Werner Wackernagel

Mutations in GNA11 in Uveal Melanoma

BACKGROUND Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. METHODS We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. RESULTS We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. CONCLUSIONS Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).

Germline mutations in BAP1 predispose to melanocytic tumors

Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1, which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Opacification of a silicone intraocular lens caused by calcium deposits on the optic

We describe opacification of a plate-haptic silicone intraocular lens (IOL) caused by calcification in a diabetic patient with asteroid hyalosis. The IOL was explanted 48 months after uneventful phacoemulsification because opacification of the posterior surface was causing significant visual disturbance. Light and scanning electron microscopy and x-ray spectrometry of the explanted IOL showed the opacification consisted mainly of calcium and phosphate, presumably hydroxyapatite, in the form of precipitations on the posterior surface of the optic.

A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity.

Introduction Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors. Methods The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library. Results This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents. Discussion VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed.

Ocular Trauma Scores in paediatric open globe injuries

Background/aims To assess the predictive value and the applicability of Ocular Trauma Score (OTS) for paediatric injuries. Methods Retrospective case series of 71 open globe injuries in children less than 18 years of age with a minimum follow-up period of 1 year. The variables of the OTS, the Paediatric Penetrating OTS (POTS), lens injuries and anterior versus posterior segment injuries were analysed for their predictive values in terms of visual outcome. The applicability and the predictive values of OTS and POTS as a whole were then evaluated. Results Initial visual acuities, retinal detachments, wound locations (p<0.001 each), lens injuries (p=0.001), posterior segment injuries (p=0.002), traumatic cataracts (p=0.010), hyphaema (p=0.011) and vitreous haemorrhages (p=0.026) had significant impacts on visual outcome. The application of OTS proved difficult, as the presence of a mild degree of a relative afferent pupillary defect (RAPD) could not accurately be evaluated in all of our patients. Calculating the OTS without evaluation of RAPD renders it easily applicable for the initial examinations while remaining significantly prognostic (p<0.001). The predictions of the POTS correlated with the actual final visual acuities (p<0.001), but several POTS variables (ie, iris prolapse, age, organic injuries and delay of surgery >48 h) had only limited impacts on visual outcome. Conclusions The OTS has a high predictive value for visual outcome after open globe injuries in children, even without evaluation of RAPD.

Circadian Macular Volume Changes in the Healthy Human Choroid

PURPOSE To investigate a potential circadian fluctuation of the choroidal volume in healthy adults by enhanced depth imaging (EDI) via spectral-domain optical coherence tomography (SD OCT). DESIGN Prospective observational case series. METHODS Thirty healthy eyes of 15 healthy subjects with a median age of 26 years (range 22-55) underwent EDI SD OCT scans for macular choroidal volume measurement every 3 hours within a 24-hour period at a single tertiary center. The mean ocular perfusion pressure was calculated for each eye at each of the 8 time points as 2/3(mean arterial pressure-intraocular pressure [IOP]). The circadian fluctuation of the macular choroidal volume as well as the association with axial length, mean ocular perfusion pressure, or IOP was assessed using a linear mixed model. RESULTS Macular choroidal volume showed a significant circadian fluctuation (P < .05) and was lowest at midday (mean ± SD, 10.14 ± 2.62 mm(3)) and highest at 3 AM (mean ± SD, 10.66 ± 2.70 mm(3)). Of all factors tested, only mean ocular perfusion pressure showed a significant association with macular choroidal volume fluctuation (P = .016). CONCLUSIONS Macular choroidal volume shows a significant circadian pattern with higher values at night and lower values during the day in young adults. Besides time, mean ocular perfusion pressure is significantly associated with this fluctuation.

Ozurdex® reduces the retinal thickness in radiation maculopathy refractory to bevacizumab

pathognomonic for classic WD. He was diagnosed with kidney sarcoidosis before the WD diagnosis and was pharmacologically immunosuppressed. After the patient had his first cataract surgery performed, a severe mostly posterior uveitis was diagnosed. It did not respond to neither topical nor systemic immunosuppressive treatment. Case reports have described uveitis after intraocular operations in patients unknown to have WD, only diagnosed later on by vitreous samples. It is uncertain whether it is the operation in itself or the use of post-operative topical steroids that provokes the development of uveitis in these WD patients (Drancourt et al. 2009). In parallel with the eye problems, the patient developed significant neurological symptoms indicating involvement of the brain. WD is a fascinating disease entity with a wide range of clinical manifestations and has been considered to be an extremely rare disease (Raoult et al. 2000). This makes it difficult for clinicians to identify cases, especially the non-classic cases, with more atypical symptoms and findings. New data indicate that Tropheryma whipplei is ubiquitous in the environment (Maiwald et al. 1998). Clinicians treating patients with diffuse symptoms involving the brain and the eyes should not forget about this very rare disease which can be treated effectively with antibiotics.

Visual acuity after Gamma-Knife radiosurgery of choroidal melanomas

Background/aims To report on conservation of visual acuity after Gamma-Knife radiosurgery of choroidal melanoma. Methods A total of 189 patients with choroidal melanoma were treated with Gamma-Knife stereotactic single-fraction radiosurgery at a single institution between June 1992 and May 2010. The main outcome measure of our retrospective analysis was conservation of pretreatment visual acuity of 20/40 or better, 20/200 or better and counting fingers (CF) or better, over time of follow-up. Patient, tumour and treatment parameters were evaluated as potential risk factors for visual loss. Results Five years after treatment, the actuarial probability of keeping visual acuity better than 20/40, 20/200 and CF was 13%, 14% and 36%, respectively. The majority of patients (84.7%) encountered a deterioration of vision after treatment. The most important risk factors for visual loss were tumour height, longest basal diameter, distance to the optic disk and/or foveola, and retinal detachment before treatment. Treatment dose, and patient characteristics (age, sex, concurrent systemic diseases) were less important. Local tumour control rate was 94.4% after a median follow-up of 39.5 months. Conclusions Visual outcome after single-fraction Gamma-Knife radiotherapy is comparable with linear accelerator (LINAC) based fractionated stereotactic radiotherapy, inferior to proton beam radiotherapy, and depends primarily on tumour size, location and pre-existing retinal detachment.

Influence of single-fraction Gamma-Knife radiosurgery on ocular surface and tear function in choroidal melanoma patients

Aim To evaluate ocular surface and tear function in patients with choroidal melanoma treated with single-fraction radiosurgery. Methods 36 patients (median age 62 years; range 26–84 years) were enrolled between 2001 and 2006 at a single institution. They were treated with the Leksell Gamma Knife in one fraction with a median dose of 30 Gy (range 25–35 Gy). In both eyes of all patients treated subjective symptom score (visual analogue scale) was evaluated, central corneal sensitivity testing, Schirmer test without local anaesthesia, and corneal and conjunctival staining were performed before therapy and 3, 6, 12, 24 and 36 months thereafter. The respective untreated fellow eye served as control. Results Three months after radiosurgery, the subjective dry eye symptom score and lissamine green staining score of the ocular surface were significantly higher in the treated eyes compared with the fellow eyes (p<0.001, p=0.028, respectively). After 12 months, a significant difference between the treated and the fellow eyes in corneal sensitivity (p=0.041) and corneal fluorescein staining (p=0.002) was found when compared with pretreatment values. After 24 months Schirmer test values without local anaesthesia were significantly reduced in the treated eyes vis-à-vis untreated fellow eyes and pretreatment values (p=0.004). The dose applied to the lacrimal gland was significantly correlated to ocular surface staining scores (p=0.001) and Schirmer test values (p=0.026) at 24 months after irradiation. Conclusions Stereotactic single-fraction Gamma-Knife radiotherapy of choroidal melanoma with a median dose of 30 Gy significantly affected ocular surface and tear function and increased dry eye symptoms and signs.

Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas

Background/aims To report on local tumour control and eye preservation after gamma knife radiosurgery (GK-RS) to treat choroidal melanomas. Methods A total of 189 patients with choroidal melanoma were treated with GK-RS, with treatment doses between 25 and 80 Grays. The main outcome measures of our retrospective analysis were local tumour control, time to recurrence, eye retention rate and the reason for and time to secondary enucleation. Patient-associated, tumour-associated and treatment-associated parameters were evaluated as potential risk factors. Results Local tumour control was achieved in 94.4% of patients. The estimated tumour control rates were 97.6% at 1 year, 94.2% at 5 years and 92.4% at 10 years after treatment. Recurrence was observed between 3.1 months and 60.7 months post-treatment (median: 13.5 months). Advanced tumour stage (Tumour, Node, Metastasis (TNM) 3–4) was the most important risk factor for recurrence (Fine-Gray model; subhazard ratio, SHR: 3.3; p=0.079). The treatment dose was not related to tumour recurrence. The eye preservation rate was 81.6% at 5 years after treatment, remaining stable thereafter. Twenty-five eyes (14.1%) had to be enucleated at between 17 days and 68.0 months (median: 13.9 months) after GK-RS, and advanced tumour stage (Cox model; p=0.005), treatment dose (p=0.048), pretreatment visual acuity (p=0.016), and retinal detachment (p=0.027) were risk factors for requiring enucleation. Conclusions GK-RS achieved a high tumour control rate, comparable to linear accelerator-based radiotherapy. Advanced TNM stage was a predictive risk factor for tumour recurrence and for secondary enucleation after GK-RS. Lower treatment doses were unrelated to tumour recurrence, although they were associated with an improved eye retention rate.