Tumor-Associated Retinal Pigmentation in Choroidal Melanoma.

PURPOSE: To report a previously unrecognized choroidal melanoma clinical feature termed tumor-associated retinal pigmentation (TARP) and determine any correlation with tumor biology. DESIGN: Imaging and histologic analysis of a retrospective cohort of patients. PARTICIPANTS: Patients with choroidal melanoma identified as having TARP on funduscopy at the Liverpool Ocular Oncology Centre (LOOC), United Kingdom, from January 2020 through January 2023. METHODS: Clinical and imaging characteristics of patients diagnosed with choroidal melanoma and exhibiting TARP on fundoscopy were documented. Details of these choroidal melanomas were collated and correlated with histopathology and molecular genetic reports. The chromosome 3 status of each tumor was assessed. In enucleated samples, immunostaining was undertaken to determine the nature of the TARP using specific markers (CD68 and MelanA). MAIN OUTCOME MEASURES: Features of TARP on widefield fundus color imaging, fundus autofluorescence (FAF), and OCT were described. Tumor chromosome 3 status and the immunoprofile of the TARP also were collated. RESULTS: Tumor-associated retinal pigmentation had a prevalence rate of 7.47 per 100 cases of choroidal melanoma at the LOOC. Twenty-three eyes with TARP were analyzed, with a mean age of 71.4 years (range, 51-88 years). The median largest basal diameter was 16.10 mm (range, 9.17-21.32 mm), and the mean tumor thickness was 8.04 mm (range, 1.40-13.80 mm). Tumor-associated retinal pigmentation was observed on widefield color fundus imaging, with hypofluorescence on FAF images and represented hyperreflective foci located in intraretinal and subretinal spaces on OCT scans. Seventeen patients (73.9%) underwent enucleation, and 6 patients (26.1%) underwent globe-sparing treatment. Molecular genetic analysis of 20 choroidal melanomas (after enucleation or radiotherapy biopsy) revealed monosomy 3 in 18 tumors (90%). Immunostaining of the TARP in enucleated eyes showed CD68+ melanophages in all 17 patients appearing as scattered cells and aggregates; MelanA findings were negative. CONCLUSIONS: Tumor-associated retinal pigmentation represents tumor-associated macrophages, not melanocytes, within intraretinal and subretinal spaces of larger choroidal melanomas. Radiation treatments need not involve this area in the treatment plan, minimizing radiation-related complications. This novel clinical sign seems to be linked to tumors of high metastatic-risk clinical and genetic characteristics, with a preponderance having monosomy 3 anomalies. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Predictors of long-term anxiety and depression in uveal melanoma survivors: A cross-lagged five-year analysis.

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.

Histopathological Changes and Clinical Outcomes following Intervention for Sub-Internal Limiting Membrane Haemorrhage.

INTRODUCTION: Haemorrhage confined to the sub-internal limiting membrane (ILM) space can be associated with good visual recovery. There is controversy as to the best management of purely sub-ILM haemorrhage, which ranges from observation to immediate surgical intervention. METHODS: We studied a retrospective case series of patients with sub-ILM haemorrhage who underwent vitrectomy with subsequent histological analysis of the removed ILM. RESULTS: Sixteen patients underwent vitrectomy for sub-ILM haemorrhage. Five patients had underlying Terson syndrome, 6 had ruptured macro-aneurysms, and 5 had Valsalva retinopathy. Seven patients demonstrated cellular proliferation on the retinal surface of the ILM with staining for glial fibrillary acidic protein and cytokeratin 7, as well as CD68pg and Prussian blue. All but 1 of these cases were isolated from patients undergoing surgery >4 weeks following initial symptoms, the other presented at >2 weeks. Serial optical coherence tomography (OCT) was available in 8 patients; serial OCT in patients with delayed intervention demonstrated persistent inner retinal layer hyper-reflectance. Fourteen of 15 patients demonstrated symptomatic recovery and showed visual improvement with acuity ranging from -0.1 to 1.8 (mean 0.43) within 3 months of intervention (1 was lost to follow-up). The post-operative vision was 0.11 logMAR (mean; range -0.1 to 0.4) at 3 months in the group with intervention within 2 weeks of symptoms, and 0.9 logMAR (mean; range 0.0 to HM) in the group with delayed surgery. CONCLUSIONS: Early surgical intervention for sub-ILM haemorrhage resulted in good visual outcomes; delayed surgery may lead to proliferative vitreoretinopathy-like changes on the inner retinal surface of the ILM, and untreated cases may demonstrate persistent inner retinal changes potentially limiting visual prognosis despite subsequent surgical intervention.

Polydimethyl Siloxane as an Internal Tamponade for Vitreoretinal Surgery.

PURPOSE: To report the efficacy and safety of polydimethyl siloxane (Siluron Xtra®) as an internal tamponade. DESIGN: Audit and adverse event screening of procedures (March 2014-2015). METHODS: Patients who had undergone vitreoretinal procedures with Siluron Xtra® tamponade were retrospectively analysed with respect to anatomical outcome, visual outcomes, and perioperative complications, in particular intraocular pressure. INCLUSION CRITERIA: all patients who had undergone Siluron Xtra® tamponade. EXCLUSION CRITERIA: No cases were excluded; however, there were no paediatric or pregnant patients within this cohort. All vitreoretinal cases were included, including retinal detachments, but also trauma, endophthalmitis, and intraocular foreign bodies. RESULTS: Twenty-eight patients had polydimethyl siloxane as an intraocular tamponade; 24 retinal detachments (83% complicated by proliferative vitreoretinopathy ≥grade C), 12 had previous failed surgery, and 4 had procedures for intraocular lymphoma, endophthalmitis, or trauma. Follow-up was 14-20 months, and mean duration of tamponade was 6.8 months (3-12 months). Anatomical success was 79% after polydimethyl siloxane injection, 58% 3 months following removal (14/24), 5 remain with long-term tamponade, and 5 with redetachment under tamponade required further intervention. Five required topical anti-glaucomatous agents, and 1 following trauma required glaucoma surgery. Cataract developed in 3/6 phakic patients, and visible emulsification occurred in a single patient. CONCLUSION: Polydimethyl siloxane seems to be an acceptable alternative tamponade agent for the management of complex retinal detachments with comparable anatomical success and comparable rates of raised intraocular pressure to other low-viscosity silicone oil agents, but more importantly, with a lower rate of emulsified oil-related complications, which is important particularly for cases requiring long-term tamponade.

Porous Versus Nonporous Orbital Implants After Enucleation for Uveal Melanoma: A Randomized Study.

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.

The Use of a Polyetheretherketone (PEEK) Implant to Reconstruct the Midface Region.

A good functional and cosmetic result after midfacial reconstructive surgical procedures is of paramount importance. We describe the use of a Polyetheretherketone (PEEK) implant to reconstruct the midface area, after extensive mutilating surgery due to an infiltrative skin tumor. A 67-year-old male patient underwent multiple and extensive surgeries to the left cheek and lower lid because of a highly aggressive metatypical basal cell carcinoma. Complete resection of the recurrent tumor resulted in a cosmetically evident absent cheek contour and facial deformity. The PEEK implant was used to restore the bony cheek contour, with good aesthetic outcome and restoration of the facial symmetry. Preoperative planning with 3-dimensional CT scans allow for customization of the implant. PEEK implants have been scantily described in the periorbital region. The material has a very low reported morbidity and also has the advantage of improving intraoperative predictability and reducing surgical time in complex reconstructive procedures.

Prevalence, temporal course and risk factors for phantom eye symptoms in uveal melanoma.

BACKGROUND: Phantom eye symptoms (PES), particularly phantom visual sensations (PVS) and phantom eye pain (PEP), are common in enucleated patients and can lead to psychological distress. Current cross-sectional studies cannot examine the temporal course of symptoms, nor can they identify dynamic risk factors or consequences of PES. METHODS: Cohort study of 105 enucleated uveal melanoma patients returning self-report questionnaires, within 4 weeks of diagnosis and 6-, 12- and 24-months post-treatment. Questionnaires measuring PVS and PEP symptoms in the week prior to completion, pain severity, Hospital Anxiety and Depression Scale scores and the Functional Assessment of Cancer Therapy scale (FACT-G) measuring quality of life. RESULTS: PVS and PEP emerged after 6 months, were relatively stable over the study and did not remit. PVS showed 6-, 12- and 24-month prevalence rates of 44.6%, 48.2% and 30.2%, and PEP 16.1%, 18.4% and 17.5% respectively. PVS were generally elementary, with only 10-15% of the total cohort experiencing complex sensations. PEP was generally neither prolonged nor intense, except in a small proportion. PVS and PEP were showed moderate associations but did not predict each other prospectively. Anxiety within 4 weeks of diagnosis was a risk factor for the initiation of PEP. Neither PVS nor PEP prospectively predicted anxiety, depression or quality of life. CONCLUSIONS: PES were prevalent and non-remitting, beginning within 6 months of enucleation. PVS and PEP may not represent symptoms of a coherent syndrome. We discuss findings with reference to theories of phantom sensations, and directions for clinical practise and research.

Managing vitreoretinal complications in uveal melanoma: Surgical treatment and practical considerations.

BACKGROUND: In the past few decades, the primary management for uveal melanoma has evolved from enucleation to eye-preserving treatments. However, despite achieving a high rate of local tumour control, complications following eye-preserving treatments still occur and are partly responsible for functional loss and secondary enucleation. METHODS: A literature review by a broad international panel. RESULTS: We summarised the current literature on utilizing vitreoretinal (VR) surgery for managing the complications of uveal melanoma. We also provided insights from the authors' personal experience and practical recommendations for clinical care. CONCLUSIONS: With the advancement of VR instruments and surgical techniques and the combination of VR and ocular oncology knowledge ("Onco-VR"), it is now possible to manage or even prevent complications such as vitreous haemorrhage, retinal detachment, and toxic tumour syndrome.

Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990-2003).

BACKGROUND: Circadian periodicity in the onset of stroke has been reported. However, it is unclear whether this variation affects the acute stroke case fatality. Time of the day variation in stroke case fatality was examined using population-based stroke registration data. METHODS: Stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During the period of 1990-2003, there were 1080 (549 men and 531 women) cases with classifiable stroke onset time. Stroke incidence was categorized as occurring at night (midnight-6 a.m.), morning (6 a.m.-noon), afternoon (noon-6 p.m.), and evening (6 p.m.-midnight). The 28-day case fatality rates and 95% confidence intervals (95% CI) were calculated by gender, age, and stroke subtype across the time blocks. After adjusting for gender, age at onset, and stroke severity at onset, the hazard ratios for fatal strokes in evening, night, and morning were calculated, with afternoon serving as the reference. RESULTS: For all strokes, the 28-day case fatality rate was 23.3% (95% CI:19.4-27.6) for morning onset, 16.9% (95% CI:13.1-21.6) for afternoon onset, 18.3% (95% CI:13.6-24.1) for evening onset, and 21.0% (95% CI:15.0-28.5) for the night onset stroke. The case fatality for strokes during the morning was higher than the case fatality for strokes during afternoon. This fatality risk excess for morning strokes persisted even after adjusting for age, gender, and stroke severity on onset in multivariate analysis. CONCLUSION: In the examination of circadian variation of stroke case fatality, 28-day case fatality rate tended to be higher for the morning strokes.

Small High-Risk Uveal Melanomas Have a Lower Mortality Rate.

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 (>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'.

Neoadjuvant intravitreal ranibizumab treatment in high-risk ocular melanoma patients: a two-stage single-centre phase II single-arm study.

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.

Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons.

Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90%-95%. Localized radiotherapy in the form of plaque brachytherapy or proton beam radiotherapy is the most common treatment modality in the UK. However, the basic mechanisms of radiation response, DNA repair and tissue reactions in UM have not been well documented previously. We have investigated the comparative radiosensitivity of four UM cell lines in response to exogenous radiation sources (both X-rays and protons), and correlated this with DNA repair protein expression and repair efficiency. We observed a broad range of radiosensitivity of different UM cell lines to X-rays and protons, with increased radioresistance correlating with elevated protein expression of ataxia telangiectasia mutated (ATM), a protein kinase involved in the signaling and repair of DNA double strand breaks. The use of an ATM inhibitor in UM cell lines enhanced radiosensitivity following both X-ray and proton irradiation, particularly in cells that contained high levels of ATM protein which are otherwise comparatively radioresistant. In proton-irradiated compared with non-irradiated primary enucleated UM patient samples, there was no significant difference in ATM protein expression. Our study therefore suggests that ATM is a potential target for increasing the radiosensitivity of more resistant UM subgroups.

Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990-2003.

BACKGROUND: We examined the circadian periodicity of ischaemic stroke (IS) onset and its relationship with conventional risk factors using 14-year stroke registration data. METHODS: Ischaemic stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During 1990-2003 there were 637 (353 men and 284 women) cases with classifiable onset time. IS incidence was categorized as occurring at night (midnight to 6 am), morning (6 am to noon), afternoon (noon to 6 pm), and evening (6 pm to midnight). The OR (with 95% CI) of having an IS in the morning, afternoon, and evening were calculated, with night serving as reference. RESULTS: There was significant diurnal variation in IS incidence (P < 0.001). The proportion of events was highest in the morning (40.7; 95% CI: 36.9-44.5), and lowest in the night (14.0; 95% CI: 11.5-16.9). In the morning an excess incidence of IS was observed in both genders, in subjects <65 years and > or =65 years, and in all IS subtypes. The morning excess of IS incidence was similar across seasons and days of the week. For all IS, morning excess was higher (odds ratio: 2.91; 95% CI: 2.29-3.70) compared to the night period. Similar trends persisted after adjusting for age, gender, and risk factors. CONCLUSION: In the examination of circadian variation of IS onset, a predominant morning peak independent of conventional risk factors was observed in a Japanese population with similar pattern across seasons of the year and days of the week.

Regressing Conjunctival Nevus in a Child.

PURPOSE: To report a case exhibiting drastic regression of a conjunctival nevus in a child. CASE REPORT: Spontaneous regression of conjunctival nevus is uncommon. We report the case of a nine-year-old Caucasian boy presenting a conjunctival-pigmented lesion situated at the plica semilunaris that underwent a significant reduction in size and color over a period of 15 months. CONCLUSION: Conjunctival nevus in children is common but regression is rare, especially at the plica. This information could form an important part of the consent process when choosing between observation and surgical excision in the management of a small conjunctival lesion with no suspicious clinical features; since the latter invasive treatment involves risks such as infection, scarring and the possible risk of general anesthesia in children.

Verteporfin photodynamic therapy for the treatment of choroidal haemangioma associated with Sturge-Weber syndrome.

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 12.2mm (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.