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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 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 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 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.

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.

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.

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.

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.

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.

Background Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. Methods Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. Results The cohort comprised 232 patients with UM having a median age of 59 years (range, 25–82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1–20.8) and tumour height was 3.4 mm (range, 0.7–10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. Conclusions Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. Precis Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.

A challenge in precision medicine is the identification of actionable driver mutations. Alterations can be identified within the tumor tissue, by small biopsy or fine‐needle aspirates, or by noninvasive methods, such as circulating tumor cells or circulating tumor DNA. This article presents a case of atypical neuroendocrine tumor metastatic to the bone and brain for which circulating tumor DNA analysis found an ALK translocation., A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well‐validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non‐small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine‐needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52‐year‐old never‐smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed. Key Points. To our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second‐generation ALK inhibitors represent a new paradigm for treating ALK‐positive patients with brain metastases.

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/aimsProton beam radiotherapy and plaque brachytherapy are commonly applied in primary uveal melanoma (UM); however, their effect on chromosome 3 classification of UM by microsatellite analysis (MSA) for prognostication purposes is unknown, where the tumour is sampled post-irradiation. This study examined the prognostic accuracy of genotyping UM biopsied before or after administration of radiotherapy, by MSA.Methods407 UM patients treated at the Liverpool Ocular Oncology Centre between January 2011 to December 2017, were genotyped for chromosome 3 by MSA; 172 and 176 primary UM were sampled prior to and post irradiation, respectively.ResultsGenotyping by MSA was successful in 396/407 (97%) of UM samples (196 males, 211 females; median age of 61 years (range 12 to 93) at primary treatment). There was no demonstrable association between a failure of MSA to produce a chromosome 3 classification and whether radiation was performed pre-biopsy or post-biopsy with an OR of 0.96 (95% CI 0.30 to 3.00, p=0.94). There was no evidence of association (measured as HRs) between risk of metastatic death and sampling of a primary UM before administration of radiotherapy (HR 1.1 (0.49 to 2.50), p=0.81). Monosomy 3 (HR 12.0 (4.1 to 35.0), pConclusions and relevanceThis study revealed that successful genotyping of UM using MSA is possible, irrespective of irradiation status. Moreover, we found no evidence that biopsy prior to radiotherapy increases metastatic mortality.

Despite an established history of intraocular antivascular endothelial growth factor (anti-VEGF) agents therapy in a variety of ocular pathologies as well as other cancer forms, use in the primary treatment of uveal melanoma has not been well assessed. This was a two-stage therapeutic and exploratory phase II, non-randomised, single centre trial involving intraocular treatment with 0.5 mg in 0.05 ml of ranibizumab via six intravitreous injections over 6 months in patients with primary ocular melanoma that otherwise required radical surgery because of tumour size. Seven patients were recruited with a median age of 66 years. At baseline, the longest basal diameter was 15.1 mm (mean, range 10-20.4 mm) with a height measured by ultrasonography of 9.2 mm (mean, range 6.6-12.7 mm). No patients achieved complete or partial response at any visit. All required enucleation. Histopathological analysis revealed mixed cell melanoma in 5/7 (71%) and spindle cell morphology in 2/7 (29%) with ciliary body involvement in 4/7 (57%) and the presence of closed loops also in 4/7 (57%). Genetic analysis demonstrated loss of chromosome 3 in 5/7 (71%) but abnormalities in chromosome 1,6 or 8 in all cases. Our study was terminated early as alternative treatments were clearly superior for local tumour control. There continues to be a role of intravitreal anti-VEGF for the treatment of the sequelae of local radiotherapy in the form of radiation retinopathy and so these agents may be used as adjuncts in the treatment of uveal melanoma rather than as a primary treatment.

Background/objectives To evaluate retinal lymphoma treatment at the University of California San Francisco. Subjects/methods Prospective observational audit. Patients were treated systemically, usually with: methotrexate, temozolomide, and rituximab induction; etoposide consolidation; and maintenance with lenalidomide or another immunomodulatory agent. Persistent disease was treated initially by ocular radiotherapy or intravitreal melphalan and latterly by vitrectomy. Results The cohort comprised eight females and two males. The median age was 58 years (range, 38–73). Ocular manifestations were initially unilateral in four patients. Vitreous and subretinal infiltrates were initially present in 16 and 12 eyes, respectively, with three eyes having vision of 20/200 or worse. Four patients had a history of central nervous system (CNS) lymphoma. The median ophthalmic follow-up was 37 months (range, 8–56). Diagnostic and therapeutic vitrectomy were performed in 10 and 2 eyes, respectively. All patients had systemic chemotherapy and eight received maintenance immunotherapy. Four patients underwent ocular radiotherapy, bilaterally in two. One patient received bilateral intravitreal melphalan injections. Two eyes of four patients developed lymphoma during the study and two patients developed CNS disease. At study close, subretinal deposits were subtle in nine eyes and more prominent in two, whereas vitreous infiltrates were minimal in nine eyes, mild in one and moderate in one. The latest visual acuity was significantly worse than at presentation in two eyes and better in two. All patients were alive with no active CNS disease. Conclusions Subretinal lymphomatous infiltrates respond to systemic chemotherapy with immunomodulatory maintenance, but dense vitreous infiltrates require therapeutic vitrectomy.

Purpose: To compare hydroxyapatite with acrylic implants after enucleation for uveal melanoma with respect to eyelid position, ocular motility, implant complications, and patient satisfaction. Methods: Patients undergoing primary enucleation for uveal melanoma between May 2005 and November 2012 at the Liverpool Ocular Oncology Centre, United Kingdom, were randomized between hydroxyapatite and acrylic implants. Questionnaires were sent to patients and ocularists to comment on the main outcomes. Results: A total of 416 patients were recruited in the study, of whom 281 were included, with 49.5% (139/281) and 50.5% (142/281) receiving a hydroxyapatite (HA) or acrylic (AC) implant. Mailed questionnaires completed at ≥18 months by patients showed no significant differences between the groups in eyelid position, prosthetic motility, socket complications, and patient satisfaction. Complications included implant extrusion (1% vs 4%), enophthalmos (26% vs 26%), and superior sulcus deformity (24% vs 24%) with HA and AC implants, respectively, (Fisher exact test p > 0.0125 in all, Bonferroni correction). Questionnaires completed by ocularists indicated no significant differences in eyelid opening, prosthetic motility, and other complications at 6 months (Fisher exact test, p > 0.05 in all); there was a higher prevalence of ptosis with AC than HA implants (46% vs 25%, p = 0.03) and a greater need for ocularists’ treatment with HA than AC (50% vs 28%, p = 0.03). Conclusions: Patient-reported outcomes after enucleation for uveal melanoma indicate no major differences between hydroxyapatite and acrylic implants in surgical outcomes and patient satisfaction. There was a higher prevalence of ptosis with AC and a greater need of ocularists’ visits with HA at around 6 months observed by ocularists.

PurposeTo report near-infrared reflectance (NIR-R), near-infrared autofluorescence (NIR-AF) and blue wave autofluorescence (BW-AF) appearance of choroidal nevi using a confocal scanning laser ophthalmoscope (cSLO).Patients and methodsNIR-R, NIR-AF and BW-AF images of choroidal nevi were compared with color fundus photos (CF). Images were graded as hyperreflective if reflectance was much greater than background, hyporeflective if less than background, and isoreflective if the same as the background.ResultsForty-two nevi of 39 patients were imaged. When compared with CF, nevi could be identified on 95% (40/42) NIR-R images (95% CI: 83.5-99.3). On NIR-R 71% (30/42) demonstrated hyperreflectance and 24% (10/42) were hyporeflective. Hyperreflectivity was demonstrated in 96% (23/24) of NIR-AF images (95% CI: 79.1-99.9) and 34% (14/41) of BW-AF images (95% CI: 20.0-50.5). On NIR-R, 29/40 (73%) were apparently smaller in comparison with CF and 11/40 (28%) had the same area. A correlation was found between NIR-R and NIR-AF (P=0.02) but not with BW-AF (P=0.15).ConclusionsNevi can be visualized well using NIR-R and NIR-AF imaging modalities, but are less frequently visible using BW-AF. These changes may be related to melanin within the choroid or chronic changes of the overlying retinal pigment epithelium.

PurposeTreatment of uveal melanoma can impair patients' psychological well-being. We evaluated patient-reported outcome measures (PROMs) of anxiety, depression, and quality of life (QoL) over 2 years following treatment in a consecutive sample of uveal melanoma patients, compared observations to population normative values and examined whether outcomes differed according to patients' age, gender, and whether or not they were treated by enucleation or had a poor prognosis (presence of monosomy 3).DesignProspective longitudinal study.ParticipantsPatients (N=411) with uveal melanoma treated between 2008 and 2011.MethodsSelf-report questionnaire study. We compared mean PROMs scores obtained 6 months, 1 year, and 2 years after treatment to published population normative values using 2-sample t-tests, and tested the association of these scores with gender, age, treatment by enucleation, and monosomy 3 using mixed-model ANOVAs.ResultsOn QoL and depression, patients were similar to or better than normative values at all time points, but there was some evidence that females were more anxious than female normative values (Ps

Purpose Choroidal haemangiomas associated with Sturge Weber syndrome most commonly affect the posterior pole and consequently result in amblyopia. Treatment is often challenging but usually unwarranted unless there is visual deterioration caused by exudative or neovascular complications. The main objective is to demonstrate the effectivity of photodynamic therapy in this context. Design and methods Retrospective analysis of prospectively collected data regarding verteporfin photodynamic therapy (PDT) in the treatment of patients with choroidal haemangiomas associated with Sturge Weber syndrome. Results Six patients (4 male, 2 female) with a median age of 28 years (range, 23–67) had a mean tumour belly diameter of 12.2 mm (range, 9–16.8). There was regression of the tumour in all cases, albeit after 3 treatments in a single case. The exudative retinal detachment resolved in 2 out of 3 patients. Visual outcome improved in 3 patients, remaining poor but stable in the other three, due to pre-existing amblyopia. Conclusions PDT is an effective and safe treatment for patients with choroidal haemangioma associated with Sturge-Weber syndrome.

BACKGROUND/AIMS: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death. METHODS: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure. RESULTS: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance. CONCLUSIONS: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment.

BACKGROUND: Uveal melanomas affect 2–8 per million Europeans each year. Approximately 35%, are treated by enucleation. Proton beam radiotherapy (PBR) can be an eye-conserving alternative to enucleation for patients who wish to retain the eye. Both treatments have adverse effects, and it is difficult for clinicians and patients to make fully informed choices between them because the relative effects of enucleation and PBR on patient-reported outcomes are unknown. METHODS: We compared differential effects of enucleation and PBR on patient-reported outcomes on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Ophthalmological module (EORTC QLQ- OPT30) in a consecutive sample of 115 treated patients ~ 6, 12 and 24 months after diagnosis. Pre-treatment demographic variables, unrelated health problems, vision in the fellow eye, tumour characteristics and prognosis for metastatic disease were statistically controlled. RESULTS: Patients treated by enucleation experienced greater functional problems at 6 months, which abated at 12 and 24 months (P = 0.020). PBR patients reported greater impairments of central and peripheral vision (P = 0.009) and reading difficulties (P = 0.002) over 24 months. Treatment modality did not influence difficulty in driving (P = 0.694), ocular irritation (P = 0.281), headaches (P = 0.640), appearance concerns (P = 0.187) or worry about recurrence (P = 0.899). CONCLUSIONS: When making treatment decisions, it is important that patients and clinicians consider long-standing difficulties of visual impairment associated with PBR and temporary 6-month difficulties in activities related to depth perception associated with enucleation.

Purpose The aim was to evaluate the impact of protocol changes in selective ophthalmic arterial infusion (SOAI) for treatment of retinoblastoma (Rb). Methods A retrospective review was completed of 35 patients with Rb who were treated with SOAI between March 2010 and January 2017. Treatment details were tabulated for each SOAI session. SOAI protocol was changed in June 2015, and differences before and after this change were evaluated using two-tail chi-square tests and independent sample t-tests to note any differences in technical complications, need for enucleation, and other outcome variables Results 125 SOAI sessions occurred. No technical complications occurred during the study. Two complications (1.6%) occurred in the postoperative setting. Both complications occurred prior to the change in protocol. Comparing the complication rates between the two protocols showed no significant difference (2.2% versus 0.0%; p = 0.505); 29 of 43 (67.4%) eyes had their vision preserved overall. Conclusions SOAI is an effective treatment for Rb. The refined protocol described herein was associated with fewer complications.

Purpose To assess the effectivity of photodynamic therapy (PDT) for the treatment of retinal capillary haemangiomas Method Retrospective case note analysis of all patients with retinal angiomas treated with PDT between 2003 and 2010. Results Six eyes of 6 patients (3 male, 3 female) with a mean age of 50 years (range, 23–78) were identified in our database. The follow up period was between 24 and 60 months (mean, 36). Tumor regression was evident in two patients; three tumors showed no demonstrable response to treatment on ophthalmoscopy or ultrasonography and one tumor progressed despite PDT and subsequent cryotherapy. One patient developed retinal neovascularisations following a period of inattendence to our clinic. Visual acuity improved in two patients following PDT, deteriorated in three patients and remained stable in a one patient. Conclusion The response of retinal haemangioblastomas to PDT is inconsistent. Other treatment modalities ought to be utilized for peripheral lesions, however PDT may be tried in juxtapapillary lesions where radiotherapy or cryotherapy is likely to result in concurrent visual loss.

Background/aim The study9s aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies with those results obtained from subsequent endoresection/enucleation of the same CM. Methods A retrospective cohort of 28 patients with CM seen between 2007 and 2014 at the Liverpool Ocular Oncology Centre was analysed. Prognostic genetic testing, for chromosome 3 status, was performed on all tumour specimens, either by MLPA or MSA, depending on DNA yield. In nine cases genetic testing was performed on a sample taken after radiotherapy; four of these had genetic information pre- and post-radiotherapy. Results Fourteen biopsy specimens were analysed by MLPA and 14 by MSA. Twenty-seven endoresection or enucleation specimens were analysed by MLPA, and a single enucleation specimen by MSA. Chromosome 3 data showed prognostic concordance for the patient-matched samples in all 28 cases including 4 cases where samples were taken pre pre- and post radiotherapy. Thirteen cases were classified as monosomy 3 and 12 as disomy 3. Two cases had a loss of chromosome arm 3q in both samples and a single case showed loss of 3p in the biopsy sample with complete monosomy 3 in the subsequent enucleation sample taken 5 months later. Conclusions Intraocular biopsy of CM yields similar prognostic information to larger surgical specimens. Initial evidence, that genetic testing can be successfully conducted post radiotherapy, is also provided. Trial registration number NITRO trial, ISRCTN35236442.

There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20+ CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918.

Purpose To evaluate Verteporfin photodynamic therapy (PDT) as primary treatment for small, posterior choroidal melanoma. Design Retrospective cohort review. Subjects, participants and controls Retrospective case note review of 20 patients with small juxtapapillary and juxtafoveal choroidal melanomas treated with PDT at the Liverpool Ocular Oncology Clinic. Methods Patient and tumour characteristics, PDT session details, visual acuity and B-scan ultrasonography measurements as well as colour fundus photographs at each examination were collated and analysed. Main outcome measures Local tumour control and Best Corrected Visual Acuity (BCVA). Results The 20 patients (14 male, 6 female) had a mean age of 61.2 years (range, 40–85) and were treated between 2001 and 2012. Seven tumours were amelanotic, while 13 were pigmented. Of 20 melanomas, 11 (55%) showed complete regression on B-scan ultrasonography and colour photography; five (25%) showed partial regression; four (20%) remained unchanged and two (10%) showed further growth, for which alternative standard treatment was required. Baseline BCVA was 0.1 logMAR (mean; range 0.0–0.6) compared to a post-PDT BCVA of 0.4 logMAR (mean; range −0.2 to 1.7) over a follow-up of 60.0 months (mean; range 25–156 months). Conclusions PDT can induce tumour regression in a significant proportion of small, posterior, choroidal melanomas but is less reliable than other forms of therapy. It may have a role in patients with special visual requirements if they accept the increased risk of treatment failure requiring radiotherapy.

Aim To report on trans-scleral local resection of choroidal melanoma for exudative retinal detachment and neovascular glaucoma (toxic tumour syndrome) after proton beam radiotherapy (PBR). Methods A non-randomised, prospective study of secondary trans-scleral local resection of choroidal melanoma for exudative retinal detachment with or without neovascular glaucoma after PBR. The patients were treated at the Liverpool Ocular Oncology Centre between February 2000 and April 2008. The trans-scleral local resection was performed with a lamellar-scleral flap, using systemic hypotension to reduce haemorrhage. Results 12 patients (six women, six men) with a mean age of 51 years (range 20–75) were included in this study. The tumour margins extended anterior to ora serrata in six patients. On ultrasonography, the largest basal tumour dimension averaged 12.4 mm (range 6.8–18.1) and the tumour height averaged 7.1 mm (range 4.2–10.7). The retinal detachment was total in seven patients. Neovascular glaucoma was present in four patients. The time between PBR and local resection had a mean of 17.4 months (range 1–84). The ophthalmic follow-up time after the local resection had a mean of 46.2 months (range 14–99). At the latest known status, the eye was conserved in 10 patients, with a flat retina in all these patients and visual acuity equal or better than 6/30 in four patients. The reasons for enucleation were: patient request for enucleation when rhegmatogenous retinal detachment complicated the resection (one patient) and phthisis (one patient). Conclusions Exudative retinal detachment, rubeosis and neovascular glaucoma after PBR of a choroidal melanoma can resolve after trans-scleral local resection of the tumour. Our findings suggest that these complications are caused by the persistence of the irradiated tumour within the eye (‘toxic tumour syndrome’).

It is challenging for patients to receive a new diagnosis of a life-threatening ocular tumor when visiting an ocular oncology clinic for the first time. Audio recording of patient-physician interactions has been shown to be an effective memory aid and stress-reducing technique for patients with various types of nonophthalmic cancer. This study evaluated a protocol for digitally recording the initial conversation between the ocular oncologist and the patient. Twenty patients were enrolled in the study, and 13 patients (65%) returned the survey. All of the patients who returned the survey reported being “very satisfied” with the audio recording, indicating that patients with a newly diagnosed ocular tumor were highly satisfied with the audio recording of their conversations with the ocular oncologist. Although larger studies are needed to confirm this conclusion, the initial results are encouraging. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:597–599.]

Background Uveal metastasis is the most common intraocular malignancy. Methods This was a retrospective study of all patients with uveal metastases referred to the Liverpool Ocular Oncology Centre between January 2007 and December 2012. Biopsy was performed as a primary investigation if the clinical examination suggested metastasis with no evidence of any extraocular metastases. Results Ninety-six patients (109 eyes) were included. Breast and lung carcinomas were the most common primary malignancies, affecting 41 and 27 patients, respectively. The median time interval between detection of primary cancer and uveal metastasis was 24 months (range 1–288 months). Thirty-nine patients underwent ocular biopsy, confirming the diagnosis in all patients. The biopsy indicated the site of origin in 24 out of the 27 without a known primary tumour. In 7 of these 27 cases, previous systemic investigations had failed to identify the primary tumour. Seventy-three patients received external beam irradiation; two patients received photodynamic therapy; and two patients had Ru-106 plaque radiotherapy. The visual acuity was stable or improved in 75.5% of the cases. Conclusions Immediate biopsy provides a quick diagnosis that may expedite treatment and improve any opportunities for conserving vision while facilitating the general oncologic management on these patients.

Unrecognized visual field loss is caused by a range of blinding eye conditions as well as serious brain diseases. The commonest cause of asymptomatic visual field loss is glaucoma. No screening tools have been proven cost-effective. Damato Multifixation Campimetry Online (DMCO), an inexpensive online test, has been evaluated as a future cost-beneficial tool to detect glaucoma. To further validate DMCO, this study aimed to test DMCO in a preselected population with neurological visual field loss. Methods: The study design was an evaluation of a diagnostic test. Patients were included if they had undergone surgery for epilepsy during 2011-2014, resulting in visual field loss. They were examined with DMCO and results were compared with those obtained with the Humphrey Field Analyzer (30:2 SITA-Fast). DMCO sensitivity and specificity were estimated with 95% confidence intervals. Results: The cohort comprised 40 patients (25 female and 15 male) with a mean age of 39 years (range 17-60 years). The mean visual acuity was >1.0 and all eyes had an intraocular pressure Conclusions: DMCO detects moderate-to-severe homonymous quadrantanopia; it can be useful in settings where the current practice is confrontation visual field examination, and where standard conventional perimetry is not available.

The management of conjunctival melanoma is difficult because of the rarity of the disease, confusing terminology, high rates of local tumor recurrence, controversies regarding treatment, a poor evidence base, unreliable prognostication, and significant mortality rates.The medical literature was reviewed, focusing on treatment and management options for conjunctival melanoma. Recent trends and developments were summarized with respect to terminology, local treatment, histology, genetic analysis, prognostication, and systemic treatment, highlighting the scope for research and possible improvements in patient care.Histopathological diagnostic terminology for primary acquired melanosis is being superseded by more explicit terminology, thus differentiating hypermelanosis from conjunctival melanocytic intraepithelial neoplasia. Topical chemotherapy and increased use of adjunctive radiotherapy have helped improve rates of local tumor control. Use of exenteration has become rare. Regional and systemic metastases are common in patients with nonbulbar conjunctival melanoma, although long-term survivors with metastases are growing in number. Prognostication is mainly based on tumor size and location, but histological and genetic data into multivariate analyses will soon be incorporated. The role of sentinel lymph-node biopsy continues to be controversial. Chemotherapy for metastatic disease is being superseded by targeted therapy based on genetic abnormalities such as BRAF mutations.The management of conjunctival melanoma requires expert care from an experienced, multidisciplinary team. The goal of therapy is to provide good local tumor control with minimal morbidity, high-quality pathology, and adequate psychological support. Maximizing patient enrollment in multicenter clinical trials is likely to strengthen evidence-based decision-making.

To determine the mode of detection of uveal melanoma and time to treatment in the United Kingdom.Prospective cohort study.A total of 2384 patients diagnosed with uveal melanoma at the Liverpool Ocular Oncology Center between 1996 and early 2011.A questionnaire was completed with every new patient, and the results were correlated with clinical features and treatment.Tumor detection, practitioner initiating referral, referral pathway, time to treatment, baseline clinical features, and primary ocular treatment.The referral process was initiated by an optometrist, family doctor, or ophthalmologist in 68.0%, 18.2%, and 13.8% of patients, respectively. On referral, 30.2% of patients were asymptomatic. Twenty-three percent of patients reported that their tumor was initially missed; these tended to have a more advanced tumor when they reached our center. The time from referral to treatment had a median of 49 days, exceeding 6 months in 19.8% of patients. This delay was longer in patients who reported that their tumor was missed (median, 92 vs. 40 days; Mann-Whitney, P0.001). Ophthalmologists delayed the referral process by more than 6 months in 10.9% of patients. Primary enucleation was performed in 33.3% of patients and was more likely in those who reported that their tumor was missed (44.8% vs. 29.8%; chi-square, P0.001).Many patients with uveal melanoma experience long delays in treatment because their tumor was missed or misdiagnosed. Such patients tend to have a more advanced tumor by the time they reach an oncology center and are more likely to require enucleation.

Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma.

Purpose: Metastasis from uveal melanoma occurs almost exclusively with tumors showing chromosome 3 loss. We used multiplex ligation-dependent probe amplification (MLPA) to detect chromosome 1p, 3, 6p, 6q, 8p, and 8q abnormalities in uveal melanomas. The purpose of this study was to correlate our MLPA results with other risk factors and metastatic death. Experimental Design: Patients were included if they had a uveal melanoma involving choroid. Correlations between baseline risk factors were analyzed using the chi-square test (without Yates's adjustment) and the Mann–Whitney test, with log-rank analysis for associations with metastatic death. Results: The patients (194 female; 258 male) had a median age of 59.4 years and a median follow-up of 1.89 years. MLPA abnormalities occurred in a wide variety of combinations. Ten-year disease-specific mortality was 0% in 133 tumors with no chromosome 3 loss, 55% in tumors with chromosome 3 loss but no chromosome 8q gain, and 71% in 168 tumors showing combined chromosome 3 loss and 8q gain. In tumors with both these abnormalities, epithelioid melanoma cytomorphology, closed loops, and high mitotic rate correlated with poor survival as did lack of chromosome 6p gain. Conclusions: These results support the use of MLPA for routine clinical prognostication, especially if the genetic data are considered together with clinical and histologic risk factors. We showed a wide variety of MLPA results, which suggests that chromosomal abnormalities in uveal melanoma accumulate in a variable sequence.

PURPOSE. To evaluate multiplex ligation-dependent probe amplification (MLPA) of uveal melanoma as a predictive tool for metastatic death. METHODS. Uveal melanoma specimens of 73 patients treated between 1998 and 2000 were included. DNA samples were analyzed with MLPA evaluating 31 loci on chromosomes 1, 3, 6 and 8, and the results were correlated with metastatic death. RESULTS. The patients (27 women; 46 men) had a median age of 60.6 years and a median follow-up of 6.2 years. Metastatic death occurred in 28 patients, correlating most strongly with chromosome 3 losses and gains on 8q (Cox univariate analysis, P

Correction: Volume: 211 Pages: 233-233 DOI: 10.1016/j.ajo.2019.11.027 Published:‏ MAR 2020 PURPOSE: To validate a staging system for metastatic uveal melanoma that will facilitate planning, reporting, and interpreting the results of clinical trials. DESIGN: Reliability and validity study. METHODS: The performance index, the largest diameter of the largest metastasis and alkaline phosphatase level at the time of diagnosis of metastases, and overall survival of 249 patients from 7 ocular oncology centers who died of dissemination were analyzed. Predicted median survival time calculated according to the Helsinki University Hospital Working Formulation was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of >= 12

The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens.

Aim To identify the prevalence of self-reported non-ocular primary malignancies in patients at the time of diagnosis with uveal melanoma (UM) and to describe the cohort’s characteristics. Methods A data query for cases of UM seen at the Liverpool Ocular Oncology Centre between January 1993 and May 2014 was performed. Only patients who had UM with other non-ocular primary malignancies were included. Demographic and clinical data were analysed. Results A total of 5042 (2563 males, 50.8%) patients with UM were found in the database; of whom, 216 (4.3%) had at least one other primary non-ocular malignancy. Of these 216 patients, 119 were males (55.1%). Forty five males (37.8%) had been diagnosed with prostate cancer, 30 (25.2%) with unspecified skin cancers, 15 (12.6%) with colon and bowel carcinoma, eight (6.7%) with systemic lymphoma and the remaining patients with less common tumours. Of the 97 females, 45 (46.4%) had been diagnosed with breast carcinoma, 19 (19.6%) had unspecified skin cancers, seven (7.2%) renal cell carcinoma, six (6.2%) colon and bowel carcinoma, and the remaining patients had other less common tumour types. In this cohort, the frequency of the most common additional malignancy in male and female patients with UM was comparable with their prevalence in the general UK population. Conclusions Additional primary malignancies can occur in association with UM; therefore, medical history taking in patients with UM should always include this aspect. Apart from providing demographic and clinical data in such cases, future collaborative studies, which would include germline mutational testing, may reveal relevant common patterns.

Expression of PERP (p53 apoptosis effector related to PMP-22) was investigated in primary uveal melanomas and its variation was analyzed in relation to clinico-pathological and cytogenetical characteristics of these tumors. The transcriptional level of PERP gene was measured by quantitative real-time RT-PCR in 26 uveal melanomas with known chromosomes 3 and 8 status. PERP protein levels were assessed by Western blot analysis of 22 fresh-frozen tumors and by immunohistochemical analysis of 16 paraffin-embedded tumor specimens. Differential expression of PERP was identified in primary choroidal melanoma specimens, both at transcriptional and protein level. Reduced PERP mRNA level was significantly associated with monosomy 3 (two-way ANOVA and t-test, p = 0.004) but not with gains in chromosome 8. Transcriptional downregulation of PERP did not present a statistically significant association with ciliary body involvement, size, PAS-positive loops or cell type. Immunoblotting and immunohistochemistry further demonstrated significantly reduced PERP protein level in monosomy 3 melanomas, as compared with disomy 3 tumors. The altered expression of PERP highlighted this apoptosis-specific target of p53 as a possible contributor to apoptosis in uveal melanoma with PERP downregulation being particularly relevant to the aggressive (monosomy 3) type of uveal melanoma. As PERP is a novel type of p53 effector that is likely to stimulate apoptosis through a mechanism distinct from that of Bcl-2-related mitochondrial effectors, further elucidation of its role in uveal melanoma pathogenesis will assist in the design of novel therapeutic approaches aimed at increasing the rate of apoptosis in this tumor.

Purpose To report on local tumor control after 106 Ru brachytherapy for choroidal melanoma. Methods and Materials A total of 458 patients with choroidal melanoma were treated at a single institution between January 1993 and December 2001. The tumors had a median longest basal dimension of 10.6 mm and a median height of 3.2 mm. The brachytherapy was administered using a 15- or 20-mm plaque. For posterior tumors, the plaque was positioned eccentrically with its posterior edge aligned with the posterior tumor margin to reduce the radiation dose to the optic disk and fovea. A minimal scleral dose sufficient to cause visible choroidal atrophy provided a permanent ophthalmoscopic record of the distribution of choroidal irradiation. If radiotherapy to the posterior tumor was uncertain, adjunctive transpupillary thermotherapy was administered 6 months postoperatively. Results The actuarial rates of tumor recurrence were 1%, 2%, and 3% at 2, 5, and 7 years, respectively. Local tumor recurrence correlated with the longest basal tumor dimension (Cox univariate analysis, p = 0.02, risk ratio 1.41, 95% confidence interval 1.06–1.88). Seven of the nine eyes with recurrent tumor were salvaged with additional conservative therapy. Conclusion The low rate of local tumor recurrence suggests that ruthenium plaque radiotherapy is effective with good case selection and if special measures are taken to ensure that the plaque is positioned correctly.

Purpose: To report on outcomes after proton beam radiotherapy of iris melanoma. Methods and Materials: Between 1993 and 2004, 88 patients with iris melanoma received proton beam radiotherapy, with 53.1 Gy in 4 fractions. Results: The patients had a mean age of 52 years and a median follow-up of 2.7 years. The tumors had a median diameter of 4.3 mm, involving more than 2 clock hours of iris in 32% of patients and more than 2 hours of angle in 27%. The ciliary body was involved in 20%. Cataract was present in 13 patients before treatment and subsequently developed in another 18. Cataract had a 4-year rate of 63% and by Cox analysis was related to age (p = 0.05), initial visual loss (p < 0.0001), iris involvement (p < 0.0001), and tumor thickness (p < 0.0001). Glaucoma was present before treatment in 13 patients and developed after treatment in another 3. Three eyes were enucleated, all because of recurrence, which had an actuarial 4-year rate of 3.3% (95% CI 0-8.0%). Conclusions: Proton beam radiotherapy of iris melanoma is well tolerated, the main problems being radiation-cataract, which was treatable, and preexisting glaucoma, which in several patients was difficult to control.

This Correspondence relates to the article by Lake et al that reported copy number and genotyping analysis on formalin-fixed, paraffin-embedded samples using genome-wide SNP arrays version 6.0.

Aims The research objective was to develop a questionnaire module to be used, in addition to the European Organisation into Research and Treatment of Cancer (EORTC) QLQ-C30, for measurement of quality of life (QL) among patients with uveal melanoma treated with methods such as transpupillary thermotherapy, plaque radiotherapy, proton beam radiotherapy, local resection, and enucleation. The present paper describes the development through Phases I–III. Methods Relevant QL issues were generated from literature search and from interviews with ophthalmologists, nurses, and patients with uveal melanoma representing three major treatment options: enucleation, plaque brachytherapy, and proton beam therapy. Results The provisional module was pretested in 61 patients from Finland, Sweden, and UK. The EORTC QLQ-OPT30 module consists of 26 items for all patients, and four additional items for patients receiving treatments other than enucleation. It measures ocular irritation, vision impairment, headache, worry about recurrent disease, problems with driving, problems with appearance functional problems due to vision impairment, and problems reading. Conclusions Several treatment modalities are available for uveal melanoma. There is limited knowledge of the impact of these treatments on QL in the long and short term. We hope that the OPT30 module together with the EORTC QLQ-C30 core questionnaire can be a useful tool in research.

Cytogenetic analysis has transformed the management of uveal melanoma in recent years and allows categorization of such tumors into low-grade tumors with a favorable prognosis and high-grade tumors that metastasize with a fatal outcome. The authors report the case of a 73-year-old man who presented with recurrent melanoma in his left socket, 26 years after enucleation for uveal melanoma. Chromosomal analysis by multiplex ligation-dependent probe amplification revealed partial loss of chromosome 3 and gains in chromosomes 6 and 8, which were missed with fluorescence in situ hybridization. The patient developed multiple liver metastases 14 months after orbital exenteration and died 8 months later. To the best of authors' knowledge, this is the first report of late recurrence of uveal melanoma after enucleation, in which multiplex ligation-dependent probe amplification chromosomal analysis has been used. The case also highlights the limitations of fluorescence in situ hybridization and the benefits of multiplex ligation-dependent probe amplification, which is more reliable at predicting survival.