Proteomics in uveal melanoma.

Uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of 5-7 per million per year. It is associated with the development of metastasis in about 50% of cases, and 40% of patients with uveal melanoma die of metastatic disease despite successful treatment of the primary tumour. The survival rates at 5, 10 and 15 years are 65%, 50% and 45% respectively. Unlike progress made in many other areas of cancer, uveal melanoma is still poorly understood and survival rates have remained similar over the past 25 years. Recently, advances made in molecular genetics have improved our understanding of this disease and stratification of patients into low risk and high risk for developing metastasis. However, only a limited number of studies have been performed using proteomic methods. This review will give an overview of various proteomic technologies currently employed in life sciences research, and discuss proteomic studies of uveal melanoma.

Teaching of manual cataract extraction in ophthalmic surgical training programmes.

BACKGROUND: Manual cataract extraction techniques such as extracapsular cataract extraction (ECCE) or manual small incision cataract (MSICS) surgery have been replaced by phacoemulsification cataract surgery. Surgical training opportunities for manual techniques of cataract extraction are limited in modern surgical training programmes. AIMS: This study evaluated the current trends of ECCE/MSICS training opportunities amongst trainees and trainers in the Irish Ophthalmic Surgical Training Program. METHODS: An electronic survey was distributed to all ophthalmic surgical trainees and consultants in the country. It addressed the experience and exposure to ECCE/MSICS. RESULTS: Nineteen of 33 (57%) trainees and 29 of 55 (55%) of consultants completed the survey. Twelve of 19 (63%) trainees viewed an ECCE procedure performed live. Twenty-seven of 29 (93%) consultants performed an ECCE procedure during their surgical career; 8 of 27 (30%) performed an ECCE within the last 1-3 years. Fourteen of 19 (74%) trainees stated they do not feel confident converting from phacoemulsification to ECCE independently. Sixteen of 19 (89%) trainees believe manual cataract extraction training should be included in their surgical training. Nineteen of 29 (65%) consultants believe training in manual cataract extraction should be part of the surgical training programme. CONCLUSIONS: There is a paucity of manual cataract extraction being performed in Ireland, limiting live surgical training in this technique. This survey highlights the limited experience of trainees in this valuable skill that is occasionally required for a successful surgical outcome. The authors conclude that wet laboratory simulated training of manual cataract extraction will bridge this gap.

Socket outcomes following enucleation for uveal melanoma: post enucleation socket syndrome can be challenging.

PURPOSE: To evaluate socket outcomes of enucleation for uveal melanoma. METHODS: This study was a retrospective chart review conducted in December 2022 of all patients who underwent enucleation surgery for uveal melanoma between 2010 and 2015 in the Royal Victoria Eye and Ear Hospital, to evaluate socket outcomes including completion of revision surgery, type of surgery, and completion of multiple revision surgeries, and potential associations. RESULTS: Between June 2010 and December 2015, 72 patients underwent enucleation for uveal melanoma in the ocular oncology service, including 25 females and 47 males, mean age 65, range 11-91 years old. There were 68 primary enucleations and 4 secondary enucleations. Complete follow-up data was available for mean 4 years, range 1-11 years. Fourteen patients underwent further surgery, including one exenteration for local recurrence. Oculoplastic surgery (n = 6, 8%), implant exposure repair (n = 3, 6%), and orbit volume expanding surgery (n = 4, 6%) were also performed. Eight patients (11%) underwent one further surgery and five patients (7%) underwent a series of procedures. There was a significant association with younger age at enucleation (age <65) with undergoing further surgery (p = 0.03, Fisher's Exact Test (FET)), and also an association of younger age with undergoing multiple further surgeries (p = 0.02, FET). There was no association found with other predictor variables, including primary versus secondary enucleation status. Most patients (75%) with PESS underwent more than one surgery. CONCLUSION: Post enucleation surgery 82% of patients did not undergo further surgery, but younger patients were more likely to undergo anophthalmic socket revision or oculoplastic surgery. Management of post enucleation socket syndrome was challenging and usually involved a series of procedures.

Prognostic Value of BAP1 Protein Expression in Uveal Melanoma.

The prognostic value of the traditional pathologic parameters that form part of the American Joint Committee on Cancer staging system and genetic classifications using monosomy chromosome 3 and structural alterations in chromosome 8 are well established and are part of the diagnostic workup of uveal melanoma (UM). However, it has not been fully clarified whether nuclear protein expression of the tumor suppressor gene BAP1 (nBAP1) by immunohistochemistry alone is as powerful a predictor of overall survival (OS) and/or disease-specific survival (DSS) as chromosome analysis. The protein expression of nBAP1 was evaluated in a retrospective cohort study of 308 consecutive patients treated by primary enucleation between January 1974 and December 2022. We correlated clinical, pathologic, and cytogenetic characteristics to identify the best prognostic indicators for OS and DSS. Loss of nBAP1 was detected in 144/308 (47%) of patients. Loss of nBAP1 expression was significantly associated with poor survival. In patients with disomy chromosome 3, nBAP1 negative is significantly associated with poorer OS but not DSS. We observed that older age (>63 years), presence of metastasis, and nBAP1 negative remained independent prognostic factors in multivariate analysis. nBAP1 protein expression proved to be a more reliable prognostic indicator for OS than the American Joint Committee on Cancer staging, M3 status, or The Cancer Genome Atlas classification in this cohort. This study provides support for accurate prognostication of UM patients in routine histology laboratories by immunohistochemistry for nBAP1 alone.

Retinal vasoproliferative tumour: differential diagnoses and treatment considerations in a paediatric patient.

An early adolescent man was referred to the ocular oncology service for evaluation of a pale, raised fundus lesion in the inferotemporal quadrant of his right eye. Unaided visual acuities were 20/20 OD and 20/20 OS. He had no medical, ocular or family history of note. Retinal vasoproliferative tumour with progressive retinal exudation was the working diagnosis. Improvement in tumour features and exudation regression were noted following a combination of argon laser therapy, cryotherapy and intravitreal steroid injection. Paediatric intraocular tumours present a complex list of differential diagnoses and offer significant diagnostic and management challenges. Discussed here are the differential diagnoses and treatment considerations in the setting of an intraocular tumour in childhood.

Ocular oncology service during the COVID-19 outbreak: uveal melanoma characteristics presenting in 2019 compared to 2020.

AIM: We aim to evaluate the impact of the COVID-19 pandemic on ocular oncology in Ireland, comparing uveal melanoma trends in 2019 to 2020. METHODS: Patients included for analysis were those that presented to the ocular oncology service from January 2019 to December 2020 in the Royal Victoria Eye and Ear Hospital in Dublin, who underwent primary treatment for uveal melanoma-proton beam therapy, brachytherapy or enucleation. RESULTS: Ninety-seven patients presented in 2019 (n = 46) and 2020 (n = 51) who underwent primary treatment for uveal melanoma. Presentation via the eye casualty department was more common in 2020. Dimensions of choroidal melanomas were increased both in basal diameter and thickness compared to those in 2019. More patients had enucleations in 2020 than in 2019 (21.6% vs 9.3%, respectively) and less had proton beam therapy (6.2% vs 12.4%). More patients had evidence of extra-scleral extension at the time of surgery in 2020 compared to 2019 (4.1%, n = 4 versus 0%, respectively). The mean duration of brachytherapy therapy was longer in 2020 (5.3 days ± 35.8) compared to 2019 (4.6 days ± 38.7). Mean time between presentation and primary treatment was 35.6 ± 28.8 days in 2019 and 24.1 ± 20.4 days in 2020. CONCLUSIONS: More advanced disease is suggested by the increased mean basal diameter and tumour thickness, extra-scleral extension and longer duration of brachytherapy. Time from diagnosis to treatment was not delayed in 2020.

Clinical Impact of Immune Checkpoint Inhibitor (ICI) Response, DNA Damage Repair (DDR) Gene Mutations and Immune-Cell Infiltration in Metastatic Melanoma Subtypes.

Molecular and histopathological analysis of melanoma subtypes has revealed distinct epidemiological, genetic, and clinical features. However, immunotherapy for advanced metastatic melanoma patients does not differ based on subtype. Response to immune checkpoint inhibitors (ICI) has been shown to vary, therefore, predictive biomarkers are needed in the design of precision treatments. Targeted sequencing and histopathological analysis (CD8 and CD20 immunohistochemistry) were performed on subtypes of metastatic melanoma (cutaneous melanoma (CM, n = 10); head and neck melanoma (HNM, n = 7); uveal melanoma (UM, n = 4); acral lentiginous melanoma (AM, n = 1) and mucosal melanoma (MM, n = 1) treated with ICI). Progression-free survival (PFS) was significantly associated with high CD8 expression (p = 0.025) and mutations in DNA damage repair (DDR) pathway genes (p = 0.012) in all subtypes but not with CD20 expression. Our study identified that immune cell infiltration and DDR gene mutations may have an impact in response to ICI treatment in metastatic melanoma but differs among subtypes. Therefore, a comprehensive understanding of the immune infiltration cells' role and DDR gene mutations in metastatic melanoma may identify prognostic biomarkers.

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model.

Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84-1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT1) expression associates with poor outcomes. CysLT1 antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines in vitro. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical in vivo orthotopic xenograft models and ex vivo patient samples. Immunohistochemical staining of an independent cohort (n = 64) of primary UM patients confirmed high CysLT1 expression significantly associates with death from metastatic disease (p = 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying the disease relevance of CysLT1 in UM. In primary UM samples (n = 11) cultured as ex vivo explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-α. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (p = 0.03), a marker of oxidative phosphorylation. In UM, high ATP5F1B is a poor prognostic indicator, whereas low ATP5F1B, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT1 and ATP5F1B in UM, and the therapeutic potential of 1,4-dihydroxy quininib with ATP5F1B as a companion diagnostic to treat MUM.

Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma.

The molecular, histopathological, genomic and transcriptomic characteristics of uveal melanoma (UM) have identified four molecular subgroups with different clinical outcomes. Despite the improvements in UM classification and biological pathology, current treatments do not reduce the occurrence of metastasis. The development of effective adjuvant and metastatic therapies for UM has been slow and extremely limited. Preclinical models that closely resemble the molecular and genetic UM subgroups are essential for translating molecular findings into improved clinical treatment. In this review, we provide a retrospective view of the existing preclinical models used to study UM, and give an overview of their strengths and limitations. We review targeted therapy clinical trial data to evaluate the gap in the translation of preclinical findings to human studies. Reflecting on the current high attrition rates of clinical trials for UM, preclinical models that effectively recapitulate the human in vivo situation and/or accurately reflect the subtype classifications would enhance the translational impact of experimental data and have crucial implications for the advancement of personalised medicine.

Classification and treatment of radiation maculopathy.

PURPOSE OF REVIEW: Radiation maculopathy is a sight-limiting consequence of radiotherapy in the management of uveal melanoma and other intraocular tumors. In this review, we consider clinical, fluorescein angiographic and optical coherence tomographic findings, propose a classification for radiation maculopathy and discuss the management of this condition. RECENT FINDINGS: Radiation macular edema (RME) can be classified by optical coherence tomography into noncystoid or cystoid edema, with foveolar or extrafoveolar involvement. Optical coherence tomographic grading of RME has been found to correlate with visual acuity. Focal argon laser might have some limited benefit in the treatment of RME. Intravitreal triamcinolone and intravitreal antivascular endothelial growth factor agents can be of short-term benefit in the treatment of RME. In a randomized controlled trial, periocular triamcinolone significantly reduced rates of RME and vision loss up to 18 months following plaque radiotherapy for uveal melanoma. SUMMARY: Currently, there is no proven treatment for established RME, though periocular triamcinolone has been shown to have a preventive benefit. An accepted classification system for radiation maculopathy would be of benefit in planning and comparing future treatment trials.

Quality of Life in Uveal Melanoma Patients in Ireland: A Single-Centre Survey.

BACKGROUND: Uveal melanoma and its treatment can influence the physical and psychological well-being of patients in a way that differs from other cancers. Factors influencing quality of life (QOL) include visual impairment, changes in appearance, day-to-day functioning, ocular discomfort, and worry regarding disease recurrence. OBJECTIVE: We aimed to study both general and disease-specific QOL in uveal melanoma patients in Ireland and compare QOL between a plaque radiotherapy group and an enucleation treatment group. This information was sought to enhance our understanding of QOL issues for uveal melanoma patients, in the context of improving care and providing appropriate psychosocial support. METHOD: The European Organisation for Research and Treatment of Cancer (EORTC) QOL questionnaires QLQ-C30 and QLQ-OPT30 were completed by patients with uveal melanoma treated by enucleation or brachytherapy. RESULTS: 138 of 206 patients completed the questionnaires. There was no significant difference in QOL scores between treatment groups. Thirty-two percent of patients reported concerns about tumour recurrence elsewhere in the body. The brachytherapy group had a significantly higher "role functioning" score (p = 0.030). Enucleation patients were more likely to have problems with appearance (p < 0.0005). Younger patients (12-54 years of age) were more likely to report headaches (p < 0.0005) and problems with reading (p = 0.042), and they had a lower cognitive functioning score (p = 0.003) than those aged ≥55 years. CONCLUSIONS: There was no significant difference in reported QOL between treatment groups. Our data identified a number of vulnerable patient subgroups. By anticipating which patients are more likely to suffer in terms of certain aspects of their QOL, we are better able to provide appropriate and timely psychosocial support.

PRDX3 is associated with metastasis and poor survival in uveal melanoma.

AIMS: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and 40% develop fatal metastatic disease. Overexpression of thioredoxin-dependent peroxidase reductase (PRDX3) has been implicated in several cancers, including prostate, breast, colorectal and lung cancer. The aim of this study was to compare the immunohistochemical expression of PRDX3 in formalin-fixed, paraffin-embedded (FFPE) primary UM tissues of patients who did and did not develop metastatic disease. METHODS: Immunohistochemical staining of PRDX3 was performed on FFPE tissue microarray samples of 92 primary UM tumours from patients who did and did not develop metastatic disease. The immunohistochemical staining was assessed by two observers who were blinded to all clinicopathological and cytogenetic details including metastatic/non-metastatic information. Based on a scoring system, expression of PRDX3 was graded as high or low. RESULTS: There were 55 tumours (59.8%) from patients who developed metastatic disease, while 37 (40.2%) were from patients who did not develop metastasis. A statistically significant difference in PRDX3 expression was observed in patients who did and did not develop metastasis (p=0.001). A significant positive correlation between high PRDX3 expression and metastasis was observed (p=0.001). A significant negative correlation between PRDX3 expression and survival was found (p=0.005). Kaplan-Meier survival analysis showed a statistically significant difference in overall survival between tumours that demonstrated low and high expression of PRDX3 (67.61 vs 130.64 months, respectively, p=0.013). CONCLUSIONS: High immunohistochemical expression of PRDX3 in primary UM tissue is associated with metastasis and poor survival.

Periocular triamcinolone for prevention of macular edema after plaque radiotherapy of uveal melanoma: a randomized controlled trial.

OBJECTIVE: To determine the efficacy and safety of periocular triamcinolone acetonide (40 mg) for the prevention of macular edema in patients undergoing plaque radiotherapy for uveal melanoma. DESIGN: Prospective, randomized, controlled clinical trial. PARTICIPANTS AND CONTROLS: One-hundred sixty-three patients with newly diagnosed uveal melanoma undergoing iodine 125 plaque radiotherapy were entered into the study. Fifty-five patients were randomized to the control group and 108 to the triamcinolone group. Eighteen-month data were available for 143 (88%) of the 163 patients. INTERVENTION: Periocular injection of triamcinolone acetonide (40 mg in 1 ml) at the time of plaque radiotherapy and 4 months and 8 months later. Optical coherence tomography was performed at each patient evaluation. MAIN OUTCOME MEASURES: Optical coherence tomography-evident macular edema, moderate vision loss, and poor final visual acuity. RESULTS: Optical coherence tomography-evident macular edema occurred significantly less often in the triamcinolone group compared with the control group up to 18 months after plaque radiotherapy (hazard estimate, 0.45; 95% confidence interval, 0.19-0.70; P = 0.001). At the 18-month follow-up, moderate vision loss (loss of 3 lines or more of best-corrected visual acuity [BCVA]) and severe vision loss (BCVA <5/200 Snellen) occurred significantly less frequently in the triamcinolone group than in the control group (31% vs. 48% [P = 0.039] and 5% vs. 15% [P = 0.048], respectively). Rates of elevated intraocular pressure and cataract progression were similar in both groups. CONCLUSIONS: Periocular triamcinolone is beneficial in reducing the risk of macular edema up to 18 months after plaque radiotherapy for uveal melanoma and significantly reduces the risk of moderate vision loss and poor visual acuity in these patients.

Uveal Melanoma in Ireland.

PURPOSE: To report the clinical features and epidemiology of uveal melanoma in Ireland. METHODS: This was an observational study of 253 patients with a new diagnosis of uveal melanoma between June 2010 and December 2015. Main outcome measures included demographics, clinical features, age-adjusted incidence, relative survival, overall survival, and distant metastases-free survival. RESULTS: The mean patient age was 61.7 years. Tumour location was choroidal in 82%, ciliochoroidal in 9%, iridociliary in 2%, and iris in 7%. Treatment modalities included brachytherapy (ruthenium-106 and iodine-125 [64%]), enucleation (27%), and proton beam radiation (8%). The mean age-adjusted incidence of uveal melanoma in Ireland from 2010 to 2015 was 9.5 per million of the population (95% confidence interval [CI]: 8.4-10.7). Four-year relative survival was 81.3% (95% CI: 72.8-87.3). Four-year overall survival was 84% (95% CI: 78-90) and 4-year distant metastases-free survival was 79% (95% CI: 73-86). CONCLUSION: Based on this data, the incidence of uveal melanoma in Ireland is high when compared with other reported incidence rates in Europe and worldwide. Relative and observed survival were in keeping with other reported European survival rates.

Fundus fluorescein angiographic characterization of diffuse choroidal hemangiomas.

PURPOSE: To evaluate the clinical usefulness of fundus fluorescein angiography (FFA) in characterizing diffuse choroidal hemangiomas in Sturge-Weber syndrome. METHODS: A retrospective case review of children attending a university hospital clinic with a diagnosis of Sturge-Weber syndrome was undertaken. The FFA findings of seven patients who had undergone angiography were reviewed. RESULTS: FFA confirmed the presence of choroidal hemangioma in each of the seven cases and delineated the extent of the choroidal lesions. No adverse effects of fluorescein injection were encountered. CONCLUSIONS: FFA is effective in diagnosing and characterizing diffuse choroidal hemangiomas, and may be performed safely in children.

Ultrasound biomicroscopy of eyelid lymphangioma in a child.

A 13-month-old girl developed a superficial, multinodular, blue-grey upper eyelid mass shortly after birth. This was clinically suspected to be a lymphangioma. Ultrasound biomicroscopy revealed a subcutaneous mass with a multicystic internal structure and fluid levels consistent with lymphangioma. Follow-up ultrasound biomicroscopy 2 years later showed stable findings.

An insight into the molecular genetics of a uveal melanoma patient cohort.

BACKGROUND/AIMS: Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance. METHODS: DNA was extracted from 36 intraocular melanoma patient samples and 4 metastatic melanoma samples among the patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel. RESULTS: Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM. CONCLUSION: Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.

A Rare Thyroid Metastasis from Uveal Melanoma and Response to Immunotherapy Agents.

Thyroid metastasis is a rare occurrence with cutaneous melanoma and even more uncommon with uveal melanoma. The management of such metastasis is uncertain due to its infrequency and, in the era of immunotherapy, the effect of these novel drugs on uncommon metastasis, such as to the thyroid, is unknown. We report the rare case of a thyroid metastasis in a patient diagnosed with ocular melanoma initially managed with enucleation. Metastatic disease developed in the lung and thyroid gland. The case patient received the immunotherapy ipilimumab with stable disease in the thyroid and progressive disease elsewhere. The patient was then further treated with a second immunotherapy agent, pembrolizumab, and remains with stable disease one year later. We discuss the current literature on thyroid metastases from all causes and the optimal known management strategies. Furthermore, we provide an original report on the response of this disease to the novel immunomodulators, ipilimumab, and pembrolizumab with stable disease four years after initial diagnosis of ocular melanoma.