Asymmetric preservation of choroidal pigmentation simulating choroidal nevus in two siblings with Waardenburg syndrome type 2A.

INTRODUCTION: In addition to sensorineural hearing loss, Waardenburg Syndrome (WS) may present with variable pigmentation of skin and choroid, which may simulate other life-threating conditions (e.g. melanoma). CASE REPORT: Two siblings ostensibly presented with unilateral choroidal pigmentary abnormalities concerning for choroidal tumour. Serial ophthalmic examination documented no lesion growth (base or height) whilst the apparent syndromic features (i.e. iris hypochromia, profound sensorineural hearing loss, SNHL), family history (autosomal dominant inheritance) and positive genetic testing (pathogenic MITF variant) led to a revised diagnosis of Waardenburg Syndrome type 2A. CONCLUSION: Sectoral preservation of choroidal pigmentation in WS is rarely associated with choroidal malignancy. Awareness of syndromic features (e.g. SNHL) and access to genetic testing may facilitate early accurate diagnosis (i.e. allay concern for malignancy), enable treatment of modifiable features (e.g. SNHL) and identify other affected relatives.

Polarization-Diversity Optical Coherence Tomography Assessment of Choroidal Nevi.

Purpose: The purpose of this study was to demonstrate the utility of polarization-diversity optical coherence tomography (PD-OCT), a noninvasive imaging technique with melanin-specific contrast, in the quantitative and qualitative assessment of choroidal nevi. Methods: Nevi were imaged with a custom-built 55-degree field-of-view (FOV) 400 kHz PD-OCT system. Imaging features on PD-OCT were compared to those on fundus photography, auto-fluorescence, ultrasound, and non-PD-OCT images. Lesions were manually segmented for size measurement and metrics for objective assessment of melanin distributions were calculated, including degree of polarization uniformity (DOPU), attenuation coefficient, and melanin occupancy rate (MOR). Results: We imaged 17 patients (mean age = 69.5 years, range = 37-90) with 11 pigmented, 3 non-pigmented, and 3 mixed pigmentation nevi. Nevi with full margin acquisition had an average longest basal diameter of 5.1 mm (range = 2.99-8.72 mm) and average height of 0.72 mm (range = 0.37 mm-2.09 mm). PD-OCT provided clear contrast of choroidal melanin content, distribution, and delineation of nevus margins for melanotic nevi. Pigmented nevi were found to have lower DOPU, higher attenuation coefficient, and higher MOR than non-pigmented lesions. Melanin content on PD-OCT was consistent with pigmentation on fundus in 15 of 17 nevi (88%). Conclusions: PD-OCT allows objective assessment of choroidal nevi melanin content and distribution. In addition, melanin-specific contrast by PD-OCT enables clear nevus margin delineation and may improve serial growth surveillance. Further investigation is needed to determine the clinical significance and prognostic value of melanin characterization by PD-OCT in the evaluation of choroidal nevi.

Exceptional response to combination ipilimumab and nivolumab in metastatic uveal melanoma: Insights from genomic analysis.

Uveal melanoma is the most common intraocular malignancy and has a poor prognosis compared to other melanoma subtypes with a median overall survival of 6-10 months. With immune checkpoint inhibitor therapy, either PD-1 inhibitor alone or combination ipilimumab/nivolumab (anti-CTLA-4/anti-PD-1), responses are rare and often not durable. We present a case report of a now 66-year-old woman with diffuse metastatic uveal melanoma previously treated with a combination of ipilimumab/nivolumab, followed by maintenance nivolumab. Almost complete resolution of all sites of metastatic disease was observed except for one liver metastasis which regressed partially on immunotherapy. Notably, the patient had a significantly elevated BMI and developed widespread vitiligo on treatment. Whole-genome and transcriptome analysis was performed on the residual liver biopsy and molecular markers that may have contributed to the exceptional response were investigated. Several alterations were observed in genes involved in T-cell responses. Estimates of tumour infiltrating immune cells indicated a high level of plasma cells compared to other uveal melanoma cases, a finding previously associated with indolent disease. The patient also carried several germline SNPs that may have contributed to her treatment response as well as widespread vitiligo. Whole-genome and transcriptome sequencing have provided insight into potential molecular underpinnings of an exceptional treatment response in a tumour type typically associated with poor prognosis. Immunological findings suggest a role for plasma cells in the tumour microenvironment. Elevated BMI and the development of vitiligo may be clinically relevant factors for predicting response to immune checkpoint inhibitor therapy, warranting further studies in patients with uveal melanoma.

The Retinoblastoma Research Booklet: A Catalyst for Patient Involvement in Retinoblastoma Research.

Peer-to-peer recruitment efforts are important in generating interest and participation of patients as partners in research but difficult to sustain when face-to-face interactions are limited. The Retinoblastoma Research and You! booklet, co-developed by patients, researchers and health professionals, serves as a guide for patient engagement in research while retaining an element of personalization. The Retinoblastoma Research and You! booklet was developed through two virtual workshops to iterate and finalize the booklet design and content. The booklet outlines how individual patients' lived experiences and skills can influence retinoblastoma research and highlights real-world examples of patient-partnered research activities at different stages of the research process.

Trends in Radiation Practices for Female Ocular Oncologists in North America: A Collaborative Study of the International Society of Ocular Oncology.

BACKGROUND: The aim of this study was to determine the known radiation exposure, attitudes, and consequent risk modifications among female ocular oncologists in North America who routinely administer radioactive plaque brachytherapy treatment and are members of the International Society of Ocular Oncology. METHODS: Nineteen female ocular oncologists completed an anonymous 17-question radiation exposure survey. RESULTS: Eleven of the participants chose to routinely wear lead protection during surgery; 8 did not. Fifteen of 19 participants reported using an unloaded "nonactive" template to prepare for plaque implantation. During pregnancy, 11 of 13 participants continued to perform plaque brachytherapy. Eight of these 11 undertook measures to decrease radiation exposure self-reported as lead wear and other. The average reported anxiety regarding fertility was 2.1 (SD, 2.2) on a scale from 1 to 10. CONCLUSION: This study corroborates prior literature that surgeons' exposure to radiation during plaque brachytherapy is minimal. Nonetheless, there remains some anxiety regarding exposure risk to women, due to potential effects on fertility and fetal health. We found variability in exposure monitoring, required training, and precautions during pregnancy amongst this group of surgeons. Improved education and clearer pregnancy guidelines may equip female ocular oncologists with optimal knowledge regarding risk of radiation exposure.

Outcomes of Proton Beam Radiotherapy for Large Non-Peripapillary Choroidal and Ciliary Body Melanoma at TRIUMF and the BC Cancer Agency.

BACKGROUND AND PURPOSE: To report outcomes and toxicity after proton beam radiotherapy for non-peripapillary choroidal and ciliary body melanoma considered unsuitable for other eye-sparing therapies. MATERIALS AND METHODS: An existing database of 77 patients with non-peripapillary tumors treated at TRIUMF, Canada, including patient, tumor, and treatment characteristics, was updated with ocular complications and follow-up status from chart reviews. RESULTS: Most of the patients had large tumors: 61% were T3/T4 tumors (AJCC classification), while 48% were large by the Collaborative Ocular Melanoma Study classification. The median thickness was 7.1 mm, and the ciliary body was involved in 35%. After 5 and 10 years, the actuarial ocular tumor control rate was 85 and 85%, metastasis-free survival was 72 and 57%, overall survival was 77 and 63%, the enucleation rate was 22 and 22%, and complete blindness was found in 38 and 38%, respectively. On univariate analysis, patients with ciliary body involvement had significantly worse metastasis-free survival and overall survival rates compared to patients without ciliary body involvement (p < 0.001). CONCLUSIONS: Proton therapy for large anteriorly located tumors resulted in acceptable ocular tumor control and survival rates. The risk of blindness and severe toxicity requiring enucleation was low, and a substantial proportion of patients maintained useful vision.

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies.

BACKGROUND: Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. METHODS: Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1(+/+)) with tumours carrying a mutation in both alleles (RB1(-/-)). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. FINDINGS: No RB1 mutations (RB1(+/+)) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1(+/+) tumours had high-level MYCN oncogene amplification (28-121 copies; RB1(+/+)MYCN(A)), whereas none of 93 RB1(-/-) primary tumours tested showed MYCN amplification (p<0·0001). RB1(+/+)MYCN(A) tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1(-/-) tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1(+/+)MYCN(A) retinoblastoma. One additional MYCN(A) tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1(+/+)MYCN(A) tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1(-/-) retinoblastoma. INTERPRETATION: Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1(+/+)MYCN(A) retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. FUNDING: National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.

Outcomes of proton radiation therapy for peripapillary choroidal melanoma at the BC Cancer Agency.

PURPOSE: To report toxicity, local control, enucleation, and survival rates for patients with peripapillary choroidal melanoma treated with proton therapy in Canada. METHODS AND MATERIALS: We performed a retrospective analysis of patients with peripapillary choroidal melanoma (≤ 2 mm from optic disc) treated between 1995 and 2007 at the only Canadian proton therapy facility. A prospective database was updated for follow-up information from a chart review. Descriptive and actuarial data are presented. RESULTS: In total, 59 patients were treated. The median age was 59 years. According to the 2010 American Joint Committee on Cancer TNM classification, there were 20 T1 tumors (34%), 28 T2 tumors (48%), and 11 T3 tumors (19%). The median tumor diameter was 11.4 mm, and the median thickness was 3.5 mm. Median follow-up was 63 months. Nineteen patients received 54 cobalt gray equivalents (CGE) and forty patients received 60 CGE, each in 4 fractions. The 5-year actuarial local control rate was 91% (T1, 100%; T2, 93%; and T3, 59%) (p = 0.038). There was a suggestive relationship between local control and dose. The local control rate was 97% with 60 CGE and 83% with 54 CGE (p = 0.106). The metastasis-free survival rate was 82% and related to T stage (T1, 94%; T2, 84%; and T3, 47%) (p < 0.001). Twelve patients died, including eleven with metastases. The 5-year actuarial rate of neovascular glaucoma was 31% (23% for T1-T2 and 68% for T3, p < 0.001), and that of enucleation was 0% for T1, 14% for T2, and 72% for T3 (p < 0.001). Radiation retinopathy (74%) and optic neuropathy (64%) were common within-field effects. CONCLUSIONS: Proton therapy provides excellent local control with acceptable toxicity while conserving the globe in 80% of cases. These results are consistent with other single-institution series using proton radiotherapy, and toxicity rates were acceptable. T3 tumors carry a higher rate of both local recurrence and metastasis.

Intraocular lens power calculations after myopic laser refractive surgery: a comparison of methods in 173 eyes.

PURPOSE: To evaluate and compare published methods of intraocular lens (IOL) power calculation after myopic laser refractive surgery in a large, multi-surgeon study. DESIGN: Retrospective case series. PARTICIPANTS: A total of 173 eyes of 117 patients who had uneventful LASIK (89) or photorefractive keratectomy (84) for myopia and subsequent cataract surgery. METHODS: Data were collected from primary sources in patient charts. The Clinical History Method (vertex corrected to the corneal plane), the Aramberri Double-K, the Latkany Flat-K, the Feiz and Mannis, the R-Factor, the Corneal Bypass, the Masket (2006), the Haigis-L, and the Shammas.cd postrefractive adjustment methods were evaluated in conjunction with third- and fourth-generation optical vergence formulas, as appropriate. Intraocular lens power required for emmetropia was back-calculated using stable post-cataract surgery manifest refraction and implanted IOL power, and then formula accuracy was compared. MAIN OUTCOME MEASURES: Prediction error arithmetic mean ± standard deviation (SD), range (minimum and maximum), and percent within 0 to -1.0 diopters (D), ±0.5 D, ±1.0 D, and ±2.0 D relative to target refraction. RESULTS: The top 5 corneal power adjustment techniques and formula combinations in terms of mean prediction errors, standard deviations, and minimizing hyperopic "refractive surprises" were the Masket with the Hoffer Q formula, the Shammas.cd with the Shammas-PL formula, the Haigis-L, the Clinical History Method with the Hoffer Q, and the Latkany Flat-K with the SRK/T with mean arithmetic prediction errors and standard deviations of -0.18±0.87 D, -0.10±1.02 D, -0.26±1.13 D, -0.27±1.04 D, and -0.37±0.91 D, respectively. CONCLUSIONS: By using these methods, 70% to 85% of eyes could achieve visual outcomes within 1.0 D of target refraction. The Shammas and the Haigis-L methods have the advantage of not requiring potentially inaccurate historical information.

Intravitreal bevacizumab for iris neovascularization following proton beam irradiation for choroidal melanoma.

OBJECTIVE: To evaluate the safety and efficacy of intravitreal injections of bevacizumab as an eye-sparing treatment for iris neovascularization (NVI) following proton beam irradiation for choroidal melanoma. DESIGN: Retrospective interventional case series. PARTICIPANTS: Four patients who received intravitreal bevacizumab for NVI following proton beam irradiation for choroidal melanoma were identified in the Department of Ophthalmology archives at the University of British Columbia. METHODS: Clinical details were reviewed. Long-term follow-up of more than 2 years was detailed for each case. RESULTS: All 4 patients responded to a single injection of bevacizumab with regression of NVI. Neovascular glaucoma (NVG) was evident in 3 cases, 2 of which had stable intraocular pressure following treatment. NVI recurred following a single injection in all patients after an interval ranging from 1 month to 12 months. A longer period of regression was seen in patients with fewer systemic neovascular risk factors and earlier treatment. CONCLUSIONS: Regression of NVI following proton beam irradiation for choroidal melanoma was seen in all treated patients. Repeated treatments may be required to maintain regression of new vessels. This treatment modality may be a useful eye-sparing adjunct in the prevention and treatment of NVG following proton beam irradiation.

Histopathologic features of multiple myeloma involving the optic nerves.

We report a case of optic nerve involvement by multiple myeloma in which progressive visual loss heralded leukemic transformation and intracranial involvement. Imaging showed enhancing nodules in the intracranial segments of both optic nerves posterior to the optic canals and in the anterior optic tract, optic chiasm, and basal leptomeninges. Postmortem histopathologic examination disclosed malignant plasma cells in the subarachnoid spaces around the optic nerves and in the optic nerves. Infarctions were present in both optic nerves near their junction with the globes. Microscopic examination also showed malignant plasma cell infiltration of the leptomeninges of the cerebrum, brain stem, optic chiasm, pituitary gland, cranial bone marrow, and subarachnoid blood vessels. This is the first reported histopathologic examination in conjunction with MRI of multiple myeloma involving the anterior visual pathway. The mechanism of optic neuropathy in this case is probably related to infiltration of the optic nerve meninges by malignant plasma cells and impaired vascular supply caused by aggregated intraluminal plasma cells and monoclonal hypergammaglobulinemia.