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.

Choroidal biopsies; a review and optimised approach.

The majority of choroidal tumours are diagnosed accurately with clinical examination and the additional data obtained from non-invasive imaging techniques. Choroidal biopsies may be undertaken for diagnostic clarity in cases such as small melanocytic or indeterminate lesions, identifying the primary tumour in the case of choroidal metastases or the subclassification of rarer conditions such as uveal lymphoma. There is however an increasing use of biopsy techniques for prognostication in uveal melanoma. This review explores the main indications and surgical techniques for tumour acquisition, and the optimised approach utilised by the current authors to improve successful yield for histological and genetic analysis.

Clinical evaluation of a paper chart for predicting ruthenium plaque placement in relation to choroidal melanoma.

PurposeTo determine the accuracy of estimated tumour location and required plaque position using fundus diagrams, and to evaluate their applicability in daily clinical practice.Patients and methodsBetween September 2013 and March 2016, all patients treated with ruthenium plaque brachytherapy for choroidal melanoma at the Department of Ophthalmology in Poznan underwent pretreatment planning with the use of printed or electronic fundus diagrams www.oculonco.comThe estimated distances were then verified intraoperatively.ResultsThere were 40 eyes of 40 patients: 15 men, 25 women, with a median age of 61 years (range: 21-88). The median longitudinal basal diameter (LBD) of the treated melanomas was 10.4 mm (range: 6.5-14.9) and the median thickness was 4.1 mm (range: 1.9-6). The final postition of the anterior tumour margin was within 1 mm of the estimated location in 39 cases (97 %), and within 2 mm in 1 case (3 %). Median follow-up was 15 months (range: 3-36). By the close of the study, there was one local tumour recurrence (3%) and one patient died of unrelated cause 1 year after treatment. No patient developed metastases by study close.ConclusionsThe plaque planning system using the paper fundus diagrams proved to be accurate, easily applicable and should aid plaque placement where computer modelling is not possible.

Photodynamic therapy as initial treatment for small choroidal melanomas.

PURPOSE: To evaluate Verteporfin photodynamic therapy (PDT) as primary treatment for small, posterior choroidal melanoma. DESIGN: Retrospective cohort review. SUBJECTS, PARTICIPANTS AND CONTROLS: Retrospective case note review of 20 patients with small juxtapapillary and juxtafoveal choroidal melanomas treated with PDT at the Liverpool Ocular Oncology Clinic. METHODS: Patient and tumour characteristics, PDT session details, visual acuity and B-scan ultrasonography measurements as well as colour fundus photographs at each examination were collated and analysed. MAIN OUTCOME MEASURES: Local tumour control and Best Corrected Visual Acuity (BCVA). RESULTS: The 20 patients (14 male, 6 female) had a mean age of 61.2 years (range, 40-85) and were treated between 2001 and 2012. Seven tumours were amelanotic, while 13 were pigmented. Of 20 melanomas, 11 (55%) showed complete regression on B-scan ultrasonography and colour photography; five (25%) showed partial regression; four (20%) remained unchanged and two (10%) showed further growth, for which alternative standard treatment was required. Baseline BCVA was 0.1 logMAR (mean; range 0.0-0.6) compared to a post-PDT BCVA of 0.4 logMAR (mean; range -0.2 to 1.7) over a follow-up of 60.0 months (mean; range 25-156 months). CONCLUSIONS: PDT can induce tumour regression in a significant proportion of small, posterior, choroidal melanomas but is less reliable than other forms of therapy. It may have a role in patients with special visual requirements if they accept the increased risk of treatment failure requiring radiotherapy.

Two-year patient-reported outcomes following treatment of uveal melanoma.

PurposeTreatment of uveal melanoma can impair patients' psychological well-being. We evaluated patient-reported outcome measures (PROMs) of anxiety, depression, and quality of life (QoL) over 2 years following treatment in a consecutive sample of uveal melanoma patients, compared observations to population normative values and examined whether outcomes differed according to patients' age, gender, and whether or not they were treated by enucleation or had a poor prognosis (presence of monosomy 3).DesignProspective longitudinal study.ParticipantsPatients (N=411) with uveal melanoma treated between 2008 and 2011.MethodsSelf-report questionnaire study. We compared mean PROMs scores obtained 6 months, 1 year, and 2 years after treatment to published population normative values using 2-sample t-tests, and tested the association of these scores with gender, age, treatment by enucleation, and monosomy 3 using mixed-model ANOVAs.ResultsOn QoL and depression, patients were similar to or better than normative values at all time points, but there was some evidence that females were more anxious than female normative values (Ps<0.001-<0.05). Younger patients (P<0.01) and female patients (P<0.01) were the most anxious overall. Enucleation was not associated with PROMs. Patients with monosomy 3 showed more depressed mood at all the three time points (P<0.05).ConclusionsPatients treated for uveal melanoma can expect, within 6 months of treatment, to have a QoL that is similar to that of the general population. Younger female patients and patients with monosomy 3 are more likely to be distressed, and clinicians will need to be alert to this.

Near-infrared reflectance and autofluorescence imaging characteristics of choroidal nevi.

PurposeTo report near-infrared reflectance (NIR-R), near-infrared autofluorescence (NIR-AF) and blue wave autofluorescence (BW-AF) appearance of choroidal nevi using a confocal scanning laser ophthalmoscope (cSLO).Patients and methodsNIR-R, NIR-AF and BW-AF images of choroidal nevi were compared with color fundus photos (CF). Images were graded as hyperreflective if reflectance was much greater than background, hyporeflective if less than background, and isoreflective if the same as the background.ResultsForty-two nevi of 39 patients were imaged. When compared with CF, nevi could be identified on 95% (40/42) NIR-R images (95% CI: 83.5-99.3). On NIR-R 71% (30/42) demonstrated hyperreflectance and 24% (10/42) were hyporeflective. Hyperreflectivity was demonstrated in 96% (23/24) of NIR-AF images (95% CI: 79.1-99.9) and 34% (14/41) of BW-AF images (95% CI: 20.0-50.5). On NIR-R, 29/40 (73%) were apparently smaller in comparison with CF and 11/40 (28%) had the same area. A correlation was found between NIR-R and NIR-AF (P=0.02) but not with BW-AF (P=0.15).ConclusionsNevi can be visualized well using NIR-R and NIR-AF imaging modalities, but are less frequently visible using BW-AF. These changes may be related to melanin within the choroid or chronic changes of the overlying retinal pigment epithelium.

Verteporfin photodynamic therapy for the treatment of sporadic retinal capillary haemangioblastoma.

PURPOSE: To assess the effectivity of photodynamic therapy (PDT) for the treatment of retinal capillary haemangiomas METHOD: Retrospective case note analysis of all patients with retinal angiomas treated with PDT between 2003 and 2010. RESULTS: Six eyes of 6 patients (3 male, 3 female) with a mean age of 50 years (range, 23-78) were identified in our database. The follow up period was between 24 and 60 months (mean, 36). Tumor regression was evident in two patients; three tumors showed no demonstrable response to treatment on ophthalmoscopy or ultrasonography and one tumor progressed despite PDT and subsequent cryotherapy. One patient developed retinal neovascularisations following a period of inattendence to our clinic. Visual acuity improved in two patients following PDT, deteriorated in three patients and remained stable in a one patient. CONCLUSION: The response of retinal haemangioblastomas to PDT is inconsistent. Other treatment modalities ought to be utilized for peripheral lesions, however PDT may be tried in juxtapapillary lesions where radiotherapy or cryotherapy is likely to result in concurrent visual loss.

Uveal Melanoma UK National Guidelines.

The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

Conjunctival squamous cell neoplasia: the Liverpool Ocular Oncology Centre experience.

PURPOSE: To report the outcome of patients with conjunctival squamous cell neoplasia (CSCN)--including conjunctival squamous cell carcinoma (SCC), conjunctival squamous intraepithelial neoplasia (C-SIN) and carcinoma in situ (CIS)-treated at the Liverpool Ocular Oncology Centre (LOOC). METHODS: Patients treated between January 1993 and September 2011 were identified and categorised as having 'primary' or 'salvage' treatment, according to whether they had undergone a surgical procedure before referral to our centre. Invasive SCC was treated by excision with adjunctive ruthenium plaque radiotherapy. C-SIN or CIS was treated with topical 5-fluorouracil (5-FU), and in a few cases, cryotherapy. RESULTS: Primary treatment was administered to 20 patients (16 males, four females). Mean age was 62 years (range, 33-85). Histological examination revealed C-SIN/CIS in ten patients and invasive SCC in nine. Median follow-up was 69 months (range, 34-168). Three patients required further topical chemotherapy for persistent/recurrent C-SIN. Salvage therapy was administered to 21 patients (15 males, six females). Mean age was 63 years (range, 26-82). Histology showed C-SIN/CIS in 11 patients and invasive SCC in ten. Median follow-up was 54.5 months (range, 36-120). At the close of this audit, there was no recurrence of invasive or metastatic disease in either the primary or salvage groups. CONCLUSIONS: Our established protocol for treatment of CSCN has proven successful in local tumour control, and avoids ocular complications. We advocate adjunctive radiotherapy in patients with invasive SCC and chemotherapy in C-SIN/CIS. For improved patient outcome, prompt referral to a specialist centre is encouraged.

Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing.

BACKGROUND: The absence of BRCA1-associated protein 1 (BAP1) expression in uveal melanoma (UM) is associated with metastatic progression and reduced survival. In this study, we examine nuclear BAP1 (nBAP1) protein expression in primary UMs (PUMs) that show both 'typical' and 'atypical' clinical courses according to their chromosome 3 status, and secondary hepatic metastatic UM (MUM), correlating the results with histological, clinical and survival data. METHODS: Nuclear BAP1 expression was immunohistochemically assessed in tissue microarrays (TMAs) of: (a) 68 PUM patients, who had been treated surgically; and (b) 13 MUM patients, with 5 cases being paired with primary tumour tissue. All cases were fully annotated. The percentage of tumour cell nuclei staining positively for BAP1 was scored by independent observers. RESULTS: Nuclear BAP1 protein expression was absent in 35 out of 68 (51%) PUM patients, correlating strongly with poor prognostic clinicopathological and genetic parameters and reduced survival (Log rank, P<0.001). Lack of nBAP1 expression importantly identified a subset of 'atypical' PUM patients with disomy of chromosome 3 but with unexpected metastatic relapse. Nuclear BAP1 expression was absent in 10 out of 13 (77%) MUM and expression was concordant in all paired PUM and MUM patients. CONCLUSIONS: Absent nBAP1 protein expression is an independent survival predictor for UM patients, easily examined using immunohistochemistry.

Intravitreal bevacizumab in the treatment of vasoproliferative retinal tumours.

AIM: To evaluate the efficacy of intravitreal bevacizumab in the treatment of retinal vasoproliferative tumours (VPT). MATERIALS AND METHODS: Six eyes of 6 patients with VPT who received intravitreal bevacizumab were retrospectively reviewed. All patients received between one and three injections of intravitreal bevacizumab depending upon response to treatment. Best-corrected visual acuity (BCVA), tumour size, and presence of co-pathology or sequelae were noted pre- and postoperatively and then analysed. Subsequent retreatments were performed in patients with recurrent or persistent VPT according to the ophthalmologist's discretion. Retreatments included photodynamic therapy with verteporfin, ruthenium-106 plaque brachytherapy, or endoresection of tumour. RESULTS: The mean follow-up duration was 33.3 months (range 10-66 months). At baseline, the mean logMAR BCVA was 1.45 (Snellen equivalent of 6/165); range 0.10-1.90 (6/8-CF). Following bevacizumab treatment the mean logMAR BCVA was 0.98 (Snellen equivalent of 6/57); range 0.5-1.9 (Snellen equivalent of 6/19 to CF). Therefore, there was no statistically significant change in visual acuity. The mean tumour thickness reduced from 2.4 to 2.1 mm following treatment with bevacizumab. However, this did not reach the statistical significance of P<0.05. Despite the visual improvement following bevacizumab therapy, five out of six patients had recurrence of tumour activity during the follow-up period and required further intervention in order to achieve sustained regression. CONCLUSIONS: Intravitreal bevacizumab appeared to result in temporary reduction of tumour thickness in 3 out of 6 VPT patients. However, neither the reduction in tumour thickness nor the change in visual acuity were statistically significant and intravitreal bevacizumab monotherapy had limited effectiveness in causing long-term regression of the lesions. Additional therapy was indicated in five out of six patients to establish long-term regression. The efficacy of bevacizumab as an adjunct is as yet undetermined and further studies are needed. Presently, we recommend other treatment modalities in the long-term management of VPTs.

The surgical approach to the management of anterior uveal melanomas.

PURPOSE: Surgical excision of peripheral iris or ciliary body melanomas can be performed antero-posteriorly (irido-cyclectomy) with mydriasis or postero-anteriorly (cyclo-iridectomy) with miosis. The aim of this study was to evaluate the results of both surgical techniques. METHODS: Patients were enrolled in the study if they underwent irido-cyclectomy or cyclo-iridectomy for iris and/or ciliary body melanoma at the Liverpool Ocular Oncology Centre between 1993 and 2012. RESULTS: The 24 patients (8 male, 16 female) had a median age of 57 years. The largest median basal tumour diameter and the median tumour thickness were 4.8 and 2.2 mm, respectively. The resection was performed antero-posteriorly in 9 (37%) patients and postero-anteriorly or circumferentially in 15 (63%). Nine tumours contained epithelioid cells. Genetic studies were performed in 10 patients, showing chromosome 3 loss in two. Postoperative complications included hypotony in 9 (37%) patients, cataract in 8 (33%), hyphaema in 8 (33%), cyclodialysis in 1 (4%), wound dehiscence in 1 (4%) and bullous keratopathy in 1 patient (4%). The median follow-up time was 2.4 years. The last known visual acuity was 6/6-6/12 in 20 (91%) patients and 6/18-6/60 in 2 (9%), with 2 (8%) requiring secondary enucleation. Local tumour recurrence developed in 1 patient (4%). Two (8%) patients died of metastatic disease. CONCLUSIONS: Surgical resection of peripheral iris melanomas achieves high rates of visual conservation and local tumour control and may be the preferred option when tissue is required for laboratory studies.

The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection.

AIM: To determine the outcome of patients that underwent liver resection for metastases from uveal melanoma. METHODS: Over a 9-year period, patients referred with uveal melanoma metastases were included. Following treatment of primary uveal melanoma, high-risk patients were offered to be enrolled into a 6-monthly non-contrast liver magnetic resonance imaging (MRI) surveillance. Following detection of liver metastases, patients were staged with a contrast-enhanced (Primovist(®)) liver MRI, computer tomography (CT) of the thorax and staging laparoscopy. RESULTS: 155 patients were referred with uveal melanoma liver metastases, of which 17 (11.0%) patients had liver resection and one patient was treated with percutaneous radio-frequency ablation. The majority of patients undergoing liver resection were treated with multiple metastectomies (n = 8) and three patients had major liver resections. The overall median survival for patients treated with surgery/ablation was 27 (14-90) months, and this was significantly better compared to patients treated palliatively [median = 8(1-30) months, P < 0.001]. Following surgery, 11 patients had recurrent disease [median = 13(6-36) months]. Patients who had undergone a major liver resection had a significantly poorer disease-free survival (P = 0.037). CONCLUSIONS: Patients who can undergo surgical resection for metastatic uveal melanoma have a more favorable survival compared to those who do not.

Effects of radiotherapy on uveal melanomas and adjacent tissues.

Most uveal melanomas are treated with radiotherapy. An adequate understanding of the effects of radiation on the tumour and the healthy ocular tissues is necessary. Ionizing radiation damages cell membranes, organelles, and DNA. Irradiated cells are lysed or undergo apoptosis, necrosis, and senescence. These effects occur in tumour cells and vascular endothelial cells, resulting in tumour shrinkage, ischaemia, infarction, exudation, and fibrosis, which can cause exudative maculopathy, serous retinal detachment, rubeosis, and neovascular glaucoma (ie, 'toxic tumour syndrome'). Such abnormalities must be distinguished from collateral damage to healthy ocular tissues that receive high doses of radiation, and these include radiation-induced retinopathy, optic neuropathy, choroidopathy, cataract, and scleral necrosis. Radiation retinopathy can be treated effectively with photodynamic therapy, anti-angiogenic agents, and intravitreal steroid injections. In some patients, optic neuropathy may improve with intravitreal steroids or anti-angiogenic agents. Neovascular glaucoma resolves with intra-cameral bevacizumab. Exudative retinal detachment can regress with intra-vitreal steroid injections. Cataract is treated in the usual manner. Scleral necrosis, if severe, may require grafting, possibly using a lamellar flap from the same eye. Depending on the bulk of the residual toxic tumour, treatment can consist of intra-vitreal steroids and/or anti-angiogenic agents, transpupillary thermotherapy or photodynamic therapy to the tumour, or surgical removal of the tumour by endo- or exo-resection. Measures aimed at preventing collateral damage include eccentric placement of ruthenium plaques or iodine seeds and delivery of a notched proton beam. The decision to treat a uveal melanoma with radiotherapy requires the ability to manage iatrogenic side effects and complications.

Imaging of retinal and choroidal vascular tumours.

The most common intraocular vascular tumours are choroidal haemangiomas, vasoproliferative tumours, and retinal haemangioblastomas. Rarer conditions include cavernous retinal angioma and arteriovenous malformations. Options for ablating the tumour include photodynamic therapy, argon laser photocoagulation, trans-scleral diathermy, cryotherapy, anti-angiogenic agents, plaque radiotherapy, and proton beam radiotherapy. Secondary effects are common and include retinal exudates, macular oedema, epiretinal membranes, retinal fibrosis, as well as serous and tractional retinal detachment, which are treated using standard methods (ie, intravitreal anti-angiogenic agents or steroids as well as vitreoretinal procedures, such as epiretinal membrane peeling and release of retinal traction). The detection, diagnosis, and monitoring of vascular tumours and their complications have improved considerably thanks to advances in imaging. These include spectral domain and enhanced depth imaging optical coherence tomography (SD-OCT and EDI-OCT, respectively), wide-angle photography and angiography as well as wide-angle fundus autofluorescence. Such novel imaging has provided new diagnostic clues and has profoundly influenced therapeutic strategies so that vascular tumours and secondary effects are now treated concurrently instead of sequentially, enhancing any opportunities for conserving vision and the eye. In this review, we describe how SD-OCT, EDI-OCT, autofluorescence, wide-angle photography and wide-angle angiography have facilitated the evaluation of eyes with the more common vascular tumours, that is, choroidal haemangioma, retinal vasoproliferative tumours, and retinal haemangioblastoma.

Personalized treatment of uveal melanoma.

Personalized treatment of uveal melanoma involves the tailoring of all aspects of care to the condition, needs, wishes, and fears of the patient, taking account of the individual's circumstances. When selecting between radiotherapy, surgical resection, and phototherapy, or when deciding how best to combine these different therapeutic modalities, it is necessary to understand the patients utilities, with respect to tumour control, visual conservation, and preservation of the eye, so as to prioritize outcomes accordingly. For example, such considerations would influence the width of the safety margins when administering radiotherapy, according to whether the patient considers it more important to conserve vision or to guarantee tumour control. With 'suspicious naevi', the choice between observation, immediate treatment, and biopsy is complicated by the lack of adequate survival data on which to base rational decisions, making it necessary for both patient and doctor to accept uncertainty. Personalized care should involve close relatives, as appropriate. It must also adapt to changes in the patient's needs over time. Such personalized care demands the ability to respond to such needs and the sensitivity to identify these requirements in the first place. Personalized treatment enhances not only the patient's satisfaction but also the 'job satisfaction' of all members of the multidisciplinary team, improving quality of care.