN3, ITGA1 and ITGA11. Functional annotation showed that these gene sets control inflammatory pathways, immune cell trafficking, cell-cell adhesion, interactions with the extracellular matrix and blood vessels, angiogenesis and epithelial-to-mesenchymal transitions. Our study provides insights into the transcriptional regulation of primary HCMs in response to inflammatory stimuli and identifies novel melanocyte-driven mechanisms potentially involved in choroidal homeostasis and inflammation.

Development of new therapeutic options for the treatment of uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilise the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors which are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualised tumour profiling. It would also be important to characterise UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible.

Analysis of Circulating Tumour Cells in Early-Stage Uveal Melanoma: Evaluation of Tumour Marker Expression to Increase Capture.

(1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has been proposed as a tool to avoid invasive biopsy of the primary tumour. However, the clinical utility of such liquid biopsy depends on the detection rate of CTCs. (2) Methods: The expression of melanoma, melanocyte, and stem cell markers was tested in a primary tissue microarray (TMA) and UM cell lines. Markers found to be highly expressed in primary UM were used to either immunomagnetically isolate or immunostain UM CTCs prior to treatment of the primary lesion. (3) Results: TMA and cell lines had heterogeneous expression of common melanoma, melanocyte, and stem cell markers. A multi-marker panel of immunomagnetic beads enabled isolation of CTCs in 37/43 (86%) patients with UM. Detection of three or more CTCs using the multi-marker panel, but not MCSP alone, was a significant predictor of shorter progression free (p = 0.040) and overall (p = 0.022) survival. (4) Conclusions: The multi-marker immunomagnetic isolation protocol enabled the detection of CTCs in most primary UM patients. Overall, our results suggest that a multi-marker approach could be a powerful tool for CTC separation for non-invasive prognostication of UM.

Plaque brachytherapy for the management of ocular surface malignancies with corneoscleral invasion.

PURPOSE: To describe the outcome of patients treated by surgical excision followed by plaque brachytherapy for primary or recurrent ocular surface malignancies with evidence of deep margin (corneoscleral) invasion. METHODS: Retrospective, non-comparative, interventional case series. Eleven consecutive patients presenting with biopsy-proven scleral and/or corneal stromal involvement from either conjunctival melanoma (CM) or squamous cell carcinoma (SCC) of the conjunctiva were reviewed. RESULTS: Five patients had CM (pT3 N0 M0 [n = 3], pT4 N0 M0 [n = 2]) and six patients had SCC (T3 N0 M0 [n = 6]). Mean age was 60.8 years and male:female (3:8). Mean follow up was 23.4 months (range 12-36 months). All patients were treated with Iodine-125 plaque following biopsy-proven corneoscleral invasion on histopathology. The treatment dose was 100 Gy to a depth of 1.5-2.5 mm. OUTCOMES: Median visual acuity and intraocular pressure were unchanged after surgery. Five patients experienced corneal ulceration in the immediate postoperative period. None experienced recurrence at the treatment site. One SCC patient and two CM patients experienced new lesions distant from the treatment site. No sight-threatening complications were observed. No patients developed distant metastases. CONCLUSION: Plaque brachytherapy is an effective and well-tolerated modality for the management of patients with ocular surface malignancy with evidence of localized corneoscleral invasion.

Primary cutaneous B cell lymphoma presenting as recurrent eyelid swelling.

Primary cutaneous lymphoma represents a distinct clinical entity within the spectrum of haematological malignancy. A case of primary cutaneous B cell lymphoma is reported, presenting in an 87-year-old female with a 2-year history of intermittent swelling and discolouration of the right upper and lower eyelids, in the absence of systemic symptoms. Histopathological examination of an incision biopsy revealed a lymphoid infiltrate in the dermis with immunophenotypic features of B cell lymphoma. Staging investigations confirmed the absence of systemic disease. Treatment with oral chemotherapy was undertaken with a good response. Ophthalmologists should include primary cutaneous lymphoma in the differential diagnosis of recurrent eyelid swelling.

Australian Cancer Network clinical practice guidelines for the management of ocular and periocular melanoma: an evidence-based literature analysis.

BACKGROUND: With recent advances in the diagnosis and management of ocular and periocular melanoma, many of which are based on results from randomized control trials, there is an increasing need for an evidence-based review of the literature for the Australasian population. The Australian Cancer Network has recently redeveloped the evidence-based Clinical Practice Guidelines for the Management of Melanoma, including a chapter on ocular melanoma. These are the first evidence-based guidelines on ocular melanoma to be created by the Australian Cancer Network. METHODS: The primary research questions were formed and a detailed literature search was undertaken. Each relevant article was assessed and graded I-IV according to the level of evidence. Articles were grouped into bodies of evidence which were then assessed. RESULTS: A total of 107 relevant articles were identified and grouped into 12 bodies of evidence. Guidelines based on this analysis were formulated and graded. These are presented below. CONCLUSIONS: The management of ocular melanoma has benefited from recent advances in imaging, molecular biology and cytogenetics, and tumours today are detected earlier and with greater accuracy than 25 years ago. With improved treatment ocular and periocular melanomas can be controlled locally, with good preservation of vision in many patients. However, there remains no cure for metastatic disease.

Paediatric uveal melanoma.

Uveal melanoma is extremely rare in the paediatric population and can be associated with various pre-existing conditions. We report the case of a 9-year-old girl with no predisposing factor who presented with choroidal melanoma. A review of the literature is presented and various clinical, histopathological and prognostic features of paediatric uveal melanoma are discussed.

Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy.

The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.

Expression and distribution of MUC18 in human uveal melanoma.

The immunoglobulin superfamily protein MUC18 is involved in transendothelial migration and signal transduction, and is expressed in malignancies including cutaneous melanoma. Recent in vitro studies showed evidence of increased MUC18 protein in some uveal melanoma cell lines with an increased potential for invasion. We assessed seven uveal and three metastasis-derived melanoma cell lines for the expression of MUC18 mRNA and protein by RT-PCR, and immunoblotting and immunocytochemistry, respectively. We also examined the expression and distribution of MUC18 in paraffin sections of primary uveal melanomas (n = 23; 5/23 spindle; 18/23 mixed and epithelioid) and normal eyes (n = 3) using a polyclonal goat anti-human antibody to MUC18 visualized with peroxidase and Vector NovaRED. Distribution and intensity of immunostaining was graded semi-quantitatively (grade 0 to 3) by 2 independent observers. All cell lines expressed MUC18 mRNA and protein ( approximately 130 kDa), and showed punctate cell membrane MUC18 immunostaining. Primary melanomas displayed heterogeneous cell membrane and cytoplasmic MUC18, with moderate to strong immunolabelling (> or =grade 2) in approximately 70% of tumours. Vasculature in tumours and in retina and choroid of all melanoma-affected and normal eyes showed intense MUC18 immunostaining. These observations further suggest a role for MUC18 in uveal melanoma growth; moreover, interactions between MUC18-positive melanoma cells and vasculature may be important for the hematogenous spread of cells during metastases.

Porous orbital implants in enucleation: a systematic review.

Orbital implants have been used for cosmesis following surgical removal of the eyeball, or enucleation, for over a century. Implant design has progressed significantly in recent years with the use of porous devices, with the theoretical advantages of reduced complications and improved cosmesis. However, in some cases the theoretical benefits have not fully translated into clinical results. In this article the use of orbital implants in enucleation, with a particular focus on the newer porous biomaterials that have gained prominence over the last 15 years, is reviewed. Specific factors identified as affecting the performance of porous orbital implants include the material used, pore size, and morphology. Mechanical factors have received little consideration in the past and may form a basis for the use of higher compliance porous materials in the future. Of the porous materials in use, current clinical evidence is not sufficient to suggest either that porous implants are superior to non-porous implants, or that one material is more suited to the application than another. Future developments in this field require randomized controlled clinical trials with extensive follow-up as complications may not become evident until over 5 years post-implantation.

Estimates of ocular and visual retention following treatment of extra-large uveal melanomas by proton beam radiotherapy.

OBJECTIVE: To assess outcomes of proton beam radiotherapy for the treatment of extra-large uveal melanomas in patients specifically referred to the University of California, San Francisco, for ocular conservation therapy. Series patients uniformly refused enucleation both at an outside institution and again as a treatment option after extensive discussion at the University of California, San Francisco. DESIGN: In a retrospective, nonrandomized cohort study, 21 patients with extra-large choroidal or ciliochoroidal melanomas measuring at least 10 mm in maximum thickness or 20 mm in maximum basal diameter or tumors located within 3 mm of the optic nerve measuring at least 8 mm in maximum thickness or 16 mm in maximum basal diameter met inclusion criteria. Main outcome measures were frequency of (1) anterior segment complications (lash loss, keratopathy, cataract, and neovascular glaucoma), (2) posterior segment complications (vitreous hemorrhage, radiation retinopathy, and radiation papillopathy), (3) treatment failure (tumor growth, enucleation, or metastases), and (4) final visual acuity. RESULTS: Median follow-up was 28 months. Mean age at treatment was 58.3 years. The frequencies of hypertension and diabetes mellitus were 14.3% and 9.5%, respectively. Mean tumor thickness and mean basal diameter were 8.6 mm and 18.7 mm, respectively. Lash loss occurred in 52.4%; dry eye, in 23.8%; cataract, in 28.6%; neovascular glaucoma, in 38.1% (100% in patients with diabetes mellitus); radiation retinopathy, in 9.5%; and radiation papillopathy, in 9.5%. No patient developed radiation-associated scleral necrosis or vitreous hemorrhage. The 2-year Kaplan-Meier estimate of local tumor growth after treatment was 33%, and the rate of distant metastasis was 10%. Visual acuity of 20/200 or better was preserved in 25% of patients, including 4 patients (19%) who experienced an average of 4 lines of Snellen visual acuity improvement. Development of neovascular glaucoma was associated with tumors in close proximity to the optic nerve (P = .04), while cataract (P = .03) and lash loss (P = .02) occurred with more anteriorly located tumors. Proton beam radiotherapy provided a 67% probability of local control and 90% probability of clinically discernible metastases-free survival at 24 months after treatment. CONCLUSION: Proton beam radiotherapy is an ocular-conserving option that may be considered for the treatment of extra-large uveal melanoma in carefully selected patients.