Proton beam radiotherapy for choroidal and ciliary body melanoma in the UK-national audit of referral patterns of 1084 cases.

INTRODUCTION: Proton beam therapy has been utilised for the treatment of uveal melanoma in the UK for over 30 years, undertaken under a single centre. In the UK, all ocular tumours are treated at one of four centres. We aimed to understand the variation in referral patterns to the UK proton service, capturing all uveal melanoma patients treated with this modality. METHODS: Retrospective analysis of data regarding all patients treated at the Clatterbridge Proton service between January 2004 and December 2014. RESULTS: A total of 1084 patients with uveal melanoma were treated. The mean age was 57 years (range 9-90 years), basal diameter of 11.5 mm (range 2.0-23.4 mm) and tumour thickness of 3.9 mm (range 0.1-15.4 mm). The majority were TNM stage I (39%) or II (36%). The distance to the optic nerve varied from 0 to 24.5 mm with 148 (14%) of patients having ciliary body involvement. There were variations in the phenotypic characteristic of the tumours treated with protons from different centres, with London referring predominantly small tumours at the posterior pole, Glasgow referring large tumours often at the ciliary body and Liverpool sending a mix of these groups. DISCUSSION: In the UK, common indications for the use of proton treatment in uveal melanoma include small tumours in the posterior pole poorly accessible for plaque treatment (adjacent to the disc), tumours at the posterior pole affecting the fovea and large anterior tumours traditionally too large for brachytherapy. This is the first UK-wide audit enabling the capture of all patients treated at the single proton centre.

Patient understanding of genetic information influences reproductive decision making in retinoblastoma.

BACKGROUND: Retinoblastoma is the most common malignant tumour of the eye in childhood, with nearly all bilateral tumours and around 17% to 18% of unilateral tumours due to an oncogenic mutation in the RB1 gene in the germline. Genetic testing enables accurate risk assessment and optimal clinical management for the affected individual, siblings, and future offspring. MATERIAL AND METHODS: We carried out the first UK-wide audit of understanding of genetic testing in individuals with retinoblastoma. A total of 292 individuals aged 16 to 45 years were included. RESULTS: Patients with bilateral disease were significantly more likely to understand the implications of retinoblastoma for siblings and children. There was a significant association between not knowing the results of genetic testing or not understanding the implications and not having children, particularly in women. Surprisingly, this was also true for individuals treated for unilateral disease with a low risk of retinoblastoma for their offspring. CONCLUSION: We are concerned that individuals may be making life choices based on insufficient information regarding risks of retinoblastoma and reproductive options. We suggest that improvement in transition care is needed to enable individuals to make informed reproductive decisions and to ensure optimal care for children born at risk of retinoblastoma.

Primary photodynamic therapy with verteporfin for small pigmented posterior pole choroidal melanoma.

PurposeThe purpose of the study was to investigate the outcomes of primary photodynamic therapy (PDT) for small pigmented posterior pole choroidal melanoma.Patients and methodsProspective interventional consecutive case series of 15 patients with small pigmented posterior pole choroidal melanoma, who were treated with three sessions of PDT and followed-up thereafter. Risk factors for failure were assessed and outcome measures at presentation were compared to those at last follow-up visit.ResultsTumor control was achieved in 12 (80%) patients in a median follow-up time of 15 months (mean 14, range 8-18). Three patients failed treatment, diagnosed in a median time of 5 months (mean 4, range 3-6), after first PDT. In all failed cases, lesions were 100% pigmented; de novo melanoma rather than transformed nevi and showed a radial growth pattern rather than increased thickness. All failed cases were subsequently successfully treated with radiotherapy. In this cohort, subretinal fluid (SRF) was significantly reduced (P<0.001), vision did not deteriorate (P=0.11) and even improved in patients with subfoveal SRF at presentation (P=0.018), tumor height significantly decreased (P=0.037) and no complications were recorded.ConclusionPrimary PDT was found to be a safe and efficient treatment modality for small pigmented posterior pole choroidal melanoma, achieving short-term tumor control in 80% of patients. PDT offers patients the opportunity to preserve vision by avoiding the retinopathy associated with conventional radiation treatments for choroidal melanoma. However, the long-term local control of these tumors remains uncertain.

Intravitreal bevacizumab monotherapy for choroidal neovascularisation secondary to choroidal osteoma.

PurposeThe purpose of this study is to present the outcomes of a series of patients with choroidal neovascular membrane (choroidal neovascularisation (CNV)) secondary to a choroidal osteoma undergoing anti-VEGF monotherapy.Patients and methodsRetrospective series of patients with choroidal neovascularization secondary to choroidal osteoma. All patients underwent clinical and imaging assessment (fundus photo, B-scan ultrasonography, fluorescein angiography, and optical coherence tomography-where available), and were managed with intravitreal anti-VEGF injections (Bevacizumab). Visual acuity and central retinal thickness were recorded pre treatment and at the end of the follow-up period.ResultsEight patients were included in this study. Of this, 6/8 had predominantly classic or classic and 2/8 patients had minimally classic or occult CNV. Each patient received 3-10 injections of bevacizumab. Median follow-up was 9 months (3-15 months). Visual acuity improved in 5 patients, by 2-6 Snellen lines. CNV completely regressed in 5 cases and partially regressed in 3 cases. Mean CRT reduction was 122 µm (6 to -230 µm).ConclusionIntravitreal bevacizumab can be an effective treatment modality in the management of vision threatening CNV secondary to choroidal osteoma.

Combined PKC and MEK inhibition for treating metastatic uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma. UM has a strong tendency for metastatic disease, and no effective treatments have yet been identified. Activating oncogenic mutations are commonly found in GNAQ and GNA11 in UM, and inhibiting key downstream effectors of the GNAQ/11 signaling pathway represents a rational therapeutic approach for treating metastatic UM. Chen et al., doi:10.1038/onc.2013.418, now confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes, and they demonstrate that MAPK activation occurs downstream of PKC activation. PKC inhibitors disrupt MAPK signaling and block proliferation of GNAQ/11 mutant UM cell lines and slow the in vivo growth of xenografted UM tumors without inducing their shrinkage. However, a combination of PKC and MEK inhibition led to sustained MAPK pathway inhibition and tumor regression in vivo. Hence, the authors concluded that MEK and PKC inhibition is synergistic, with superior efficacy to treatment of GNAQ/GNA11 mutant UMs with either drug alone.

Intravitreal anti-VEGF treatment in eyes with combined choroidal neovascularisation and vitreomacular traction syndrome.

PURPOSE: To report the effect of intravitreal anti-vascular endothelial growth factor injections (IVI) on visual acuity in eyes with choroidal neovascularisation (CNVM) and co-existent vitreomacular traction (VMT) or when VMT has developed during the course of treatment. METHODS: Retrospective interventional case series of seven eyes in seven patients. VMT was monitored with serial optical coherence tomography scans. RESULTS: The mean age at presentation was 74 years (range 64-95 years). All patients presented with blurring of central vision, rather than distortion. The aetiology of CNVM was wet age-related macular degeneration in five eyes (72%), angioid streaks in one eye (14%) and pathological myopia in one eye (14%). Ranibizumab was used in four eyes (57%) and bevacizumab in three (43%) for the active CNVM component. The mean follow-up was 11 months (range 2-28 months). None of the eyes in this series required surgery for the VMT component, nor were there any cases of spontaneous resolution of VMT. Visual acuity was stabilised or improved in five of the seven eyes (71%) with IVI. Visual acuity results across the whole group were gain of three or more lines of Snellen visual acuity in two eyes (28%), gain of up to three lines in three eyes (42%), no change in visual acuity in one eye (14%) and loss of up to three lines in one eye (14%). There were no eyes losing more than three lines of Snellen visual acuity. In four eyes with pre-existing VMT, visual acuity improved in three with IVI. In three eyes that developed VMT after IVI, visual acuity improved in two with IVI. Delay from diagnosis of CNVM to treatment with IVI contributed to a poor response. CONCLUSIONS: Most eyes improved visual acuity with IVI for combined CNVM and VMT. Despite the often dramatic features of VMT on optical coherence tomography, treatment of co-existing CNVM should be prompt. Vitreoretinal surgery was not required in this series, but is held in reserve if there is still potential for gain in vision following CNVM resolution.

Evidence-based medicine audit as a tool for improving emergency ophthalmology.

AIM: To audit the proportion of interventions in emergency ophthalmology that are evidence based and to determine whether the quality of care can be improved. METHODS: Audit of diagnosis-intervention pairs was carried out retrospectively in March 2003. The outcomes were assessed for evidence level reached in the Medline database 1966-2003 and the Cochrane Database of Systematic Reviews. Locally agreed guidelines were issued and the study repeated prospectively in March 2004, when new medical staff were at a similar level of experience. The participants had no prior knowledge of the study to avoid prescribing bias (Hawthorne's phenomenon). RESULTS: In the first part of the audit in 2003, 71% of interventions were evidence based, with 36% derived from systematic reviews, meta-analysis or randomised controlled trials (evidence levels 1-3). After guidelines for care were implemented in 2004, there was an improvement in the number of evidence-based interventions to 82% (P=0.04), and levels 1-3 were reached in 60% (P=0.02). The proportion with no evidence or against evidence dropped from 29 to 18% (P=0.04). An additional benefit was to reduce the number of re-attendances required. CONCLUSION: Evidence-based medicine can be used to improve the quality of care in the acute ophthalmic setting, both in refining the standard of interventions and in reducing the number of hospital visits.

Autogenous temporalis fascia patch graft for porous polyethylene (Medpor) sphere orbital implant exposure.

BACKGROUND: Temporalis fascia has been recommended for hydroxyapatite sphere exposure. The aim of this study was to identify potential risk factors for exposure of porous polyethylene (Medpor) sphere implants and evaluate the use of autogenous temporalis fascia as a patch graft for exposure. METHODS: A retrospective review of consecutive cases of porous polyethylene sphere orbital implant exposure. RESULTS: Five cases presented between May 2000 and October 2001 (three males, two females; mean age 44.5 years). Three had enucleation (two with primary implants) and two had evisceration (one with primary implant). Exposure occurred in one primary, two secondary, and two replacement implants. Orbital implant diameter was 20 mm in four cases and 16 mm in one case (contracted socket). The mean time from implantation to exposure was 23 months (range 0.7-42.6). Three patients had secondary motility peg placement before exposure. The average time from last procedure (sphere implant or peg insertion) to exposure was 3 months (range 0.7-12.6). Four patients required surgical intervention, of which three needed more than one procedure. Autogenous temporalis fascia grafting successfully closed the defect without re-exposure in three of these four patients. The grafts were left bare in three patients, with a mean time to conjunctivalise of 2.4 months (range 1.6-3.2). CONCLUSIONS: Exposed porous polyethylene sphere implants were treated successfully with autogenous temporalis fascia graft in three of four patients. This technique is useful, the graft easy to harvest, and did not lead to prolonged socket inflammation, infection, or extrusion.

G-protein deactivation is rate-limiting for shut-off of the phototransduction cascade.

Photoreceptors detect light through a seven-helix receptor (rhodopsin) and heterotrimeric G protein (transducin) coupled to a cyclic GMP phosphodiesterase. Similar pathways are used to amplify responses to hormones, taste and smell. The amplification of phototransduction is reduced by a fall in cytoplasmic Ca2+ , but it is not known how the deactivation of rhodopsin and transducin influence this response and hence the extent and duration of phosphodiesterase activity. Here we investigate this by recording the electrical response to flashes of light in truncated rod photoreceptors. By removing ATP to block the deactivation of rhodopsin by phosphorylation, we show that this reaction limits the amplitude of the response and begins within 3.2 s of a flash in a solution containing 1 microM Ca2+, falling to 0.9 s in a zero-Ca2+ solution. In contrast, the activation and amplitude of the response were unaffected when transducin deactivation by GTP hydrolysis was blocked by replacing GTP with its nonhydrolysable analogue GTP-gammaS, demonstrating that there is little GTP hydrolysis occurring over the period in which photoexcited rhodopsin is quenched. The rapid deactivation of rhodopsin is therefore a Ca2+-sensitive step controlling the amplitude of the light response, whereas transducin deactivation is slower and controls recovery.

The action of cytoplasmic calcium on the cGMP-activated channel in salamander rod photoreceptors.

1. Truncated salamander rod photoreceptors were internally perfused to investigate the action of cytoplasmic Ca2+ on cGMP-activated channels in the outer segment. 2. Switching from 1 microM Ca2+ to 0 Ca2+ increased the cGMP-activated current by a factor of 7.1 +/- 0.5 when measured in the first 60 s after the outer segment was opened to the bath, but only 2-fold after 5 min or more. This was attributed to the loss from the outer segment of a soluble factor required for Ca2+ to inhibit the cGMP-activated channel. 3. Short exposures to 0 Ca2+ caused an irreversible increase in the cGMP-activated current measured in 1 microM Ca2+, indicating that lowering [Ca2+] accelerated the loss of the channel inhibitor from the outer segment. 4. Channel activation occurred with a half-time of 6.7 s on switching to 0 Ca2+. Replacing 1 microM Ca2+ inhibited the current again with a half-time of 11.0 s. 5. The inhibition of the cGMP-activated current by Ca2+ could be described by a Hill curve with half-maximal suppression at 55 +/- 13 nM Ca2+ and a Hill coefficient of 1.4 +/- 0.4. 6. Addition of calmodulin (1 microM), or the calmodulin inhibitors mastoparan and calmidazolium (5 microM), did not alter the action of Ca2+ on the cGMP-activated current. 7. The increased affinity of the cGMP-activated channels in response to a fall in [Ca2+] has the magnitude, speed and Ca2+ dependence to suggest that it will promote recovery of the cGMP-activated current in response to the light-induced fall in [Ca2+] that normally occurs inside the outer segment.