Iris melanoma in an Australian cohort.

BACKGROUND: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS: Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.

There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a fivefold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived 2 years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was > 20 times higher than in an aggregated population genome database (P < 5 × 10-5), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in the screening of potential UM-prone families as well as stratification of immunotherapy.

Correction to: Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.

The authors regret that the online version of this article contains an error. The MBD4 mutation in sample MM138 was given an incorrect dbSNP ID. The correct ID is rs769076971.

Combined photodynamic therapy and transpupillary thermotherapy for small choroidal melanoma.

OBJECTIVE: The objective of this study was to determine whether combining verteporfin-based photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) achieves adequate tumour control while maintaining visual acuity in individuals with small choroidal melanoma of amelanotic, melanotic, and variable pigmentation. DESIGN: Individuals with posterior choroidal melanomas up to 3 mm in height underwent verteporfin-based PDT followed by immediate TTT. Further combined laser therapy was performed if a poor response was noted at 12 weeks or beyond. Tumours that demonstrated significant further growth were treated with brachytherapy or enucleation. A total of 37 eyes of 37 patients from the Terrace Eye Centre in Brisbane, Australia were studied. Average age of participants was 59.62 ± 12.45 years, and 17 of 37 participants were female (46%). METHODS: This was a retrospective, noncomparative interventional study. RESULTS: Seven of the 37 participants (19%) had recurrence of their tumour requiring further brachytherapy or enucleation. There was no statistically significant difference in visual acuity before and after treatment. There were no baseline characteristics that predicted treatment outcome. Ten individuals developed complications including epiretinal membrane (16%), scotoma (8%), cataract (3%), and macular edema (3%). No individuals experienced extraocular extension or progressed to metastatic disease. The mean follow-up time was 49 months. CONCLUSION: Combined PDT and TTT achieved 81% tumour control in this study while preserving visual acuity. However, higher rates of local recurrence compared with brachytherapy warrant close follow-up to identify recurrences early.

Germline Variants in Patients Affected by Both Uveal and Cutaneous Melanoma.

Uveal melanoma (UM) and nonacral cutaneous melanoma (CM) are distinct entities with varied genetic landscapes despite both arising from melanocytes. There are, however, similarities in that they most frequently affect people of European ancestry, and high penetrance germline variants in BAP1, POT1 and CDKN2A have been shown to predispose to both UM and CM. This study aims to further explore germline variants in patients affected by both UM and CM, shedding light on the underlying genetic mechanism causing these diseases. Using exome sequencing we analysed germline DNA samples from a cohort of 83 Australian patients diagnosed with both UM and CM. Eight (10%) patients were identified that carried pathogenic mutations in known melanoma predisposition genes POT1, MITF, OCA2, SLC45A2 and TYR. Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility.

Conjunctival Lymphoma.

Lymphoma of the conjunctiva is an ocular malignancy derived from clonal proliferation of lymphocytes. The majority of conjunctival lymphoma is extranodal marginal zone B-Cell lymphoma (EMZL), however diffuse large B-cell (DLBCL), follicular (FL), mantle cell (MCL) and T- cell subtypes are also seen. Clinical manifestations are non-specific, but include unilateral or bilateral painless salmon-pink conjunctival lesions. Approaches to treatment have centered around local immunomodulation, often with Interferon-α2b or Rituximab (anti-CD20 monoclonal antibody) with or without radiation. Although conjunctival lymphoma is generally considered an indolent disease, recent advances in next-generation sequencing have improved clinicians' ability to predict future recurrence or systemic disease through assessment of cytogenic and molecular features. In this paper, we review the classification, clinical features, diagnostic techniques, and emerging strategies for management and prognostication of conjunctival lymphomas.

Choroidal melanoma with synchronous Fuchs' adenoma and novel ATRX mutation.

BACKGROUND: To report a case of Fuchs' adenoma occurring in an eye with a large choroidal melanoma. We have reviewed the literature to describe the clinical presentation, ultrasound characteristics and pathological features of these entities. CASE PRESENTATION: A 69-year-old Caucasian man presented with vision loss from a large choroidal melanoma. Enucleation showed an incidental Fuchs' adenoma in the same eye. Whole-exome sequence analysis was also performed on the patient's blood and melanoma, which showed a rarely-reported ATRX mutation. CONCLUSIONS: Fuchs' adenoma is an under-diagnosed benign age-related hyperplasia of the non-pigmented ciliary epithelium (NPCE). Given its location and characteristics, it can be mistaken for choroidal melanoma and clinicians are reminded how to differentiate between these pathologies and that they may co-exist.

Retrospective study of an as required dosing regimen of intravitreal bevacizumab in neovascular age-related macular degeneration in an Australian population.

PURPOSE: To investigate the efficacy of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) using an as required dosing regimen. METHODS: A retrospective study of 210 patients (231 eyes) with choroidal neovascularization resulting from neovasacular AMD. Patients were treated with 1.25 mg intravitreal bevacizumab at a vitreoretinal practice in Adelaide, South Australia. Patients were followed up at 2-4 weeks and then at 1-month intervals; repeat injections were offered in the event of recurrence. Recurrence was defined as either a decrease of best-corrected visual acuity or an increase in macular oedema, subretinal fluid or intraretinal fluid on optical coherence tomography, after complete or partial resolution in previous follow-up visits. Patient data were collected for 12 months of follow up or until the patient's treatment was changed to ranibizumab. RESULTS: Significant improvement in visual acuity and central retinal thickness was demonstrated at 1 month with an improvement of vision from logMAR equivalent 0.76 to 0.68 (P < 0.001) and a decrease of central retinal thickness from 306 µm to 244 µm (P < 0.001). This overall improvement was continued throughout the 12-month follow-up period; however, follow up was poor with 12-month data available for only a small number of patients (7.8%). Ocular and systemic side-effects were rare at 3.5% and 0.4%, respectively. CONCLUSION: Eyes with neovascular AMD treated with intravitreal bevacizumab for up to 12 months had significant functional and anatomical improvement. Further studies need to confirm the long-term safety and efficacy of this treatment.

Traumatic rupture of the superior oblique muscle tendon resulting in acquired Brown's syndrome.

Traumatic rupture of the superior oblique tendon is a rare cause of acquired Brown's syndrome. This report describes a case of traumatic rupture of the superior oblique tendon, distal to the trochlea, after injury with a plant hook. The ruptured tendon was reapproximated. Postoperatively, asymptomatic Brown's syndrome developed, although residual function of the superior oblique muscle was retained. Full-thickness upper eyelid lacerations, especially those caused by a hook, must be explored carefully to exclude superior oblique tendon rupture. Careful reapproximation of the tendon can result in residual muscle function.

Genomic analysis of adult case of ocular surface giant congenital melanocytic nevus and associated clinicopathological findings.

INTRODUCTION: Conjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course. CASE DESCRIPTION: This is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely NRAS p.Gln61Arg. CONCLUSION: This is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

A Panel of Circulating MicroRNAs Detects Uveal Melanoma With High Precision.

PURPOSE: To determine if a circulating microRNA (miRNA) panel could be used to distinguish between uveal melanoma and uveal nevi. METHODS: We report on a multicenter, cross-sectional study conducted between June 2012 and September 2015. The follow-up time was approximately 3 to 5 years. Blood was drawn from participants presenting with a uveal nevus (n = 10), localized uveal melanoma (n = 50), or metastatic uveal melanoma (n = 5). Levels of 17 miRNAs were measured in blood samples of study participants using a sensitive real-time PCR system. RESULTS: A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma. Importantly, miR-211 was able to accurately distinguish metastatic disease from localized uveal melanoma (P < 0.0001; area under the curve = 0.96). When the six-miRNA panel was evaluated as a group it had the ability to identify uveal melanoma when four or more miRNAs (93% sensitivity and 100% specificity) reached or exceeded their cut-point. CONCLUSIONS: This miRNA panel, in tandem with clinical findings, may be suited to confirm benign lesions. In addition, due to the panel's high precision in identifying malignancy, it has the potential to augment melanoma detection in subsequent clinical follow-up of lesions with atypical clinical features. TRANSLATIONAL RELEVANCE: Uveal nevi mimic the appearance of uveal melanoma and their transformation potential cannot be definitively determined without a biopsy. This panel is most relevant at the nevus stage and in lesions with uncertain malignant potential as a companion diagnostic tool to assist in clinical decision-making.

Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma.

Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

Sutureless vitrectomy.

Sutureless vitrectomy has rapidly been accepted as an essential part of a vitreoretinal surgical setup. The size and structure of the wound along with near intact conjunctival covering makes the incision self-sealing and safe. This allows the vitrectomy instruments to be used without creating an initial limited peritomy to expose bare sclera, and obviates the need for sutures at the end of the procedure. Wound construction is the essential step in ensuring postoperative wound stability. Both one-step and two-step wound constructions have been described. Key points include an oblique, tunneled approach to ensure a valve-like effect as well as misalignment of conjunctival and scleral wounds by displacing conjunctiva during construction. Advantages include decreased operative times in certain cases and decreased postoperative inflammation, early postoperative rehabilitation, improved patient comfort, and minimal conjunctival damage. Complications are based around wound competence, hypotony, and its relationship to endophthalmitis rates. Early reports highlighted an increase in endophthalmitis though further studies are required to accurately assess the incidence. Endophthalmitis has not been reported in cases that underwent fluid/air exchange. This review focuses on techniques, benefits, complications, personal experiences, and the safety profiles of sutureless vitrectomy systems. A literature review was undertaken using 'Medline' and 'Pubmed'. Search terms included sutureless vitrectomy, 20 gauge, 23 gauge, 25 gauge, and transconjunctival and small gauge vitrectomy.

Delayed complications of silicone implants used in orbital fracture repairs.

PURPOSE: To report a series of patients who developed late complications secondary to silicone implants used in orbital fracture repairs and review the literature. DESIGN: Retrospective interventional case series. METHODS: Analysis of records of patients who developed complications following repair of orbital wall fractures with silicone implants. RESULTS: Over a 5-year period, 4 patients were seen with complications arising from a silicone orbital implant. There were 3 males and 1 female whose ages ranged from 41-73 years. The time interval between initial insertion of implant and development of complications was 1.5, 6, 10, and 20 years. The complications noted were worsening diplopia, recurrent orbital cellulitis, lower lid retraction with restricted upgaze, and orbital abscess. Computed tomographic scans demonstrated the implant in all cases. Histologic examination revealed nonspecific chronic inflammation and fibrosis in all cases and foci of squamous epithelium in one case. Treatment included surgical removal of the implant, resulting in complete resolution or significant improvement in symptoms and signs in all cases. CONCLUSION: The use of silicone implants is associated with a wide range of complications, which may occur many years following the original surgery. Surgical removal of the implant usually leads to resolution of symptoms. Given the potential of silicone implants to cause delayed complications, their use in orbital fracture repair is not recommended.

Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4.

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

A survey of visual impairment and blindness in children attending seven schools for the blind in Myanmar.

PURPOSE: To determine the causes of visual impairment and blindness amongst children in schools for the blind in Myanmar; to identify the avoidable causes of visual impairment and blindness; and to provide spectacles, low vision aids, orientation and mobility training and ophthalmic treatment where indicated. METHODS: Two hundred and eight children under 16 years of age from all 7 schools for the blind in Myanmar were examined and the data entered into the World Health Organization Prevention of Blindness Examination Record for Childhood Blindness (WHO/PBL ERCB). RESULTS: One hundred and ninety nine children (95.7%) were blind (BL = Visual Acuity [VA] < 3/60 in the better eye) and 3 had severe visual impairment (SVI = VA < 6/60 to 3/60 in the better eye). Most children had corneal abnormalities as the major anatomical site of SVI/BL (100, 49.5%), however the cause of SVI/BL was unknown in the majority (88, 43.6%). Measles keratitis was the commonest identifiable cause (17.4%) and 88 children had avoidable causes of SVI/BL (43.6%). Nearly 16% of children required an optical device and 24.2% required medical attention, with a potential for visual improvement through intervention in 15.8%. CONCLUSION: Nearly half of the children in schools for the blind in Myanmar had potentially avoidable causes of SVI/BL. With measles being both the commonest identifiable and commonest avoidable cause, the data supports the need for a measles immunization campaign. There is also a need for a dedicated pediatric eye care center with regular ophthalmology visits to the schools, and improved optometric, low vision and orientation and mobility services in Myanmar.

Orbital arteriovenous malformations.

OBJECTIVE: To present the clinical features, management, and outcomes in a series of patients with orbital arteriovenous malformations (AVMs). METHODS: Clinical records of patients with orbital AVMs confirmed using angiography were reviewed as a retrospective, noncomparative, interventional case series. RESULTS: Eight patients (3 women and 5 men) with unilateral AVMs and a mean age of 39 years (median, 36.5 years; range, 26-70 years) were reviewed. Findings existed for an average of 11.2 years before diagnosis and included periocular mass (7 patients, 88%); periocular edema, pulsation/bruit, proptosis, episcleral congestion, and previous trauma (4 patients each, 50%); elevated intraocular pressure (3 patients, 38%); pain and reduced visual acuity (2 patients each, 25%); and restriction of extraocular movements, and diplopia (1 patient each, 12%). All of the patients except 1 underwent surgical resection, with 3 (38%) receiving preoperative embolization of feeder vessels; all of the patients had initial resolution of manifestations after treatment. CONCLUSIONS: Angiography is essential for diagnosis and for planning the management of orbital AVMs. Treatment depends on patient-specific features and includes observation, embolization, and surgical excision or combined preoperative embolization/excision. Given their vascular nature, the main cause of poor management outcomes is perioperative hemorrhage. Outcomes after a multidisciplinary approach are good, with few recurrences reported at follow-up.