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Introduction: It can be challenging to distinguish between choroidal naevi and melanomas in the community setting, particularly without access to ultrasonography, required to measure the thickness of melanocytic choroidal tumours. We aimed to determine whether thickness measurement is required for MOLES scoring of melanocytic choroidal tumours. Methods: The dataset of a recent MOLES evaluation was reviewed. Patients were selected for the present study if their MOLES tumour size category was determined by tumour thickness measured with ultrasonography (US). The largest basal tumour diameter and tumour thickness were then measured from ultra-widefield fundus images and optical coherence tomography (OCT) images, respectively. Results: The tumour size category was determined by tumour diameter in 203/222 (91.4%) with no influence of tumour thickness. The tumour thickness influenced the MOLES score in 19/222 (8.6%) patients. In 11/19 patients with OCT measurements of tumour thickness, the US measurement exceeded the OCT by more than 25% in 5 patients, more than 50% in 2 patients and more than 75% in 1 patient. As a result, the revised tumour thickness based on OCT determined the size category in 4/216 (1.8%) patients. The Optos measurements increased the diameter score by 1 in 5 patients. As a result, the revised tumour thickness determined the size category in 4/216 (1.8%) patients. If both the revised diameter and thickness scores were considered, the MOLES score reduced in 4 patients. If both the diameter and thickness scores were considered, the MOLES score reduced in 5 and increased in 1. Only 0.94% (2/211) of melanocytic choroidal tumours assessed with MOLES when using Optos ultra-widefield fundus images diameter and OCT to measure tumour diameter and thickness, respectively, required a change in management from a reduction in MOLES score from 1 to 0. Discussion/Conclusion: This study suggests that the MOLES category for size is influenced more by the tumour diameter, if it can be measured accurately, than by the thickness. This study suggests ignoring tumour thickness if this cannot be measured accurately with OCT, unless the tumour has a mushroom shape.

OBJECTIVES To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p

Purpose Prognostication in cancer is growing in importance as increasingly accurate tools are developed. Prognostic accuracy intensifies ethical concerns that a poor prognosis could be psychologically harmful to survivors. Uveal melanoma (UM) prognostication allows survivors to be reliably told that life expectancy is either normal (good prognosis) or severely curtailed because of metastatic disease (poor prognosis). Treatment cannot change life expectancy. To identify whether prognosis is associated with psychological harm, we compared harm in UM survivors with good and poor prognoses and those who declined testing and compared these outcomes to general population norms. Methods Non-randomized 5-year study of a consecutive series of 708 UM survivors (51.6% male, mean age 69.03, SD=12.12) with observations at 6, 12, 24, 36, 48 and 60 months. We operationalized psychological harm as anxiety and depression symptoms, worry about cancer recurrence (WREC) and poor quality of life (QoL). Results Compared to other groups, survivors with poor prognoses showed initially elevated anxiety and depression and consistently elevated worry about local or distant recurrence over 5 years. Good prognoses were not associated with outcomes. Generally, no prognostic groups reported anxiety, depression and WREC or QoL scores that exceeded general population norms. Conclusions Using a large sample, we found that harm accruing from a poor prognosis was statistically significant over 5 years, but did not exceed general non-cancer population norms. Implications for Cancer Survivors Survivors desire prognostic information. At a population level, we do not believe that our findings show sufficiently strong links between prognostication outcome and psychological harm to deny patients the option of knowing their prognosis. Nonetheless, it is important that patients are informed of potential adverse psychological consequences of a poor prognosis.

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.

Clinical relevance: The malignant potential of choroidal melanocytic tumours detected incidentally in the community is thought to be low, but this has not been assessed using a validated screening tool. An accurate characterisation of the malignant potential of these lesions has implications for resource allocation, service provision, education, and training.Background: MOLES (Mushroom shape, Orange Pigment, Large size, Enlargement, and Subretinal fluid) categorises tumours as 'common naevus', 'low-risk naevus', 'high-risk naevus', and 'probable melanoma'. The MOLES system recommends that patients with common naevi (score = 0) undergo review by a community optometrist every two years, ideally with sequential colour photography. For the remaining patients (score ≥ 1), specialist imaging and assessment are recommended, with referral triaged as non-urgent for patients with low-risk (score = 1) or high-risk naevi (score = 2) and urgent for patients with probable melanoma (score > 2).Methods: Lesions flagged as choroidal melanocytic tumours on retinal photographs taken during the Australian National Eye Health Survey were retrospectively analysed by an ocular oncologist. Each lesion was assigned a MOLES score and categorised as common, low-risk, high-risk or probable melanoma.Results: Seventy-seven choroidal naevi were identified. Seventy-five (97%) of the choroidal naevi were categorised as common naevi, with a MOLES score of 0. Two (3%) choroidal naevi had a score of 1 and diagnosed as low-risk naevi due to their size. No naevi had a score of 2 or more.Conclusion: All choroidal naevi detected in this nationally representative population survey were innocuous. This suggests that the vast majority of choroidal melanocytic tumours that are incidentally detected in Australia can be managed in primary eye care settings without the need for specialist referral. MOLES provides a simple evidence-based method for choroidal naevi assessment in primary care.

Background: The aim of this study was to report 2 cases of pulmonary air embolism developing several hours after choroidal melanoma endoresection without the use of air infusion during the surgery, with fatality in 1 patient. Methods: The method of this study was case report. Participants: Two patients with large choroidal melanomas who collapsed several hours after endoresection without air infusion as a result of pulmonary air embolism. Results: A 72-year-old man collapsed 4 h and 30 min after endoresection without air infusion. Computerized tomography angiography confirmed air embolism. The patient died after 86 min of cardiopulmonary resuscitation. A 41-year-old woman collapsed 5 h and 30 min after endoresection, performed without air infusion and with close monitoring, which included right internal jugular vein catheterization intraoperatively. Transthoracic and transesophageal echography, performed preoperatively, intraoperatively, and postoperatively, revealed air embolism only after collapse occurred. Imaging showed the embolism to be biventricular because of patent foramen ovale. The patient was treated promptly with extracorporeal membrane oxygenation and mechanical ventilation, which resulted in a full recovery. Conclusions: Air embolism can develop after endoresection for choroidal melanoma, despite avoiding air infusion. Further studies are needed to understand how this occurs. Special measures are indicated to detect this complication and to treat it promptly and effectively.

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.

Objective: To define the characteristics of solitary idiopathic choroiditis (SIC) in a consecutive series of patients and propose a nomenclature change to idiopathic scleroma. Materials and Methods: Electronic patient records were retrospectively interrogated to identify all patients diagnosed with SIC between 2002 and 2019 in a tertiary referral ophthalmic hospital in the United Kingdom. Results: Thirty-four eyes of 34 patients were found to have SIC. The mean age at diagnosis was 48 years (range 24–78) and 23 patients (68%) were female. All lesions were located posterior to the equator, most frequently in the inferotemporal quadrant (13 eyes, 38%). The lesions had a mean largest basal diameter of 1.2 ± 0.4 disc diameters (range 0.5–2) and their distance to the optic disc had a mean of 1.2 ± 0.9 disc diameters (range 0–3.3). All lesions were intrascleral on enhanced depth imaging optical coherence tomography, demonstrating a hypo-reflective zone within the sclera, with an underlying hyper-reflective zone in some cases. No lesion enlarged or developed features consistent with active inflammation after a median follow-up time of 0.9 years (range 0–16.8). Discussion/Conclusion: Optical coherence tomography shows SIC to be an intrascleral lesion. Furthermore, we found no evidence of any inflammatory component. A nomenclature change to idiopathic scleroma is appropriate to prevent unnecessary investigation.

Purpose: To report the outcome of a previously vitrectomized eye having less lymphoma disease burden compared with the contralateral nonvitrectomized eye over the course of 3.5 years while on systemic chemotherapy. Methods: Case report. Results: A 51-year-old man with vitreoretinal lymphoma with central nervous system involvement underwent vitrectomy in his left eye. Over the following 3.5 years on systemic chemotherapy, the left eye had less lymphoma disease burden compared with the contralateral nonvitrectomized right eye. Conclusion: Therapeutic vitrectomy may be a useful adjunct to systemic chemotherapy in vitreoretinal lymphoma, particularly in cases of vitreous predominant disease manifestation.

OBJECTIVE The fear of cancer recurrence (FCR) in later survivorship can lead to poorer mental health, quality of life and physical and functional recovery. Later-occurring FCR may be a consequence of late-emerging physical symptoms and functional problems from cancer or its treatment. Based on the self-regulation model, we predicted that persistent or escalating symptoms and functional problems would prospectively predict FCR observed 2-5 years after diagnosis and treatment. METHODS This is a five-year study of 708 uveal melanoma (UM) patients, measuring self-reported visual and ocular symptoms, functional problems and FCR at 6, 12, 24, 36, 48 and 60 months post-diagnosis. A mixed measures design over four levels with observations staggered to represent prospective prediction. Criterion variables were FCR at 24, 36, 48 and 60 months. Predictors were symptom and function scores measured at the previous two observations to FCR. Controls were FCR measured at the previous observation to the criterion FCR measure and demographic, clinical and treatment variables. RESULTS Linear mixed modelling showed that FCR was uniquely predicted by enduring symptoms, those that emerged two observations previously, but not symptoms arising at the previous observation. FCR was predicted by functional problems, which emerged in the observation prior to FCR, but not the observation previous to that. CONCLUSIONS Persistent or emerging post-treatment symptoms and functional limitations are probable risk factors for late-occurring FCR in UM survivors. IMPLICATIONS FOR CANCER SURVIVORS Monitoring symptoms and functional limitations assists in identifying at-risk survivors and targeting preventive interventions. Self-regulation theory suggests that helping survivors to more realistically appraise symptoms and functional problems may prevent FCR.

Purpose: Vivid Vision Perimetry (VVP; Vivid Vision, Inc) is a novel method for performing in-office and home-based visual field assessment using a virtual reality platform and oculokinetic perimetry. Here we examine the reproducibility of VVP Swift and compare results with conventional standard automated perimetry (SAP) and spectral-domain (SD) OCT. Design: Cross-sectional study. Participants: Fourteen eyes of 7 patients with open-angle glaucoma (OAG) (average age, 64.6 years; 29% women) and 10 eyes of 5 patients with suspected glaucoma (average age, 61.8 years; 40% women) were enrolled. Methods: Patients with OAG and suspected glaucoma were enrolled prospectively and underwent 2 VVP Swift examinations. Results were compared with 1 conventional SAP examination (Humphrey Visual Field [HVF]; Zeiss) and 1 SD OCT examination. Main Outcome Measures: Mean sensitivity (in decibels) obtained for each eye in 2 VVP Swift test sessions and a conventional SAP examination, thickness of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) for the SD OCT examination, and mean test durations of the VVP Swift and SAP examinations. Results: The mean test duration of VVP Swift in both eyes (8.5 minutes ) was significantly shorter (P < 0.001) than SAP (12.2 minutes). The average absolute difference of the mean sensitivity between the 2 VVP Swift sessions was found to be 0.73 dB (95% confidence interval [CI], 0.40–1.06). A statistically significant association was found between average mean sensitivity measurements from the VVP and mean deviation (MD) measurements obtained by the HVF with a Pearson correlation coefficient of 0.86 (95% CI, 0.70–0.94; P < 0.001). Mean visual sensitivity measurements from the VVP Swift test were significantly associated with average RNFL thickness (r = 0.66; P = 0.014) and GCC thickness (r = 0.63; P = 0.02), whereas the correlation coefficients between HVF MD and RNFL and GCC were 0.86 (P < 0.001) and 0.83 (P < 0.001), respectively. Conclusions: Our results demonstrated that the VVP Swift test can generate reproducible results and is comparable with conventional SAP. This suggests that the device can be used by clinicians to assess visual function in glaucoma.

OBJECTIVES: To report associations with visual function and quality of life (QOL) in artificial eye wearers. METHODS: Multicentre, observational, cross-sectional, nationwide study, within the National Health Service England. Items were adopted from the National Eye Institute Visual Function Questionnaire, and incorporated in the National Artificial Eye Questionnaire (NAEQ). The NAEQ was completed by 951 respondents. Multiple regressions assessed associations between the QOL scores and the experiences of artificial eye wearers, their routine management, changes over time, baseline and demographic parameters. RESULTS: Parameters predictive of a better QOL composite score included longer artificial eye wear (β = 0.18, p 10 years mean 79.45 ± 0.70; p = 0.001). Both better prosthesis appearance (β = 0.14, p = 0.022) and improved motility (β = 0.13, p = 0.042) predicted a better dependency score. Use of lubricating ointment predicted a worse dependency score (β = 0.23, p = 0.003). Neither the frequency of removal, nor the cleaning frequency of the artificial eye correlated with QOL scales. CONCLUSIONS: Multiple factors in the artificial eye experience were found to predict visual function and QOL aspects. This study underscores the need to generate a dedicated QOL questionnaire for use in anophthalmic patients.

Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (&gt, 2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than ‘watch-and-wait strategies’.

Purpose To study Damato Multifixation Campimetry Online (DMCO), an inexpensive online visual field test, used for screening at optician shops in Denmark. Methods This was an evaluation of a diagnostic test and customers were included if minimum 50 years old, with a visual acuity of minimum 0.5 and with less myopia than 6 D. Standard equipment was a computer, a wireless mouse and a computer monitor. We used the ‘DMCO STANDARD 4,5’ algorithm for screening. DMCO results were electronically transmitted to the authors. Customers with a positive DMCO test received an eye examination including the reference standard Humphrey Visual Field Analyzer 30–2 SITA Fast test. A subset of control participants with a negative DMCO test received the same examination in order to estimate the number of false and true negatives. DMCO specificity and sensitivity were estimated according to five reference standards with 95% confidence intervals. Results The population comprised 627 individuals, 381 women and 246 men, from 13 optician shops. Mean age was 62 years (SD 7.4). DMCO was positive in 32 individuals and 27 individuals were classified as ‘true positives’ with diagnoses such as glaucoma, cataract and neurological visual field defects. Of the 595 individuals with a negative DMCO test, 110 were examined and nine individuals were classified as ‘false negatives’ according to diagnoses. Depending on reference the specificity was 97–99% and sensitivity was 14–69%. Conclusion Screening with DMCO demonstrated high specificity, whereas sensitivity was unsatisfactory. Future studies with enough power to estimate the true sensitivity is needed.

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.

We thank Capasso et al [...]

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

Objective Cancer survivors commonly experience long-term anxiety and depression. Anxiety and depression might result from problems emerging during survivorship rather than illness and treatment. This study tested three potential causal paths: (a) concerns about physical symptoms and functional problems and fear of cancer recurrence (FCR) arising during survivorship directly cause anxiety and depression, (b) an indirect path whereby FCR mediates effects of concerns about physical symptoms and functional problems on anxiety and depression, and (c) a reciprocal path whereby anxiety and depression cause concerns about physical symptoms and functional problems and FCR, which exacerbate later anxiety and depression. Methods Sample of 453 uveal melanoma survivors who completed observations 6-, 12-, 24-, 36-, 48- and 60-months post-diagnosis and did not miss two consecutive observations. Cross-lagged analyses were conducted to predict Hospital Anxiety and Depression Scale subscale scores. Symptoms and functional problems were measured using the EORTC OPT 30 scale, and FCR operationalised by the EORTC OPT 30 worry about recurrence scale. Covariates were age, gender, treatment modality, and visual acuity of the fellow eye and chromosome-3 status (which accurately predicts 10-year survival), worry and anxiety or depression. Results All paths received some support, although the indirect path emerged only for anxiety in females. Concerns about physical symptoms, functional problems, and FCR originated in survivorship and appeared to both influence and be influenced by anxiety and depression. Conclusions Findings emphasise the importance of actively monitoring survivors to prevent, detect, and intervene in the development of anxiety and depression during survivorship.

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.

Purpose To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. Design Cohort study. Participants Thirty-two children with retinoblastoma. Methods We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. Main Outcome Measures Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. Results Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. Conclusions Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

At the time of writing this article, the COVID-19 pandemic is severely disrupting the care of patients with choroidal melanoma in Britain and elsewhere. Vast numbers of individuals are developing severe illness with thousands of fatalities.1 Many ophthalmic workers have died (such as Li Wenliang) or are absent from duty because of illness or isolation. Others are redeployed at COVID-19 units. Patients are avoiding medical care, because they are afraid of catching coronavirus. Routine community optometry has largely been suspended. Non-urgent hospital clinic appointments are being deferred, as are surgical procedures, laser sessions and intravitreal injections of antiangiogenic agents. This lull will inevitably be followed by a surge of referrals and a backlog of patients needing assessment and treatment. Patients with choroidal melanoma will present with more advanced disease with lost opportunities for conserving vision and the eye in some cases.2 There will inevitably be deaths from metastatic disease, undoubtedly stirring concerns about whether any fatalities might have been prevented if the COVID-19 epidemic had not delayed treatment.3 The immediate crisis is expected to be followed by long-term national and personal financial difficulties, which will diminish healthcare resources and which will make it unaffordable for many patients to attend hospital clinics, especially if these are located far from their home. COVID-19 may permanently disrupt healthcare if it causes perennial epidemics, like influenza. These constraints demand drastic improvements in clinical practice to avoid unnecessary costs for patients and to conserve healthcare resources while maintaining quality of care after the COVID-19 …

Purpose To develop parsimonious models for estimating metastasis mortality in patients with choroidal melanoma for situations where use of the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) or Tumor, Node, Metastasis (TNM) staging system is not possible. Methods A backward-selection algorithm identified largest basal tumor diameter (LBTD) and chromosome 3 status (C3S) as the most informative predictors of metastatic death. We defined two prognostic models, based on LBTD with or without known C3S, that took into account competing risks of death from other causes by using the Aalen estimator. The bootstrap procedure was used to estimate discrimination accuracy, expressed by the C-index. Results The cohort was comprised of 8348 patients with choroidal melanoma, 4174 of whom had known chromosome 3 status; of the 1553 deaths that occurred among these patients, 956 were attributed to metastasis. For LBTD with or without known C3S, the metastatic-death-specific C-indices at 2, 5, and 10 years were 0.85, 0.85, and 0.84 and 0.79, 0.77, and 0.74, respectively, as compared with 0.81, 0.79, and 0.76 for Kaplan-Meier prognostication using the 8th edition of the TNM staging system. Conclusions We have developed parsimonious models for predicting the absolute risks of metastatic death from choroidal melanoma that take into account competing causes of death and which compare favorably with the current version of the TNM staging system. There is a need for further studies to validate the use of these models in situations where use of the TNM or LUMPO is not possible.

Purpose To investigate whether early detection and treatment of uveal melanoma by screening was associated with a lower mortality rate. Methods Retrospective assessment of prospectively collected data comparing 132 patients with uveal melanoma referred by the National Diabetic Screening Service with 608 control patients referred through other means. Results Mean tumor diameter was smaller in the diabetic screening group (11.1 mm vs. 12.5 mm) as was tumor thickness (3.4 mm vs. 5.4 mm). The prevalence of high-risk monosomy 3 was also lower (17/40, 43% vs. 62/110, 56%). Despite a higher rate of systemic comorbidities in the patients diagnosed through screening and despite older age at diagnosis, the 5-year all-cause mortality was similar in both groups (17% vs. 20%); however, the metastatic mortality was lower in the diabetic screening group (11/132, 8% vs. 95/608, 16%). Conclusion Despite higher rates of comorbidities, the patients detected at diabetic screening had a lower 5-year mortality rate. The diabetic screening programme enabled detection and treatment of posterior uveal melanomas at an earlier stage. However, the confounding factors of lead and length time bias are not to be ignored.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3&rsquo, s performance using discrimination and calibration methods. LUMPO3&rsquo, s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

We report a 61-year-old female who presented to our service with recent growth of a thickened, pigmented, sub-conjunctival lesion within an area of ocular melanocytosis in her left eye. Lamellar sclerectomy was performed. Histopathological assessment revealed a localized melanocytic proliferation with features of blue nevus arising within the area of ocular melanocytosis. There was a small zone of cells showing cytological atypia and expansion of the scleral stroma. We believe this case to be the first report of intrascleral blue nevus arising within an area of ocular melanocytosis. Given the cytological atypia, the blue nevus may perhaps represent an intermediate stage within a progression from ocular melanocytosis towards melanoma. Patients with oculodermal melanocytosis merit regular long-term surveillance for early detection of melanoma, not only in the uvea, but also in the orbit and potentially the ocular surface.

Purpose: To test the hypothesis that patients treated with radiotherapy for choroidal melanoma enjoy better quality of life (QoL) than patients who have undergone enucleation. Methods: In this nonrandomized study, patients with choroidal melanoma treated at the Royal Liverpool University Hospital, Liverpool, UK, were invited to complete QoL questionnaires approximately 6 months postoperatively and then on each anniversary of their primary treatment. These instruments consisted of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-OPT30 questionnaire, Hospital Anxiety & Depression Scale, and the Functional Assessment of Cancer Treatment questionnaire. Patient-reported outcomes were correlated with demographics, ocular treatment, social factors, presenting tumor and ocular status, self-reported general health, marital status, and employment status. Results: The 1596 patients were treated with radiotherapy (72.3%) or enucleation (27.7%). Enucleation was associated with male sex (χ2, P = .004), older age (t test, P < .001), larger tumor diameter (t test, P < .001), monosomy 3 (χ2, P < .001), depression (linear regression, 95% confidence interval [CI], .17 to 1.01), and reduced physical and functional well-being (linear regression, 95% CI, −1.14 to −0.12 and −1.96 to −0.47), respectively. Poor QoL was attributed to the ocular disease by 21% and 20% of enucleated and irradiated patients, respectively (χ2, P = .938). Conclusions: Patient-reported outcomes and QoL were worse in patients who had undergone primary enucleation for choroidal melanoma. These outcomes may partly have been caused by factors predisposing to enucleation rather than enucleation itself, because enucleated patients tended to be older, with more advanced disease at presentation, and a worse prognosis for survival. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

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/Aims: Current retinoblastoma staging systems do not adequately describe the disease, especially in eyes with multiple tumors. The aims of this study were to develop methods for documenting individual tumors and to score disease burden over time. Methods: A coding system was devised to describe each tumor according to affected eye, meridian, anteroposterior location, activity, growth pattern, type of seed, and treatment. A scoring system for quantifying disease burden was developed, taking account of tumor number, size, spread, and secondary effects on the eye. Results: Our coding system allowed contemporaneous tumor documentation, producing datasets that enabled generation of fundus diagrams, Kaplan-Meier curves, and tables summarizing disease progression in individual tumors and eyes. Our data showed disparities between ocular and tumor documentation, e.g., indicating earlier tumor development in the left eye but younger age at presentation if disease was worse in the right eye. Actuarial rates of local treatment failure were lower when individual tumors were analyzed than when data were reported in terms of whole eyes. Conclusion: Our methods for documenting individual retinoblastomas have facilitated the review of patients’ progress in our routine practice and may provide data that could be used to refine retinoblastoma classifications in the future.

Objective We examined the role of posttreatment symptoms and functional problems and of worry about recurrent disease (WREC) in predicting probable anxiety and depression cases 24 months after diagnosis in survivors of posterior uveal melanoma. We examined whether WREC mediates links between symptoms, functional problems, and probable anxiety and depression cases. Methods Prospective cohort study of 261 treated uveal melanoma survivors 6, 12, and 24 months after diagnosis. Hierarchical logistic regression analyses predicting anxiety and depression 24 months after diagnosis identified by Hospital Anxiety and Depression Scale cutoff scores. Symptoms, functional problems, and WREC 6-month posttreatment were entered into the analyses as predictors, then the same variables at 12 months. We controlled anxiety or depression at 6 and 12 months and chromosome 3 status, which accurately predicts 10-year survival. Mediation of links between 6-month symptoms and functional problems and 24-month anxiety and depression by 12-month WREC was tested. Results Anxiety caseness at 24 months was predicted by 6-month ocular irritation, headache, and functional problems and 12-month WREC. Depression caseness at 24 months was predicted by 6-month headache and functional problems. Worry about recurrent disease at 12 months mediated prediction of anxiety caseness by 6-month symptoms and functional problems. Chromosome 3 status predicted neither anxiety nor depression. Conclusions Survivors reporting symptoms, functional problems, and WREC should be monitored for anxiety and depression. Appropriate reassurance that symptoms do not signify future disease might help prevent anxiety.

Background and purpose The purpose of this article is to estimate the distribution of superselective intra-arterial chemotherapy (IAC) delivery to ocular target tissue using quantitative digital subtraction angiography (qDSA). Materials and methods From March 2010 to January 2016, 50 ophthalmic artery contrast DSAs obtained immediately prior to IAC infusions in 22 patients were analyzed. This study was conducted under a retrospective review IRB (no. 10-01862). Parametric color-coded DSAs (iFlow, Siemens Medical) were post-processed (MATLAB, The Mathworks Inc.) using two methods: two box regions of interest (pre-retina and globe) and four custom regions of interest (ROIs—ophthalmic artery, choroid, supraclinoid internal carotid artery (ICA), cavernous ICA). Mean interobserver reliability of custom ROI selection is presented as a 95% confidence interval of interclass correlation, and fractional chemotherapy delivery to selected ROIs as means ± standard deviation in this study. Results The estimated fraction of chemotherapy delivered to the globe with the first method was 79.5%. Percentage regional delivery using the second method was as follows: ophthalmic artery, 85.8%; choroid, 60.5%; supraclinoid ICA, 14.2%. The cavernous ICA ROI (encompassing distal catheter and potential reflux) gave a signal equivalent to 9.3% of total delivery. Conclusion Parametric color-coded qDSA can estimate the fraction of IAC delivered to the retina and other orbital structures in ocular retinoblastoma patients. This information can inform delivery location and dosing strategies on a patient-specific basis.

Background: Ocular melanomas threaten patients with early death, visual handicap, and loss of the eye. The aims of this study were to identify aspects of care that patients with ocular melanoma considered most important and to determine whether patients felt their needs had been adequately addressed. Methods: A cross-sectional study including US ocular melanoma patients and their caregivers. An online survey of US ocular melanoma patients was designed and conducted by the Ocular Melanoma Foundation. Results: The cohort included 180 patients with uveal melanoma and 4 with conjunctival melanoma. Median follow-up was 3 years. A third of patients reported that their uveal melanoma had initially been diagnosed as a nevus. Most uveal melanomas were treated with brachytherapy. Almost 50% of patients had no genetic tumor analysis. Screening methods reported most commonly were computed tomography and liver function tests. Metastatic disease developed in 11% of patients. Few patients (13.3%) reported an offer of psychological support. Most dissatisfaction was with lack of advice on financial aspects of care and lack of psychological counseling, with women tending to express more dissatisfaction with care. Many patients complained about the way ophthalmologists delivered bad news to them. Conclusions: This patients' perspective highlights directions for research, education, and other measures to improve the care of patients with ocular melanoma in the US and elsewhere.

Proton beam therapy (PBRT) is an essential tool in the treatment of certain ocular tumors due to its characteristic fall-off and sharp beam parameters at critical structures. Review of clinical cases in our ocular PBRT program identified patients with silicone oil used as an intraocular tamponade following pars plana vitrectomy for repair of retinal detachment. Patient’s eye may be filled with silicone oil prior to PBRT for an ocular tumor. The objective of this study was to extend our knowledge of the physical characteristics of proton beams in silicone oil by measuring dose within a silicone tank itself, hence better representing the surgical eye, as well as applying the range changes to EYEPLAN software to estimate clinical impact. The relevant proton beam physical parameters in silicone oil were studied using a 67.5 MeV un-modulated proton beam. The beam parameters being defined included: 1) residual range; 2) peak/plateau ratio; 3) full width at half maximum (FWHM) of the Bragg peak; and 4) distal penumbra. Initially, the dose uniformity of the proton beam was confirmed at 10 mm and 28 mm depth, corresponding to plateau and peak region of the Bragg peak using Gefchromic film. Once the beam was established as expected, three sets of measurements of the beam parameters were taken in: a) water (control); b) silicone-1000 oil and water; and c) silicone-1000 oil only. Central-axis depth-ionization measurements were performed in a tank (“main tank”) with a 0.1cc ionization chamber (Model IC-18, Far west) having walls made of Shonka A150 plastic. The tank was 92 mm (length) × 40 mm (height) × 40 mm (depth). The tank had a 0.13 mm thick kapton entrance window through which the proton beam was incident. The ionization chamber was always positioned in the center of the circular field of diameter 30 mm with the phantom surface at isocenter. The ionization chamber measurements were taken at defined depths in increments of 2 mm, from 0 to 35 mm. To define the effect of silicone oil on the physical characteristics of proton beam, the above-defined three sets of measurements were made. In the first run (a), the Bragg-peak measurements were made in the main tank filled with water. In the second run (b), a second smaller tank filled with 10 mm depth silicone oil was placed in front of the water tank and the measurements were repeated in water. In the third run (c), the water in the main tank was replaced with silicone oil and the measurements were repeated in silicone directly (no second tank in runs “a” and “c”). Finally, the effects of change in range on dose distribution based on the EYEPLAN® treatment planning software of patients with lesions in close proximity to the disc/macula as well as ciliary body tumors were studied. The uniformity of the radiation across the treatment volume shows that the radiation field was uniform within ± 3% at 10 mm depth and within ±4% at 28 mm depth. Parameters evaluated for the three runs (a, b, c) included: 1) residual range; 2) peak/plateau ratio; 3) FWHM of the Bragg curve; and 4) distal penumbra. The measured data revealed that the un-modulated Bragg peak had a penetration at the isocenter of: a) 30 mm in water; b) 31.5 mm in silicone and water; and c) 32 mm range in silicone oil. The peak/plateau ratio of the depth dose curve is 3.1:1 in all three set-ups. The FWHM is: a) 9 mm in water; b) 10 mm in silicone and water; and c) 11 mm in silicone oil. The distal penumbra (from 90% to 20%) was: a) 1.1 mm; b) 1.4 mm; and c) 2 mm. Clinical relevance of the extended distal range in silicone was studied for impact in EYEPLAN treatment software, including cases in which tumors were in close proximity to the optic disc/nerve and macula as well as cases in which anterior ciliary body tumors were treated. The potential change of range by 2 mm in silicone would impact the dose-volume histograms (DVH) importantly for the posterior structures. In ciliary body/anterior tumors, an increase in distal range in silicone could result in optic disc/macula dose and length of optic nerve treated, compared with original EYEPLAN model DVHs. The use of silicone oil as a surgical tamponade in the treatment of retinal detachments has important implications for PBRT treatment planning. In patients with intraocular silicone oil, the physical parameters of the beam should be closely examined and DVHs for posterior structures should be analyzed for potential increased doses to the macula, disc, and length of optic nerve in the field. The change in beam parameters due to silicone oil is essential to consider in treatment planning and DVH interpretation for ocular patients with posterior as well as anterior ocular tumors.

Background/Aims: To report the case of a 77-year-old male with a blind, painful eye, referred for suspected corneal mass, with finding of choroidal B-cell lymphoma on pathology of enucleated globe. Methods: This is a retrospective case report of a single patient. Results: A 77-year-old male with a longstanding history of poor vision in the left eye was referred for a scarred, vascularized corneal mass. The patient had reported occasional mild ocular discomfort in the left eye and loss of light perception over the last year. Visual acuity was 20/20 in the right eye and no light perception in the left eye. Intraocular pressure was 32 mm Hg in the left eye. Fundoscopic visualization was not possible due to corneal opacity. B-scan ultrasound showed an infiltrative, low-reflective choroidal lesion and inferior retinal detachment. Pathology from the enucleated globe revealed diffuse sheets of CD20+ small B cells replacing the choroid, characteristic of a low-grade small B-cell extranodal marginal zone lymphoma. Conclusion: This is an unusual presentation of choroidal lymphoma in an eye with severe corneal opacification and scarring, and underscores the diagnostic value of ultrasonography in examination of eyes without view to the posterior segment.

Simple Summary Long-term surveillance following radiotherapy for choroidal melanoma is important for detecting recurrence. There is a perceived notion that regular ultrasonography is required to detect recurrence. The skills required to perform ocular ultrasound are not widely available, which can prevent patients being seen close to home. We aimed to determine whether local treatment failure can reliably be detected with colour fundus photography alone. We found that in 74 out of 75 patients (98.7%), with a clear view of their fundus, recurrence could be detected using colour photography alone. One patient with a clear fundal view developed extraocular extension which was detected on ultrasound without visible change in the intraocular part of the tumour. We conclude that most treated choroidal melanomas can be monitored without ultrasonography if they can be adequately imaged with colour photography. Abstract Prompt detection and treatment of local treatment failure after radiotherapy for choroidal melanoma optimises any opportunities for conserving vision and the eye, possibly reducing an increased risk of metastatic disease. Long-term surveillance is therefore required but is hampered by the perceived need to perform ultrasonography, which may not be available at a patient’s local hospital. The aim of this study was to determine whether local treatment failure can reliably be detected with colour fundus photography alone, and, if so, in which patients. Patients were included in the study if diagnosed with local treatment failure between April 2016 and February 2021 after eye-conserving therapy for choroidal melanoma. Wide-field colour and fundal autofluorescence (FAF) images, optical coherence tomography (OCT), and ultrasonography (US) were analysed by two of the authors (GN and UH). The cohort included 87 patients with local treatment failure. In 75 patients with clear media, tumour progression was detected by colour photography alone in 74 (98.7%) patients. Sensitivity was not increased by the addition of either OCT or AF. One patient with clear media developed extraocular extension detected with US without visible change in the intraocular part of the tumour. In the other 12 patients, US was required because of opaque media and a consequently poor fundal view. Local treatment failure after radiotherapy for choroidal melanoma is detected in 98.7% of cases with colour photography when the media are clear. Ultrasonography is useful when photography is prevented by opaque media or tumours having locations in the far periphery.

To determine the accuracy of estimated tumour location and required plaque position using fundus diagrams, and to evaluate their applicability in daily clinical practice. Between September 2013 and March 2016, all patients treated with ruthenium plaque brachytherapy for choroidal melanoma at the Department of Ophthalmology in Poznan underwent pretreatment planning with the use of printed or electronic fundus diagrams www.oculonco.com The estimated distances were then verified intraoperatively. There were 40 eyes of 40 patients: 15 men, 25 women, with a median age of 61 years (range: 21–88). The median longitudinal basal diameter (LBD) of the treated melanomas was 10.4 mm (range: 6.5–14.9) and the median thickness was 4.1 mm (range: 1.9–6). The final postition of the anterior tumour margin was within 1 mm of the estimated location in 39 cases (97 %), and within 2 mm in 1 case (3 %). Median follow-up was 15 months (range: 3–36). By the close of the study, there was one local tumour recurrence (3%) and one patient died of unrelated cause 1 year after treatment. No patient developed metastases by study close. The plaque planning system using the paper fundus diagrams proved to be accurate, easily applicable and should aid plaque placement where computer modelling is not possible.