Brachytherapy of Choroidal Melanomas Less Than 10 mm in Largest Basal Diameter: Comparison of 10-mm and 15-mm Ruthenium Plaques.

PURPOSE: To compare tumor control, vision, and complications between patients with a choroidal melanoma of <10 mm in largest basal diameter (LBD) irradiated with 10-mm or 15-mm ruthenium plaques. DESIGN: Retrospective, comparative case series. PARTICIPANTS: One hundred sixty-four consecutive patients with a choroidal melanoma of <10 mm in LBD, 76 and 88 treated with the 10-mm and 15-mm plaque, respectively, from 1998-2014 in a national ocular oncology service. METHODS: Diagnosis was based on growth or high-risk characteristics. The apical dose was 100 to 120 Gy aiming to deliver ≥250 Gy to the sclera. Plaque positioning was modeled retrospectively. An increase of ≥0.3 mm in thickness and ≥0.5 mm in LBD indicated local recurrence. Outcomes were compared with cumulative incidence analysis and Cox regression. Median follow-up time for patients still alive was 8.4 years. MAIN OUTCOME MEASURES: Recurrence rate, low vision, blindness, radiation maculopathy, and optic neuropathy. RESULTS: Melanomas treated with the 10-mm plaque were smaller (median thickness, 1.9 mm vs. 2.6 mm; LBD, 7.1 mm vs. 8.6 mm) and located closer to foveola (median, 2.0 mm vs. 2.8 mm) than those treated with the 15-mm plaque (P < 0.001). The 2 plaques provided a safety margin in 43% versus 40% eyes, provided no safety margin to guard foveola in 17% versus 33%, and did not entirely cover tumor mainly close to the disc in 32% versus 18% of eyes, respectively (P = 0.052). The incidence of a local recurrence was comparable (13% vs. 15% at 10 years; P = 0.31) and associated with plaque positioning (hazard ratio [HR], 2.81 for no safety margin; P = 0.041). At 5 years, the incidence of low vision was 14% versus 24%, and that of blindness was 3% versus 6%. Distance to the foveola was associated with loss of both levels of vision (HR, 0.65 per 1 mm vs. 0.68 per 1 mm; P ≤ 0.001 vs. P = 0.004). The incidence of radiation maculopathy was comparable (19% vs. 18% at 5 years), whereas that of optic neuropathy tended to be higher with the 15-mm plaque (2% vs. 9%; P = 0.054). CONCLUSIONS: The 10-mm ruthenium plaque contributes to better visual preservation, particularly with tumors close to fovea, without increase in local recurrence rate, and may therefore be preferable to the 15-mm plaque.

Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma.

Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1-associated protein 1 (BAP1). Recently, germline and somatic loss-of-function (LOF) variants in the methyl-CpG-binding domain 4 (MBD4) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.

Population-based analysis of BAP1 germline variations in patients with uveal melanoma.

Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish-Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3' UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS.

A novel transthyretin Lys70Glu (p.Lys90Glu) mutation presenting with vitreous amyloidosis and carpal tunnel syndrome.

OBJECTIVE: We describe a novel TTR mutation with vitreous opacities and carpal tunnel syndrome. MATERIALS AND METHODS: A 78 year-old woman with vitreous opacities, her daughter with dry eye syndrome, and brother with carpal tunnel syndrome were tested for a mutation in the TTR gene. The vitreous opacities were removed and stained with Congo red and immunohistochemistry against wild type TTR. Skin and gut biopsies and specimens of soft tissue were examined histopathologically. Leukocyte DNA from the proband was analysed by direct sequencing of exons 1 to 4 of the TTR gene and DNA from her daughter and brother using segregation analysis. RESULTS: A point mutation c.268 A>C, in the TTR gene, leading to a missense mutation p.Lys90Glu was found in all subjects. The vitreous opacities were pearl string-like. Histopathology showed red to green birefringence in Congo red, typical to amyloid, and the specimens were immunoreactive with antibodies against TTR. CONCLUSION: We present a novel autosomally inherited Lys90Glu mutation in the TTR gene. This is the first reported FAP family with this mutation in Finland.

BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma.

PURPOSE: Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish patients with uveal melanoma who live in a high-risk region for this cancer. DESIGN: Cohort study. PARTICIPANTS: In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives. METHODS: Sequencing BAP1. MAIN OUTCOME MEASURES: Pathogenic variants in BAP1. RESULTS: We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma. CONCLUSIONS: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.

Cyclophotocoagulation with the transscleral contact red 670-nm diode laser in the treatment of glaucoma.

PURPOSE: To retrospectively evaluate the results of cyclophotocoagulation (CPC) with the transscleral contact red 670-nm diode laser in treating glaucoma. METHODS: Cyclophotocoagulation was performed in 60 eyes of 60 patients with a mean age of 74 +/- 11 years (range 49-90 years). The treatment was delivered via a fibre-optic probe. The power per application was 430 mW. Exposure time was 10 seconds. RESULTS: The mean overall follow-up time after the initial CPC was 26 +/- 20 months (range 3-75 months). Preoperative intraocular pressure (IOP) was 27 +/- 11 mmHg (n = 60). After one or more CPC treatments, mean IOP decreased to 20 +/- 7 mmHg (n = 51) at 1 month, 19 +/- 5 mmHg (n = 45) at 3 months, 18 +/- 5 mmHg (n = 29) at 6 months, 19 +/- 7 mmHg (n = 22) at 1 year, 18 +/- 7 mmHg (n = 16) at 2 years, 14 +/- 4 mmHg (n = 8) at 3 years, and 18 +/- 6 mmHg (n = 60) at the last follow-up. An IOP of 8-21 mmHg or a > 30% decrease in IOP was obtained in 33 of 41 eyes (80%) with baseline IOP > 21 mmHg at the last follow-up. Hypotonia (IOP < 8 mmHg) did not develop in any of the eyes studied. CONCLUSIONS: Cyclophotocoagulation with the red 670-nm diode laser is an effective and well tolerated means of treating glaucoma.

Transscleral red-laser cyclophotocoagulation combined with limited anterior retinal cryocoagulation in neovascular glaucoma.

PURPOSE: To evaluate transscleral contact red-laser cyclophotocoagulation (CPC), using a visible red 647-nm krypton or 670-nm diode laser and limited transscleral anterior retinal cryocoagulation in neovascular glaucoma. METHODS: In a retrospective case series, 35 eyes of 35 consecutive patients treated during a period of 6 years were included in the study. Inclusion was dependent on follow-up of at least 1 month. Patients who had undergone previous cyclodestructive procedures and patients who received an additional glaucoma operation in conjunction with CPC were excluded. In the combined procedure, the power per CPC application was 370-450 mW and exposure time was 10 seconds. One to two rows of cryoapplications were given to 360 degrees of the anterior retina. RESULTS: The success rate in terms of intraocular pressure (IOP of 8-21 mmHg or a decrease in IOP > 30%) was 89% at the last follow-up (17 +/- 15 months). Iris neovascularization regressed in 51% of eyes. Hypotonia developed in one (3%) eye (IOP of 5 mmHg). No cases of phthisis bulbi were seen. Visual acuity (VA) declined in 49% of eyes. CONCLUSIONS: A combination of transscleral contact red-laser CPC with limited anterior retinal cryocoagulation is efficient in lowering IOP in neovascular glaucoma and is well tolerated. During follow-up, a decrease in VA occurs in a significant proportion of patients.

Fungal endophthalmitis caused by Paecilomyces variotii following cataract surgery: a presumed operating room air-conditioning system contamination.

PURPOSE: To report a case of delayed fungal endophthalmitis by Paecilomyces variotii following uncomplicated cataract surgery. To our knowledge this is the first reported case of postoperative endophthalmitis by this species. METHODS: We report the longterm clinical follow-up of an 83-year-old female who underwent uncomplicated sutureless, small-incision cataract surgery. She developed recurring uveitis 4 months after surgery. Vitreous tap and finally complete vitrectomy with removal of the capsular bag including the intraocular lens were performed. Fungi were studied by histopathology and culture. RESULTS: At histopathological examination, the fungi were found to be closely related with the capsular bag. A few mononuclear inflammatory cells were encountered. At culture, Paecilomyces variotii, a common ubiquitous non-pathogenic saprophyte, was identified. Despite systemic, intravitreal and topical antifungal therapy after vitrectomy the uveitis recurred several times, but no fungal organisms were isolated from the repeat intraocular specimen. At 18 months postoperatively the subject's visual acuity was finger counting at 2 metres. At the time of surgery the operating room air-conditioning system was undergoing repairs. Cases of fungal endophthalmitis after contamination from air-conditioning ventilation systems have been reported before, but none of the cases reported have been caused by P. variotii. CONCLUSION: P. variotii, a non-pathogenic environmental saprophyte, may be disastrous if introduced into the eye. International recommendations on the environmental control of the operating room air-conditioning ventilation system should be strictly followed. No intraoperative surgery should be undertaken while the air-conditioning system is undergoing repairs or service.

Corneal innervation, corneal mechanical sensitivity, and tear fluid secretion after transscleral contact 670-nm diode laser cyclophotocoagulation.

PURPOSE: To examine the effect of 670-nm diode laser cyclophotocoagulation on corneal morphology, density of corneal subbasal nerves, corneal mechanical sensitivity, and the rate of tear fluid secretion in human eyes. PATIENTS AND METHODS: Transscleral contact cyclophotocoagulation was performed in 10 eyes of 10 consecutive patients on 180 degrees of the pars plicata of the ciliary body, using a 670-nm diode laser (power = 430 mW, application time = 10 seconds). In vivo confocal microscopy, with special attention to corneal morphology and the density of the subbasal nerves in the central and inferior perilimbal cornea, was performed preoperatively, and at 3 days and 1 month postoperatively. Corneal mechanical sensitivity was tested preoperatively, and at 3 days and 1 month postoperatively, using a Cochet-Bonnet esthesiometer. The rate of tear fluid secretion was measured preoperatively and 1 month postoperatively, using the Schirmer basic secretion tear test with topical anesthesia. RESULTS: After cyclophotocoagulation, in vivo confocal microscopy did not reveal any changes in any of the corneal layers or in the corneal subbasal nerves. After treatment, as compared with baseline (paired samples test, > 0.05), there was no statistically significant change in the mechanical sensitivity values in any part of the cornea or in the Schirmer basic secretion tear test result. CONCLUSION: The results of this preliminary study suggest that cyclophotocoagulation with the 670-nm diode laser does not impair corneal innervation.