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Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with 10% cBAP1.

Purpose To report the long-term outcomes of patients with small, pigmented, posteriorly located choroidal melanoma undergoing primary treatment using photodynamic therapy (PDT) with verteporfin at the London Ocular Oncology Service. Design Retrospective, interventional, consecutive case series. Participants All patients undergoing primary treatment using PDT with verteporfin from April 2014 to December 2015 and followed until December 2019. Methods This is a long-term follow-up study of the same cohort of patients previously reported by our group in 2017 and 2018. Main Outcome Measures Local tumor control, visual outcomes, and metastasis-free survival. Results Twenty-six patients were included with a mean (± standard deviation) age and tumor thickness of 62 ± 14 years and 1.3 ± 0.5 mm, respectively. Tumors were posteriorly located (mean distance to optic nerve and fovea = 2.0 ± 2.2 mm and 1.6 ± 1.5 mm, respectively), and the majority were fully pigmented (73%). Overall, patients were followed for a median (interquartile range [IQR], range) of 49.5 (15.3, 7.0–66.0) months from first PDT to last follow-up. Over the course of this study, 14 of 26 (54%) have developed a local recurrence at a median of 20.0 months (20.5, 4.7–60.9 months). The most common pattern of recurrence was an isolated increase in basal dimensions (9/14; 64%). Median (IQR) final logarithm of the minimum angle of resolution visual acuity of the whole cohort was 0.2 (0.5). The only statistically significant difference in baseline and outcome characteristics between treatment failures and nonfailures was the distance to the fovea (median [IQR], 0.5 [1.3] vs. 2.5 [2.8]; P = 0.002) and final logarithm of the minimum angle of resolution visual acuity (median [IQR], 0.50 [0.80] vs. 0.00 [0.14]; P = 0.002), respectively. Conclusions Although treatment of small pigmented posterior choroidal melanoma with PDT effectively preserves visual acuity, 5-year treatment-success calculated by Kaplan–Meier analysis was only 38.4%. Recurrences after PDT tend to occur along the tumor edges, often with minimal increase in thickness. Given the substantial risk of treatment failure, primary PDT with vertepofrin is recommended in exceptional cases of choroidal melanoma, for which other treatments with greater tumor control are not a feasible option.

Objective The objective of this study is to characterise the natural history of conjunctival naevi in a paediatric and adolescent population. Methods All children and adolescents referred to Moorfields Ocular Oncology Service for evaluation between January 2015 and 2020 were included. Exclusion criteria included age >20 years old and lack of anterior segment photographs. A total of 77 patients were included with a mean age of 12 years (standard deviation: 3.9; range, 4-20). The main outcome measures were: number of conjunctival naevi that grew, changed in pigmentation, required excisional biopsy, or were histologically malignant. If there was growth, the percentage increase in size was measured. Results At their first visit, 13% of patients (10/77) were discharged to local follow-up and 10% (8/77) proceeded to excisional biopsy, four further patients underwent excisional biopsy after a period of follow-up. On histopathological assessment, 92% (11/12) of lesions were benign conjunctival naevi. One patient, who had suspicious clinical features at presentation, had conjunctival melanoma. Fifty-nine patients were followed over a median of 1.1 years (interquartile range: 1.54; range, 3 months to 4 years). Eight per cent (5/59) of conjunctival naevi enlarged in diameter by a mean percentage increase in size of 2%, whereas 5% (3/59) showed increased pigmentation and 8.5% (5/59) showed decreased pigmentation. Conclusions Growth of conjunctival naevi in children is infrequent (8%) and the large majority of those excised are benign. Because of a lack of evidence, these patients are often followed for years in ophthalmic practice. This series demonstrates that prolonged follow-up may not be necessary.

BACKGROUND AND OBJECTIVE: Circumscribed choroidal haemangioma (CCH) has several characteristic clinical and angiographic features. We aimed to compare indocyanine green angiography (ICG) findings of CCH captured on a traditional digital camera system (DCS) to newer scanning laser ophthalmoscopy (SLO) platforms. STUDY DESIGN/MATERIALS AND METHODS: A total of 35 patients over a 10-year period diagnosed with CCH using ICG were included (18 imaged with DCS and 17 with SLO). RESULTS: On early ICG frames, intrinsic vessels were apparent in two-thirds (12/18; 67%) of the DCS group compared with all of eyes in the SLO group (p = 0.020). In addition, at maximal hyperfluorescence, most eyes imaged with DCS had a feathery appearance (16/18; 89%) compared with those in the SLO group which all (17/17; 100%) displayed a granular appearance (p 30 min) without compromising diagnostic accuracy.

BACKGROUND: Diagnosis of small choroidal melanoma is mainly based on tumour thickness, subretinal fluid, or lipofuscin pigment. Ultra-wide-field imaging (UWF) allows depiction of choroidal lesions through a red (RC) and a green channel (GC). Aim of the study was to determine the utility of this tool in the detection of small choroidal melanoma. METHODS: Retrospective cross-sectional study of patients with small choroidal pigmented lesions up to 3 mm in thickness. All patients underwent clinical and imaging assessment including UWF. Lesions were subcategorized based on thickness and lesion type. A qualitative assessment ensued using the red and green channels feature. RESULTS: A total of 152 patients were included. Melanotic naevi (76/152,50%) and small choroidal melanomas (55/152,36%) were the predominant types. Thickness was

To assess the long-term visual outcomes in patients with posteriorly located choroidal melanoma treated with ruthenium plaque brachytherapy between January 2013 and December 2015.A retrospective review was conducted on consecutive patients treated with ruthenium plaque brachytherapy for post-equatorial choroidal melanoma with available Snellen visual acuity before and after treatment, and the development and treatment of radiation complications.There were 219 patients with posterior choroidal melanoma treated with ruthenium plaque brachytherapy. Median follow up was 56.5 months, range 12-81 months. Final visual acuity was ≥6/12 in 97 (44.3%) patients, 6/12 to 6/60 in 57 (26.0%),6/60 in 55 (25.1%) and 10 (4.6%) eyes were enucleated. Radiation maculopathy was the most common radiation complication encountered, occurring in 53 (24.2%) patients. Of these, final visual acuity was 6/12 in 10 patients (18.9%), 6/12 to 6/60 in 26 (49.1%),6/60 in 16 (30.2%) and 1 eye (1.9%) was enucleated. Twenty-five (47%) with radiation maculopathy were treated with intravitreal anti-angiogenic therapy, 27 (51%) were monitored and one (2%) was treated with scatter photocoagulation. Eyes treated with intravitreal anti-angiogenic therapy had better final vision than those observed or treated with retinal laser (chi-square, p = 0.04). On multivariate analysis, close proximity to the optic nerve and fovea, and large or notched plaque type was associated with final vision worse than 6/12.Most patients treated with ruthenium plaque brachytherapy for posterior choroidal melanoma retain 6/60 vision, with almost half retaining 6/12 vision at long term follow up.

Ocular surface squamous neoplasia is the most common tumour of the ocular surface. It is a spectrum of disease from intraepithelial dysplasia to invasive squamous cell carcinoma. Recent years have seen an increase in the use of topical chemotherapeutic agents to treat this condition, often as primary treatment without full-thickness biopsy. This practical approach provides a critical appraisal of the evidence base with the goal being to aid the clinician in the management of these patients.

Purpose To describe the 3 distinct patterns of choroidal nevi in swept-source (SS) OCT and apply that classification to a cohort of consecutive choroidal nevi. Also, we aim to describe the findings of these lesions in near-infrared reflectance (NIR) at different wavelengths (820 and 1050 nm). Design Single-center, retrospective, observational study. Participants One hundred four consecutive patients with choroidal nevi. Methods Retrospective analysis of choroidal nevi imaged with SS OCT and NIR. Main Outcome Measures Lesions were classified according to OCT patterns as type A (high reflectivity with optical shadowing), type B (medium reflectivity with partial visualization of the scleral boundary), and type C (hyporeflective with complete visualization of the scleral boundary). Results Of 104 choroidal nevi, 97 lesions (93.3%) could be classified into 1 of the SS OCT patterns. Forty-nine percent corresponded to type A, 26% corresponded to type C, and 18.3% corresponded to type B. In NIR (n = 820), 76% of lesions were hyperreflective, whereas in NIR (n = 1050), most of the lesions were hyporeflective (59.6%; inverse reflectance). Conclusions Choroidal nevi present distinct patterns according to SS OCT features. Clinical implications are yet to be determined. In NIR, inverse reflectance may be a consequence of the confocality of the device, rather than a property of the lesions.

Objective: The aim of this study was to determine the sensitivity and specificity of the MOLES scoring system in differentiating choroidal melanomas from nevi according to Mushroom shape, Orange pigment, Large tumor size, Enlarging tumor, and Subretinal fluid (SRF). Methods: Color photographs, fundus-autofluorescence images, and optical coherence tomography of 222 melanocytic choroidal tumors were reviewed. Each MOLES feature was retrospectively scored between 0 and 2 and tumors categorized as “common nevus,” “low-risk nevus,” “high-risk nevus,” and “probable melanoma” according to the total score. MOLES scores were compared with the experts’ diagnosis of melanoma. Results: The MOLES scoring system indicated melanoma in all 81 tumors diagnosed as such by ocular oncologists (100% sensitivity) and nevus in 135 of 141 tumors given this diagnosis by these experts (95.7% specificity). Of the 6 tumors with discordant diagnoses, 4 had basal diameters exceeding 6 mm, all with SRF and/or orange pigment, and 2 small tumors showed either significant SRF with traces of orange pigment, or vice versa. Conclusions: The MOLES system for diagnosing melanocytic choroidal tumors compares well with expert diagnosis but needs to be evaluated when deployed by ophthalmologists and community optometrists in a wide variety of working environments.

The COVID-19 pandemic has had an unprecedented impact on the National Health Service in United Kingdom. The UK Ocular Oncology Services evaluated the impact on the adult eye cancer care in the UK. All four adult Ocular Oncology centres participated in a multicentre retrospective review comparing uveal melanoma referral patterns and treatments in a 4-month period during the national lockdown and first wave of the COVID-19 pandemic in 2020 with corresponding periods in previous 2 years. During the national lockdown, referral numbers and confirmed uveal melanoma cases reduced considerably, equalling to ~120 fewer diagnosed uveal melanoma cases compared to previous 2 years. Contrary to the recent trend, increased caseloads of enucleation and stereotactic radiosurgery (p > 0.05), in comparison to fewer proton beam therapy (p

Purpose To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT). Methods Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed. Results The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1-6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented. Conclusions Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive.

PurposeTo report the outcomes of intravitreal methotrexate (MTX) injections to rescue eyes with relapsed primary intraocular lymphoma (PIOL).MethodsRetrospective case series of patients with ocular relapse of PIOL who had initially received systemic chemotherapy (all five cases) and external beam radiotherapy (EBRT) to brain and orbits (two cases). Injections of MTX (400 µg/0.1 mL) were given one time per week for 1 month, every other week for 4 months, followed by a maintenance phase of one injection one time per month for 8 months (total of 20 injections in a year).ResultsFrom April 2008 to February 2016, there were nine eyes of five patients (three men; average age at first presentation 62 years) treated with our rescue protocol of intravitreal MTX injections. Ocular relapse occurred at a mean interval of 15 months (range 5–34 months) after the completion of initial systemic treatment. At mean follow-up of 31 months (range 5–104 months), tumour control was achieved in eight out of nine eyes (89%); one eye failed, with persistent retinal infiltrates despite increasing the frequency of injections, resulting in severe keratopathy. The only other complication occurred in one eye, developing cystoid macular oedema from MTX injections that resolved with topical anti-inflammatory medications and reduced frequency of MTX. There were no cases of reduced vision or ocular relapse, but two patients died (one of central nervous system lymphoma).ConclusionsIntravitreal MTX was a safe and effective treatment modality for relapsed PIOL after systemic chemotherapy and radiotherapy, achieving local tumour control in 89%, and hence represents an optimal choice. However, given the rare nature of PIOL, larger collaborative studies with longer follow-up are needed to corroborate this.

While the majority of cases of conjunctival melanoma (CM) involve the bulbar conjunctiva, concurrent pigmentation of the ipsilateral eyelid can be seen in up to 15% of cases. Although extension of conjunctival melanoma into the eyelid (AJCC cT3b) occurs in 1% of cases, non-contiguous lesions are very rare with only 5 clearly documented reports in the English literature. Several pathophysiological mechanisms have been proposed, including separate primary melanomas, patchy involvement from primary acquired melanosis (which may be sine pigmento) and exfoliation of malignant tumour cells into the tear film. Herein we present a case of eyelid melanoma arising in a patient previously treated for CM at a non-contiguous site and provide a comprehensive review of the relevant literature.

PurposeThe purpose of the study was to investigate the outcomes of primary photodynamic therapy (PDT) for small pigmented posterior pole choroidal melanoma.Patients and methodsProspective interventional consecutive case series of 15 patients with small pigmented posterior pole choroidal melanoma, who were treated with three sessions of PDT and followed-up thereafter. Risk factors for failure were assessed and outcome measures at presentation were compared to those at last follow-up visit.ResultsTumor control was achieved in 12 (80%) patients in a median follow-up time of 15 months (mean 14, range 8-18). Three patients failed treatment, diagnosed in a median time of 5 months (mean 4, range 3-6), after first PDT. In all failed cases, lesions were 100% pigmented; de novo melanoma rather than transformed nevi and showed a radial growth pattern rather than increased thickness. All failed cases were subsequently successfully treated with radiotherapy. In this cohort, subretinal fluid (SRF) was significantly reduced (P

Melanoma of the eye is rare, but can mimic a range of disorders. This report highlights 2 cases of choroidal melanoma with vision loss mimicking neurological diagnoses. The first patient is a 41-year-old white male with a known history of multiple sclerosis and a previous episode of optic neuritis in the right eye, who presented with a 6-month history of decreased vision in the same eye, and occasional photopsiae. He was treated with 2 courses of oral steroids for presumed recurrent optic neuritis. After a temporary improvement in his symptoms, his vision worsened, following which he had a head MRI, which revealed a solid intraocular mass. He was subsequently diagnosed with a choroidal melanoma for which he was treated successfully with ruthenium-106 plaque brachytherapy. The second patient is a 57-year-old female, who presented with a progressive cerebellar syndrome under investigation by the neurology service, as well as decreased vision in the right eye. Her visual acuity gradually deteriorated and her neurological assessment, which included a PET-CT, revealed uptake in the right eye. The diagnosis of a choroidal melanoma was made, and following conservative treatment with proton beam radiotherapy, she had an enucleation of the eye. Intraocular tumours can masquerade as many different entities. Unexplained unilateral visual loss, especially if it is atypical for a neurological syndrome, should prompt dilated fundoscopy and referral to an ophthalmologist.

A 54-year-old woman who presented with photopsia was found to have elevated intraocular pressure in both eyes and optic disc cupping in the right eye. Angle infiltration was noted on gonioscopy. She was previously been diagnosed with metastatic breast cancer. This case report describes a rare case of glaucoma as a complication of ciliary body and iris metastases secondary to invasive ductal breast cancer.

BackgroundConjunctival melanoma is the second most common conjunctival malignant tumour after squamous cell carcinoma, usually arising from primary acquired melanosis and less commonly from a conjunctival naevus or de novo. We report four cases of conjunctival melanoma masquerading as ocular surface squamous neoplasia.MethodsFour patients (2 females and 2 males; mean age 60.7 years; range 41–72 years) were referred for suspicious conjunctival lesions. In all cases, the lesions had a perilimbal location, were non-pigmented (cases 1 and 3) or mildly pigmented (cases 2 and 4), had a fleshy (cases 1, 2 and 4) or papillomatous (case 3) appearance and involved the corneal surface. In each case, our main clinical differential diagnosis included conjunctival intraepithelial neoplasia and squamous cell carcinoma. All four patients underwent an excisional biopsy with double freeze-thaw cryotherapy and alcohol keratoepitheliectomy.ResultsIn all four cases, the histopathological diagnosis was of invasive conjunctival melanoma with extension to the deep surgical margins. Adjuvant therapy consisting of strontium-90 β radiotherapy (all 4 patients) and topical Mitomicyn C (patient 2) was administered.ConclusionConjunctival melanoma can clinically resemble ocular surface squamous neoplasia. Clinical impressions therefore need to be confirmed histopathologically.

Background Retinoblastoma, uveal and conjunctival melanomas are important malignancies within the remit of ocular oncology. Outlined are the diagnostic features and management principles, as well as advancements in the field and current challenges. Sources of data Original papers, reviews and guidelines. Areas of agreement Most eyes with retinoblastoma (International Intraocular Retinoblastoma Classification (IIRC) Group A-D) are salvaged, whereas advanced cases (Group E) remain a challenge. Despite a high rate of local tumour control in uveal melanoma, metastatic spread commonly occurs. Conjunctival melanoma is treated by complete resection, but high rates of local recurrence occur, with the possibility of systemic relapse and death. Areas of controversy Use of the IIRC in retinoblastoma, and systemic screening in melanomas. Growing points Utilization of novel treatment modalities in retinoblastoma and an increasing understanding of the genetic basis of melanomas. Areas timely for developing research Improvements in chemotherapy delivery in retinoblastoma and prognostic tests in melanomas.

Summary The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab. He developed sequential autoimmune transaminitis, diabetes and uveitis, which necessitated discontinuation of maintenance nivolumab 3 months after commencement of treatment. The patient continues to demonstrate an ongoing partial response 10 months from the initial combination immunotherapy, with evidence of depigmentation of the primary ocular tumour. This article is protected by copyright. All rights reserved.

Purpose To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design Retrospective, multicenter observational study. Participants Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7–17.9 years) and 185 were young adults. Methods Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively ( P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Peripheral nerve sheath tumors of the uveal tract arise mainly in the sheath of peripheral nerves that are found in the uvea. The ciliary nerve is most often affected and hence these tumors tend to be located anteriorly, in the ciliary body or peripheral choroid. There are several systemic predisposing risk factors, which include schwannomatosis, neurofibromatosis 1 (NF1) and 2, and other rare genetic syndromes. The benign tumors can be subclassified as neurofibroma and schwannoma. The malignant nerve sheath tumors are more difficult to subclassify if they lose the histological characteristics of their benign counterparts. In this chapter we discuss uveal neurofibroma and schwannoma.

PURPOSE: The purpose of this study was to report the results of staging primary uveal melanoma with whole-body (18) fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) and abdominal ultrasound. MATERIALS AND METHODS: From January 2012, patients with uveal melanoma over 4 mm in thickness were staged with FDG PET/CT and abdominal ultrasound. RESULTS: Over 2 years, 108 patients with medium-to-large melanoma underwent dual imaging. According to the tumor, node, and metastasis classification, there were 75% T3, 11% T2, and 14% T1 uveal melanomas. Only, three of 108 patients (2.8%) were found to have metastatic uveal melanoma. All three had liver metastases confirmed following biopsy; one of three had additional extrahepatic widespread metastases. In these three patients, liver findings using both imaging techniques were consistent in one patient. In the second case, abdominal ultrasound missed the diagnosis of metastatic disease; however, FDG PET/CT revealed intense metabolic activity of the liver. In the third case, PET/CT missed the liver metastases; however, this was identified on abdominal ultrasound. PET/CT identified incidental second primary malignancies in 10 patients (9%). Second malignancies were found in the lung, breast, colon, thyroid, and adrenal gland. Abdominal ultrasound detected benign hepatic abnormalities in 20 patients (18%). CONCLUSIONS: Whole-body PET/CT and abdominal ultrasound complement each other in the staging of uveal melanoma. Benign hepatic abnormalities found using ultrasound is common. Of importance, a second asymptomatic primary malignancy associated with uveal melanoma was detected almost one in 10 patients.

This report concerns a 49-year-old female with cutaneous malignant melanoma and systemic metastases. These resolved following combination immunotherapy with ipilimumab and nivolumab. She subsequently experienced unilateral floaters, an increase in iris pigmentation and pigmentary glaucoma. The eye progressively lost vision and became painful due to iris neovascularization. The clinical diagnosis was of cutaneous melanoma metastatic to the vitreous, ciliary body and iris. Enucleation was performed for symptom control, with histopathology confirming the clinical diagnosis. The immune privilege of the eye may preclude ocular metastasis control with immunotherapy. Ocular symptoms in such patients merit referral to an ophthalmologist.

Background: Medulloepithelioma is a rare congenital neoplasm derived from precursors of the nonpigmented ciliary epithelium of the ciliary body. The average patient age at clinical presentation is 3.8 years. Case Presentation: We present the case of a 78-year-old male with progressive lens subluxation and ocular hypertension who was found to have a ciliary body mass. After enucleation for presumed ciliary body melanoma, histopathology showed a nonteratoid medulloepithelioma. Cytogenetic analysis revealed abnormalities in chromosomes 3 and 8. Conclusion: Medulloepithelioma is often initially misdiagnosed. Though congenital in nature, it can exhibit rapid growth, have chromosomal abnormalities, and must be considered in all age groups.

The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

Background and Objective: In ocular oncology, orange-color lipofuscin is commonly associated with choroidal melanoma. We herein report a case series of choroidal metastases with overlying lipofuscin pigment. Methods: A retrospective case series of 3 consecutive patients with choroidal metastasis with overlying orange-color pigment. Results and Discussion: Three women who presented to the London Ocular Oncology Service with suspicious choroidal lesions were included in this study. Median age of presentation was 59 years old (mean: 58). On clinical examination, visual acuity of the affected eyes was 6/24 in 2 cases and counting fingers in one. All lesions were pale and showed subretinal fluid, and orange color lipofuscin overlying the tumours, which was also demonstrated as speckled hyperflourescence on autofluorescence. At presentation to our service, 2/3 patients were already diagnosed with metastatic disease from primary breast and lung cancer, and one had no known extraocular malignancy, but was diagnosed with metastatic lung cancer following systemic workup. Conclusion: Findings of this study suggest that orange lipofuscin pigment, although commonly associated with choroidal melanoma, can also be found overlying choroidal metastasis. In case both entities are considered part of the differential diagnosis, presence of orange pigment should be carefully interpreted and further ocular and extraocular evaluation is advised.

AimsTo investigate the outcomes of primary photodynamic therapy (PDT) for pigmented posterior pole cT1a choroidal melanoma.MethodsRetrospective interventional consecutive case series of 26 patients (26 eyes) with pigmented posterior pole cT1a choroidal melanoma, who were treated with 3 sessions of PDT and followed-up thereafter.ResultsIncluded were 11 males and 15 females that presented at a median age of 66 years (mean: 64) with transformed naevi (n=11) or suspicious lesions (n=15) with ≥3 risk factors for growth, with lipofuscin in all. In all cases, diagnosis was clinically based (no tissue biopsy). Tumour control was achieved in 16 (62%) patients in a median follow-up time of 29 months (mean: 27). Ten patients failed treatment by form of radial expansion, diagnosed in a median time of 13 months (mean: 12) from last treatment. By Kaplan-Meier analysis, success rate after 1, 2 and 3 years was 85%, 59% and 51%, respectively. On statistical analysis, number of suspicious features was found to be the only risk factor predicting failure (P=0.046). One patient developed macula-sparing branch retinal artery occlusion after treatment. Following PDT, subretinal fluid resolved in all cases and visual acuity significantly improved in all treatment-success cases (P=0.043). There were no cases of metastatic spread.ConclusionPrimary PDT resulted in tumour regression of small, pigmented choroidal melanoma in 62% after a mean of 27 months. Treatment was more effective in tumours with three or less risk factors for growth, and resulted with fluid elimination and significant improvement in vision in treatment-success cases.

Purpose To determine the long-term therapeutic outcome for different treatments of circumscribed choroidal hemangioma (CCH). Design Retrospective observational study. Subjects Patients with newly diagnosed CCH. Methods Observation, verteporfin (Visudyne) photodynamic therapy (PDT), lens-sparing external beam radiotherapy (LS-EBRT), or plaque brachytherapy. Main Outcome Measures Best-corrected visual acuity (BCVA) at baseline and throughout follow-up, tumor dimensions, and OCT central thickness (where available) at baseline and throughout follow-up were recorded. Results There were 60 treatment-naive consecutive cases with CCH between January 2000 and June 2014; 42 (70%) received treatment. These were LS-EBRT (23/60 [38%]; mean follow-up, 45.5 months), PDT (16/60 [27%]; mean follow-up, 38 months), and plaque radiotherapy (3/60 [5%]; mean follow-up, 92 months). Macular location, mottled or orange pigment, and absence of drusen were significantly more frequent in the treatment group. In the LS-EBRT group, median thickness reduction on ultrasound B scan was 1.6 mm (mean ± standard deviation, 1.65±1.6; range, −6.5 to +0.7). The mean ± standard deviation BCVA gain was 0.22±0.34, with >3 Snellen lines in 48% of cases. Kaplan-Meier estimates were 80% for any gain and 40% for >3 Snellen lines gain at 5 years. In the PDT group, the median decrease in thickness was 0.95 mm (mean ± standard deviation, 1.0±0.8; range, −2.5 to +0.2). The mean ± standard deviation BCVA gain was at 0.3±0.51, with >3 Snellen lines in 30% of cases. Kaplan-Meier estimates were 93% for any gain and 68% for >3 Snellen lines at 5 years. Double versus single duration PDT had more favorable outcomes with a greater reduction in tumor thickness (P = 0.04), central retinal thickness (P = 0.02), and improvement in visual acuity (median, 0.33 vs −0.05). There was no difference in decrease in tumor thickness or BCVA gain between the LS-EBRT and PDT groups. With plaque brachytherapy, the mean decrease in thickness was 2.5 mm, but BCVA loss of >2 Snellen lines was noted in all 3 cases at the end of follow-up. Radiation complications developed in 10 of 23 cases (43.5%) from the LS-EBRT group and 2 of 3 cases (67%) from the plaque brachytherapy group. Conclusions LS-EBRT is equivalent to PDT in CCH management for post-treatment BCVA and tumor thickness reduction. The risk of LS-EBRT and plaque brachytherapy was late radiation-related complications. Double duration PDT was more favorable than single duration.

Purpose To report on cases of late extraocular relapse of previously resected iris melanoma, without concurrent intraocular recurrence. Design Retrospective case series. Methods A retrospective chart review of 4 patients diagnosed with late subconjunctival relapse of previously resected iris melanoma. Results Three female patients and 1 male patient underwent iris tumor resection and presented to our service with suspicious conjunctival lesions at a median of 22 years later (mean: 21 years). None showed intraocular relapse. Treatment of the conjunctival tumors included excisional biopsy (n = 4), followed by cryotherapy (n = 3) and/or brachytherapy (n = 3). In all cases, histopathology confirmed malignant melanoma, with no intraepithelial component or associated melanosis. Genetic sequencing (n = 3) showed wild-type BRAF and NRAS in all. GNA11 mutation was found in 1 case. On array-based comparative genomic hybridization (n = 3), gain of 6p was found in 2 cases and gain of 8 in 2. Overall, findings were strongly suggestive of a diagnosis of late extraocular relapse from previously resected iris melanoma. In a median of 2.5 years (mean: 7.7 years) from the subconjunctival relapse, no further episodes of intraocular/extraocular recurrence were recorded, and all patients were free from distant metastasis. Conclusions Patients undergoing iris melanoma resection are at risk of developing late solitary extraocular relapse even more than 30 years after surgery. In the absence of an intraocular component, diagnosis may be challenging, as tumors mimic a primary conjunctival lesion. Management by excisional biopsy followed by adjuvant therapy was successful, and histopathology and genetic analysis supported a diagnosis of extraocular uveal tumor spread rather than a primary conjunctival tumor.

PURPOSE: Extramedullary hematopoiesis (EMH) usually occurs in patients with loss of bone marrow hematopoietic function, and in a vast majority of cases, it involves the liver, the spleen, or the lymph nodes. We report EMH in the iris of patients enucleated for choroidal melanoma (CM). METHODS: We report a series of three patients with CM, two treated with primary enucleation and one with secondary enucleation. RESULTS: Histopathology revealed EMH in the iris of all patients. CONCLUSION: EMH of the iris can be associated with CM in the absence of any hematological or systemic disorders. To the best of our knowledge, our work is the first report of this abnormal histopathological finding.

Primary intraocular lymphoma (PIOL) is an ocular malignancy that is a subset of primary central system lymphoma (PCNSL). Approximately one-third of PIOL patients will have concurrent PCNSL at presentation, and 42–92% will develop PCNSL within a mean of 8–29 months. Although rare, the incidence has been rising in both immunocompromised and immunocompetent populations. The majority of PIOL is diffuse large B-cell lymphoma, though rare T-cell variants are described. Recently, PIOL has been classified by main site of involvement in the eye, with vitreoretinal lymphoma as the most common type of ocular lymphoma related to PCNSL. Diagnosis remains challenging for ophthalmologists and pathologists. PIOL can masquerade as noninfectious or infectious uveitis, white dot syndromes, or occasionally as other neoplasms such as metastatic cancers. Laboratory diagnosis by cytology has been much aided by the use of immunocytochemistry, flow cytometry, biochemical finding of interleukin changes (IL10:IL6 ratio > 1), and cellular microdissection with polymerase chain reaction amplification for clonality. Use of several tests improves the diagnostic yield. Approaches to treatment have centered on systemic methotrexate-based chemotherapy, often with cytarabine (Ara-C) and radiotherapy. Use of intravitreal chemotherapy with methotrexate (0.4 mg/0.1 mL) is promising in controlling ocular disease, and intravitreal rituximab (anti-CD20 monoclonal antibody) has also been tried. Despite these advances, prognosis remains poor.

Background To report our experience with sentinel lymph node biopsy for staging patients with conjunctival melanoma. Methods A prospective review of patients with conjunctival melanoma who underwent sentinel lymph node biopsy at St Bartholomew9s Hospital from May 2008 to May 2012. The selection criterion for sentinel node biopsy depended on the tumour thickness (≥2 mm) and location of the conjunctival melanoma. The main outcome measures were the incidence of sentinel lymph node positivity and the procedure-related complications. Results In 4 years, 26 out of 70 patients met the selection criteria for sentinel lymph node biopsy. 4 patients declined and 22 patients consented for the procedure. Technetium-99m failed to identify a sentinel lymph node in four of the 22 patients (18%). Of the remaining 18 patients, two were found to have subclinical micrometastasis in regional lymph nodes. Median follow-up was 20 months (range 6–36 months). No false-negative events were observed. Complications of the procedure included transient blue staining of the epibulbar surface in five patients and transient facial nerve palsy in one patient. Conclusions Sentinel lymph node biopsy is a safe procedure with minimal complications. It should be considered for the staging of conjunctival melanomas, especially melanomas in non-limbal location or conjunctival melanomas ≥2 mm thick.

PURPOSE: To describe the results of photodynamic therapy (PDT) for juxtapapillary and peripheral retinal capillary hemangioma (RCH). PATIENTS AND METHODS: Interventional case series of four eyes (four patients) with juxtapapillary RCH and one eye (one patient) with peripheral RCH. Two eyes with juxtapapillary RCH had received two sessions of full-fluence, double-duration PDT; whereas other two eyes had received single session of half-fluence, single-duration PDT. The peripheral RCH was treated with a single session of full-fluence, single-duration PDT. RESULTS: Two patients had von Hippel-Lindau disease. Follow-up duration ranged from 4 months to 1 year. Pre-PDT visual acuity (VA) ranged from 20/200 to HM (juxtapapillary RCH) and 20/100 (peripheral RCH). Among the eyes with juxtapapillary RCH, tumor regression with partial resolution of macular edema was noted in two eyes (one eye each with half-fluence and full-fluence PDT), whereas two eyes had no change in tumor size with persistent macular edema. VA remained stable in three eyes and declined in one eye. In an eye with peripheral RCH, regression of tumor and macular edema with VA improvement was noted. Post-PDT complications included epiretinal membrane (one eye) and transient exudative retinal detachment (one eye). CONCLUSION: PDT can be effective in reducing macular edema associated with RCH but this does not always correspond with an improvement in VA especially for juxtapapillary tumors.

Purpose To report two cases of mesectodermal leiomyoma of the ciliary body presenting as anterior staphyloma. Methods Two case reports with cytopathologic correlation. Results First patient (15-year-old boy) presented with a nodular lesion in the sclera. Second patient (31-year-old woman) was found to have a brown ciliary body mass. Growth of the lesion and extrascleral extension was noticed after several years of follow-up. Ultrasonography, light microscopy, and immunohistochemistry of both cases are described confirming mesectodermal leiomyoma of the ciliary body. Conclusion Mesectodermal leiomyoma, despite its rarity, should be considered in the differential diagnosis of uveal tract tumors. Clinically, the diagnosis is difficult and histopathological and immunohistochemical assesment is necessary to avoid inappropriate diagnosis and erroneous treatment.

To report a case of a choroidal melanoma and a discrete choroidal nevus that has transformed into a malignant melanoma 5 years after initial diagnosis.Retrospective case report.A diffuse macular choroidal melanoma and a discrete choroidal nevus located superonasal to the optic disk were diagnosed in the right eye of a 63-year-old woman in 2009. The patient was treated by ruthenium plaque radiotherapy for the choroidal melanoma, which consequently flattened and scarred. On a routine eye check in 2014, the nevus was found to have been transformed into a choroidal melanoma. It was treated with ruthenium plaque radiotherapy.Although extremely rare, patients with a uveal melanoma can develop an additional discrete uveal melanoma. This case highlights the importance of monitoring benign choroidal nevi in patients with a history of choroidal melanoma.

Purpose To report the results of ruthenium-106 plaque radiotherapy for iris malignant melanoma. Methods A retrospective study of 15 patients with pure iris melanoma treated with ruthenium-106 plaque radiotherapy from June 1998 to June 2006. The main outcome measures were tumour control and ocular complications. Results Of the 15 patients, 8 had biopsy-proven melanoma (6 incisional and 2 excisional biopsies). In the remaining seven patients enlargement of the lesion was documented. The median follow-up was 96 months (ranging from 14 months to 12 years). Common radiation-related complications included cataract in 9 (60%) patients, dry eyes in 3 (20%) patients and elevated intraocular pressure in 4 (27%) patients. Vision was preserved in 80% of patients. Local tumour control was obtained in all patients. Conclusions Ruthenium-106 plaque radiotherapy is an effective treatment for primary malignant iris melanoma, resulting in excellent local control with preservation of vision. Main complications included cataract, dry eyes, and glaucoma.

Importance Patients with myotonic dystrophy (MD) have an increased risk of malignancy including uveal melanoma. This case series further explores the association between these 2 diseases. Objective To describe a cohort of patients with uveal melanoma associated with MD, including a case of iris melanoma, and MD-associated uveal melanoma in relatives. Design, Setting, and Participants Retrospective case series at 3 tertiary referral centers (Wills Eye Hospital, Philadelphia, Pennsylvania; Mayo Clinic, Rochester, Minnesota; and Moorfields Eye Hospital, London, England), between January 1, 2000, and August 31, 2017. The study included 6 patients with MD and uveal melanoma. Main Outcomes and Measures Melanoma response to treatment and development of metastatic disease. Results There were 6 patients, 4 men and 2 women, with MD and uveal melanoma. The mean patient age at melanoma diagnosis was 47 years (median, 43 years; range, 30-67 years), and the tumor involved the choroid in 5 patients (83%) and iris in 1 patient (17%). The diagnosis of MD was known since young adulthood in 2 patients (33%) and was discovered in adulthood in 4 patients (67%). The main clinical features of MD included muscle weakness (n = 5; 83%), myotonia (n = 4; 67%), polychromatic cataract (n = 4; 67%), complications with general anesthesia (n = 4; 67%), myalgia (n = 3; 50%), cardiac arrhythmia (n = 2; 33%), and frontal baldness (n = 2; 33%). Genetic testing revealed MD type 1 (4 of 4 tested patients), and 2 patients demonstrated positive family history of MD with classic clinical features and preferred no testing. Melanoma treatment included plaque radiotherapy (n = 4; 67%), photodynamic therapy (n = 1; 17%), and declined treatment (n = 1; 17%). At follow-up of 6, 6, 41, 42, and 87 months (5 patients), findings included melanoma regression (4 of 5 tumors), melanoma recurrence (1 of 5 tumors), and no metastatic disease (5 of 5 patients). Conclusions and Relevance Six adult patients with MD demonstrated uveal melanoma involving the choroid or iris, emphasizing the association between these 2 diseases. Further research seems warranted to explore the pathogenesis of uveal melanoma in MD. These findings support the consideration of ophthalmic examination for uveal melanoma in patients with MD.

Aims: To report the ocular survival and event-free survival following primary multiagent chemotherapy for group D, heritable bilateral retinoblastoma (RB). Methods: The RB database was used to identify children with heritable, bilateral RB treated with primary chemotherapy (six cycles of vincristine, etoposide and carboplatin). Only Group D eyes with more than 12 months’ follow-up were analysed. The timing, number and type of salvage treatments were recorded. Kaplan–Meier estimates for the ocular survival and event-free survival (percentage of eyes that avoided external beam radiotherapy and/or enucleation) were performed as a function of time. Results: Of 18 group D eyes, two (11%) were treated successfully with chemotherapy alone, nine (50%) underwent successful salvage treatment, and seven (39%) were enucleated. The median time from completing chemotherapy to enucleation was 9 months (range 4 to 25 months). Ocular survival was 67% at 2 years. External beam radiotherapy proved successful salvage treatment in five of nine eyes, so the event-free survival was 34% at 2 years. Conclusion: Multiagent chemotherapy alone is rarely sufficient for the preservation of group D eyes. External beam radiotherapy and plaque radiotherapy remain important salvage treatments for advanced, heritable retinoblastoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with an annual incidence of 4 to 10 per million in the white population. The 5-year overall survival (OS) rate is approximately 70% to 80%. Up to 50% of patients with UM develop metastases, usually after a long disease-free interval (2-5 years). If metastatic disease is present, the prognosis is dismal with a 1-year OS rate of 10% to 40%. Currently, no effective systemic treatment improving OS is available for patients with metastatic UM, nor has any adjuvant treatment shown survival benefit. Our research group and others have performed several prospective dendritic cell (DC) vaccination studies in patients with cutaneous melanoma showing little toxicity and promising immunologic and clinical results. [...]

Purpose To describe the indications for secondary enucleations in uveal melanoma and analyze associations and outcomes. Design Retrospective interventional case series. Methods Data of patients who underwent secondary enucleation for uveal melanoma in the London Ocular Oncology Service, between 2008 and 2014, were retrieved from medical records analyzed. Cox regression model was performed to analyze associations with secondary enucleation and metastases and Kaplan-Meier estimates to assess the probability of metastatic spread and death. Results During the study period 515 enucleations were performed for uveal melanoma, 99 (19%) of which were secondary enucleations. Tumors were located at the ciliary body in 21 eyes (21%), juxtapapillary in 31 (31%), and choroid elsewhere in 47 (48%). Primary treatment included Ru 106 plaque radiotherapy, proton beam radiotherapy, and transpupillary thermotherapy in 85, 11, and 3 eyes, respectively. Indications for secondary enucleation were tumor recurrence in 60 (61%), neovascular glaucoma in 21 (21%), and tumor nonresponse in 18 eyes (18%). Twenty patients (20%) were diagnosed with metastasis and 12 out of 20 died of metastatic spread. On multivariate analysis, juxtapapillary tumor location was found to associate with tumor nonresponse ( P = .004) and nonresponding patients with metastatic spread ( P = .04). Conclusions Indications for secondary enucleations for uveal melanoma were tumor recurrence, neovascular glaucoma, and tumor nonresponse. This review identified a possible high-risk group (nonresponse), which proved radioresistant to treatment. These tumors were more frequently found in the juxtapapillary location and were associated with metastatic spread.

Uveal melanoma (UM), involving the iris, choroid and ciliary body, is the commonest intraocular tumor in adults. Half of patients develop metastasis with a high mortality despite currently available systemic therapies including immune checkpoint blockade. Studies show that while CTLA4 antagonism has a modest effect in UM, PD1/PDL1 blockade is largely ineffective whereas trials of combination checkpoint blockade are yet to report. We confirmed previously that deficiency of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine synthesis, sensitizes UM cells to arginine deprivation using pegylated arginine deiminase or ADI-PEG20. Early trials of ADI-PEG20 in UM have shown safety and efficacy in the clinic and thus we tested the potential for a combined immunometabolic strategy. ASS1-deficient UM cell lines (OMM1, OMM2.5, MEL270) were analyzed for the immune checkpoint protein PDL1 along with their sensitivity to arginine depletion. We also tested metastatic UM for ASS1 and PDL1 expression, and the impact of ADI-PEG20 treatment using samples from a current clinical trial (NCT02029690). We showed that ASS1 and PDL1 protein expression were absent in the 3 UM cell lines and in a majority of primary tumors (75/102 for ASS1 and 83/102 for PDL1; 5% threshold of expression) and all metastatic tumor biopises (n=16/16 for both). Transfection of ASS1 in OMM1, OMM2.5, MEL270 led to an increase in PDL1 expression by qPCR, western blotting and FACS, which was reversible following knockdown of ASS1. Induction of PDL1 expression by ASS1 was accompanied by interferon (IFN)-alpha and beta (but not IFN-gamma) release into the cell supernatant, and was abrogated using the pan-STAT inhibitor ruxolitinib. Next, PDL1 expression was significantly increased in the 3 ASS1-negative UM cell lines with ADI-PEG20 treatment by 24hrs and was associated with Type I IFN signaling which waned along with PDL1 expression by 48hrs. The ADI-PEG 20 induction of PDL1 was abolished using ruxolitinib, indicating that the upregulation of Type I IFNs is critical for regulation of the PDL1 checkpoint protein. While analysis of UM biopsies of patients progressing on ADI-PEG20 revealed upregulation of ASS1 (n=2/2; and thus resistance to ADI-PEG20) a concomitant increase in PDL1 was not observed (n=0/2). Collectively, our data show that ASS1 is absent in a majority of patient biopsies of primary and metastatic UM tumors and is tightly correlated with PDL1 expression. UM cells lines displayed sensitivity to ADI-PEG20, which upregulated levels of PDL1 expression via Type 1 interferon signaling that may enhance the currently limited efficacy of checkpoint blockade in UM. Further studies are ongoing of the IFN-mediated signaling between ASS1 and PDL1 in UM in response to arginine deprivation with ADI-PEG20. Citation Format: Ramsay S. Khadeir, Melissa M. Phillips, Mandeep Sagoo, Victoria Cohen, Caroline Thuang, Peter W. Szlosarek. The impact of ADI-PEG20 on PDL1 expression in ASS1 deficient uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2017-5569