Microvessel count predicts survival in uveal melanoma.

Microvessel density has become established as an important prognostic indicator for many tumor types. This study investigates the microvessel density as a prognostic factor for survival in patients with uveal melanoma, which is the commonest intraocular tumor and has a clear tendency for metastatic spread to the liver. Factor VIII-related antigen was identified immunohistochemically in bleached sections from 123 tumors. Maximum blood vessel density in an area of 0.25 mm2 was recorded, along with other accepted prognostic information. Microvessel density was the single most important prognostic factor on univariate testing, and in a Cox proportional hazard model, tumor size was the only other variable to be entered. No other accepted prognostic factor entered the model. We conclude that microvessel density is an important prognostic factor for survival in patients with uveal melanoma and allows the identification of high-risk patients for whom adjuvant therapy should be considered.

Determining patient preferences in the management of neovascular age-related macular degeneration: a conjoint analysis.

PurposeTo determine the opinions from a patient perspective on relevant variables in the delivery of treatment for neovascular age-related macular degeneration (nAMD).MethodsPilot interviews with patients and doctors were conducted to identify what variables in the provision of a nAMD service were important. This led to the generation of two sets of scenario options. Subsequently 100 patients undergoing active treatment for nAMD in the National Health Service University Hospital, United Kingdom underwent interview assessment. They were asked to rank their preferences for provision of their care with reference to these two sets of scenario options. Using conjoint analysis, percentage preferences, and utility scores for each variable in each scenario design were calculated.ResultsNinety-five patients completed the preference ranking for both scenarios. Eight patients ranked worse vision as preferable to better vision and were excluded on the basis that they had not understood the task. The results of the remaining 87 patients are presented. The most important factor to patients was having good vision, followed by a one-stop service and less frequent follow up. The least important factors were label status of the drug, cost to the health service, and grade of the injector.ConclusionPatients regard good vision and minimal visits to the hospital above the status of injector, label status of drug, or cost to the NHS.

Falls and health status in elderly women following first eye cataract surgery: a randomised controlled trial.

BACKGROUND/AIM: A third of elderly people fall each year. Poor vision is associated with increased risk of falls. The authors aimed to determine if first eye cataract surgery reduces the risk of falling, and to measure associated health gain. METHODS: 306 women aged over 70, with cataract, were randomised to expedited (approximately 4 weeks) or routine (12 months wait) surgery. Falls were ascertained by diary, with follow up every 3 months. Health status was measured after 6 months. RESULTS: Visual function improved in the operated group (corrected binocular acuity improved by 0.25 logMAR units; 8% had acuity worse than 6/12 compared with 37% of controls). Over 12 months of follow up, 76 (49%) operated participants fell at least once, and 28 (18%) fell more than once. 69 (45%) unoperated participants fell at least once, 38 (25%) fell more than once. Rate of falling was reduced by 34% in the operated group (rate ratio 0.66, 95% confidence interval 0.45 to 0.96, p = 0.03). Activity, anxiety, depression, confidence, visual disability, and handicap all improved in the operated group compared with the control group. Four participants in the operated group had fractures (3%), compared with 12 (8%) in the control group (p = 0.04). CONCLUSION: First eye cataract surgery reduces the rate of falling, and risk of fractures and improves visual function and general health status.

Detection of melanocytes from uveal melanoma in peripheral blood using the polymerase chain reaction.

PURPOSE: Uveal melanoma is the most common intraocular malignancy in adults and can cause loss of vision in the affected eye and death from metastasis, usually to the liver. The techniques currently used to detect cellular dissemination from the tumor are inadequate, and lack the sensitivity required for the detection of low levels of melanocytes in the peripheral blood of patients. The detection of circulating melanocytes is important as an early indication of the possibility of metastasis. METHODS: The viability of reverse transcription/polymerase chain reaction amplification of the tyrosinase gene to detect circulating melanocytes was examined as a first sign of dissemination from uveal melanoma. RESULTS: It was shown that it is possible to detect as few as ten circulating melanocytes in 5 ml of blood. Blood-borne dissemination was also detected in three of six patients with uveal melanoma examined. Two of these patients had clinically confirmed widespread metastases. A positive result was also recorded in one patient in whom there was no other evidence for tumor dissemination. Overt metastatic disease developed in this patient 9 months after blood collection. CONCLUSIONS: The success of this technique has important implications for the detection of circulating tumor cells from uveal melanoma, as an early indication of dissemination. This may be important when considering the administration of adjuvant therapy.

Anterior hyaloidal fibrovascular proliferation after extracapsular cataract extraction in diabetic eyes.

Four patients with proliferative diabetic retinopathy developed anterior hyaloidal fibrovascular proliferation after extracapsular cataract extraction and posterior chamber lens implantation. This complication of cataract extraction has been described after vitrectomy in diabetic eyes. Risk factors for this entity after extracapsular cataract extraction include proliferative diabetic retinopathy, iris neovascularization, and anterior ischemic retina. Anterior hyaloidal fibrovascular proliferation was observed an average of 12 months postoperatively and affected vision in one of four patients. No progression was seen within an average of six months of follow-up, and no complications such as traction retinal detachment and vitreous hemorrhage developed.

Views of older people on cataract surgery options: an assessment of preferences by conjoint analysis.

BACKGROUND: Key issues in the quality of care for people with cataracts in the UK include hospital waiting lists, complication rates from surgery, and the use of junior surgeons. The main objective of this study was to investigate the relative importance that older people attach to these factors when given theoretical choices over options for cataract surgery. METHOD: A systematic sample of 194 individuals aged 60-84 years on a general practice register in Nottingham were invited to take part in an interview based survey. Respondents ranked 11 "cataract surgery packages" containing different waiting list lengths, complication risks, and surgeon grades. Conjoint analysis was performed to determine the relative importance of these factors for individuals and for the group as a whole. RESULTS: Of the 194 subjects invited to participate, 146 (72%) completed the interview. For the group as a whole the "averaged importance" of the factors was: complication risk 45.8%; waiting time 41.1%, surgeon grade 13.1%. Analysis of importance scores for individuals showed that some were particularly concerned about complication risk while others were more concerned about waiting times. There was a strong negative correlation between importance scores for these factors (Spearman's rho -0.78, p<0.001). CONCLUSIONS: Most respondents thought that either risk of damage to sight and/or waiting time were important, while surgeon grade was relatively unimportant. The findings show that some potential cataract patients prefer a greater risk of complication combined with a short wait than a low complication rate and a longer wait.

Is the first day postoperative review necessary after cataract extraction?

BACKGROUND: In current ophthalmic practice day-case surgery cataract patients are conventionally discharged and then reviewed the following morning thus limiting the advantages of what 'true' day-case surgery strives to achieve. The aim of this study was to see if there was a difference in outcome between 'true' day-case cataract surgery and non-day-care surgery. METHODS: A total of 387 consecutive cataract operations were followed, comprising 122 local anaesthetic day-cases, 149 local anaesthetic non-day-cases, 63 general anaesthetic non-day-cases, and 53 general anaesthetic day-cases. RESULTS: Although not randomised the groups were comparable with respect to age, operator grade, sex, presence of diabetes, anaesthetic type, pre and postoperative visual acuities, and time to first planned outpatient visit. There were 10 early postoperative complications in the day-case group (5.71% of total) and 14 in the non-day-case group (6.6% of total), the commonest complications in both groups were raised intraocular pressure, corneal oedema, and wound leaks. One patient in each group had an early complication that necessitated attending the casualty department. The visual outcomes in both groups were comparable. CONCLUSIONS: These findings suggest that there were no preventable complications within the constraints of the number of operations studied and that no additional risk is attached to 'true' day-case surgery relative to non-day-case surgery.

Axon deviation in the human lamina cribrosa.

AIMS: To examine the course taken by individual retinal ganglion cell axons through the human lamina cribrosa. METHODS: Retinal ganglion cell axons were labelled using the retrograde tracer horseradish peroxidase applied directly to the optic nerve in two normal human eyes removed during the course of treatment for extraocular disease. RESULTS: A majority of axons took a direct course through the lamina cribrosa but a significant minority, in the range 8-12%, deviated to pass between the cribrosal plates in both central and peripheral parts of the optic disc. CONCLUSIONS: It is postulated that these axons would be selectively vulnerable to compression of the lamina cribrosa in diseases such as glaucoma in which the intraocular pressure is increased.

Retinal detachment following anterior chamber lens implantation for the correction of ultra-high myopia in phakic eyes.

The development of retinal detachment is reported in three eyes, of two patients, following implantation of an anterior chamber intraocular lens (AC-IOL) in phakic eyes for the correction of ultra-high myopia. The presence of an AC-IOL may hamper the identification of retinal breaks and removal of the intraocular lens may prove necessary to improve visualisation. Shallowing of the anterior chamber may also occur during, or following, vitreoretinal surgery with risk of endothelial contact. The risks and relative contraindications of AC-IOL implantation into phakic eyes are discussed.

Development and validation of a patient based measure of outcome in ocular melanoma.

BACKGROUND: Patients with uveal melanoma can be treated by a number of modalities. As none of the different treatments offer a survival advantage, a key factor in choosing among treatments is their differential impact on patients' quality of life. A short, patient based questionnaire was developed and validated for evaluating outcomes following treatment for uveal melanoma. METHODS: The 21 item measure of outcome in ocular disease (MOOD) assesses the patient's view of outcome in terms of visual function and the impact of treatment. The reliability and validity of the three MOOD scores (total, vision, impact) were evaluated in 176 patients who had been treated for uveal melanoma (75 brachytherapy, 78 proton beam radiotherapy, 23 enucleation). Of these, 165 patients also completed the SF-36. RESULTS: All three MOOD scales met standard criteria for acceptability, reliability, and validity. The proportion of missing data was low, and responses to all items were well distributed across response categories. Internal consistency, assessed by Cronbach's alpha coefficients, exceeded the standard criterion of 0. 70 for all three summary scores. Item total correlations ranged from 0.22 to 0.77 (mean item total correlation 0.58), indicating good homogeneity. Test-retest correlations for all three summary scores exceeded 0.85. Scaling assumptions, assessed by item convergent and discriminant validity correlations, were met for the vision and impact scores. The MOOD showed good content validity, as assessed by review by ophthalmologists and patients. Construct validity was demonstrated by high intercorrelations between the vision and impact scores and the total scale; higher scores for patients who reported being very satisfied compared with those who were not very satisfied and for those who reported persistent red eye compared with those who did not have this complication (known group differences/hypothesis testing); moderate correlations between the MOOD and the SF-36 and visual acuity (convergent validity); and low correlations between the MOOD and age and sex (discriminant validity). CONCLUSIONS: The MOOD is a practical and scientifically sound patient based measure which can be used in research and audit to evaluate outcomes following treatment for uveal melanoma. It takes 5 minutes to complete and meets standard psychometric criteria for reliability and validity.

Modelling uveal melanoma.

BACKGROUND/AIM: There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease. METHODS: Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease. RESULTS: The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease. CONCLUSIONS: There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes-namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

Reassessment of the PAS patterns in uveal melanoma.

BACKGROUND: Previous work has highlighted the prognostic importance of patterns of periodic acid Schiff (PAS) staining (the Folberg patterns) in uveal melanoma. These patterns have been ascribed to blood vessels but the patterns are different from those seen with other staining techniques for blood vessels. It has recently been shown that microvessel density is the dominant prognostic factor in uveal melanoma. This study reinvestigates the nature and significance of the PAS patterns. METHODS: The PAS patterns were compared with the patterns seen with conventional connective tissue stains and with the patterns seen in sections stained for the presence of blood vessels (by immunohistochemistry for factor VIII related antigen). The PAS patterns were determined on a panel of 117 cases of uveal melanoma. The prognostic significance of each of these patterns was determined and, as more than one pattern can exist in a tumour, principal components analysis was performed to determine the number of underlying factors. RESULTS: Comparison of the PAS patterns with other stains demonstrates that they are based on connective tissue including fibrovascular tissue. Five of the nine PAS patterns carried prognostic significance on univariate analysis. Principal components analysis suggested that these patterns represented three underlying factors, which were tentatively identified as representing disordered growth (factor 1), emergence of rapidly growing subclones (factor 2), and section orientation (factor 3). CONCLUSIONS: The PAS patterns are based on fibrovascular tissue and can be ascribed to three underlying factors. The first two of these factors carried prognostic significance and the first (disordered growth) retained independent prognostic significance in a multivariate Cox model which included microvessel density and tumour size.

Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma.

AIMS/BACKGROUND: Proton beam radiotherapy can effectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome. METHODS: The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group. RESULTS: Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy. CONCLUSIONS: Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory.

c-myc, p53, and Bcl-2 expression and clinical outcome in uveal melanoma.

AIMS: Overexpression of c-myc protein has independent prognostic significance in a variety of primary and metastatic cutaneous melanomas which suggests a possible role for this gene in melanomagenesis. We have therefore examined the importance of this oncogene in uveal melanoma and studied the coexpression of two other gene products, Bcl-2 and p53, which might contribute to its effect. METHODS: The percentage of cells positive for nuclear c-myc expression was estimated by flow cytometric analysis of nuclei extracted from paraffin blocks. The expression of Bcl-2 and p53 protein was assessed by immunohistochemistry. A total of 71 tumours were studied and the results compared with survival with a mean follow up period of 6 years. RESULTS: c-myc was expressed in > 50% of the cells by 70% of the tumours, and was independently associated with improved survival in a Cox multiple regression-model. Although Bcl-2 was expressed by the majority of the cells in 67% tumours, it was without effect on prognosis. None of the cases studied showed convincing positivity for p53. Analysis of coexpression showed that the best survival was seen in c-myc+/Bcl-2+ tumours and the worst in c-myc-/Bcl-2-tumours. CONCLUSION: The finding of improved rather than reduced survival in c-myc positive tumours is at variance with skin melanoma. There was no evidence to suggest that c-myc was modulated by upregulation of Bcl-2 or p53 inactivation/mutation. Although Bcl-2 is unlikely to have any effect on tumour growth or metastasis, it could contribute to the general lack of susceptibility to apoptosis in these tumours.

Does raised intraocular pressure begin in utero?

AIM: To determine whether fetal and infant growth, as assessed by weight at birth and weight at 1 year, are related to intraocular pressure. METHODS: 717 men and women born in Hertfordshire between 1920 and 1930, for whom records of birth weight and weight at 1 year were available, were examined. Visual fields were assessed using the Takagi central 25 degrees 75 point static threshold screening program. Tonometry was performed using the Perkin's tonometer. The disc was assessed by direct ophthalmoscopy through dilated pupils. RESULTS: A significant inverse relation was found between systolic blood pressure and birth weight. However, no association was found between birth weight or weight at 1 year and intraocular pressure, cup/disc ratio, or visual field defects. CONCLUSIONS: There was no evidence to support fetal or infant growth as being important factors for the subsequent development of raised intraocular pressure.

The prognostic significance of c-myc oncogene expression in uveal melanoma.

The role of the c-myc oncogene has been little investigated in uveal melanoma. In this study an analysis of c-myc oncoprotein expression was undertaken using flow cytometry in 71 patients with posterior uveal melanoma. Nuclear c-myc oncoprotein was detected in all of the tumours, and survival analysis revealed a significant association between high oncoprotein positivity and improved survival (log rank test: chi2 = 6.47, P = 0.01). Multifactorial analysis using Cox's proportional hazards model revealed nuclear c-myc oncoprotein to be an independent prognostic marker more accurate than other clinicopathological parameters (log rank test: chi2 = 6.61, P = 0.01). However, this result of high oncoprotein expression correlating with improved outcome is surprising and in contrast to our previous studies using the same method on cutaneous melanoma, where high levels of nuclear c-myc expression have been found to correlate with poor outcome both in primary and secondary disease. This study suggests that the pattern of oncogene expression in uveal melanoma is distinct from cutaneous melanoma and that the underlying biology of these tumours is different.

Uveal melanoma: is solar ultraviolet radiation a risk factor?

Age-standardized mortality rates for cancers of the eye among adults in England and Wales are compared with those for cutaneous malignant melanoma. While cutaneous malignant melanoma rates have increased three-fold since 1950-54, rates for cancers of the eye have remained relatively constant over the same period. Collectively, the inconclusive findings of case-control studies for an association between exposure to ultraviolet radiation and uveal melanoma, the lack of supporting dosimetry data, together with the lack of an upward trend in mortality rates for cancers of the eye, suggests that exposure to ultraviolet radiation may not be a major factor in the etiology of uveal melanoma.

Immunohistochemical techniques: the effect of melanin bleaching.

This study addresses two questions: i) which antigens can withstand bleaching by 2.5 g/L of potassium permanganate followed by 10 g/L of oxalate, before immunohistochemical staining; and ii) are any other steps in the immunohistochemical staining technique resistant to bleaching? A panel of 10 antigens was stained immunohistochemically and the results compared with staining performed with a bleaching step interpolated at different steps in the procedures. Four antigens (HMB-45, S-100, factor VIII-related antigen and collagen type IV) were unaffected by bleaching; two antigens (CD-20 and CD-45) had their staining enhanced by bleaching; one had the staining reduced (hsp27); and in three it was abolished (CD-45Ro, CD-31 and Ulex/anti-ulex antibody) by bleaching. Two antibodies (UCHL-1 and L-26) showed evidence for altered specificity following bleaching. None of the steps after application of the primary antibody was resistant to bleaching. Three chromagens used for peroxidase demonstration-amino ethyl-carbazole, diaminobenzidine and chloro-naphthol-were also found to be sensitive to bleaching. While some antigens were resistant to the effects of bleaching, some were not, and no other step in the immunohistochemical procedure could withstand bleaching.

The immunoalkaline phosphatase technique in immunohistochemistry: the effect of permanganate-oxalate melanin bleaching upon four final reaction products.

Melanin bleaching prior to the application of primary antibody can alter the immunoreactivity of a number of antigens. The effect of melanin bleaching subsequent to antigen visualisation by four different chromogens used with an immunoalkaline phosphatase technique was investigated. Vector black was the only final reaction product that withstood exposure to the permanganate-oxalate sequence for a time sufficient to bleach melanin.

Intensive cataract training: a novel approach.

PURPOSE: To evaluate the safety of an intensive cataract surgery training programme. METHODS: An intensive cataract surgery training programme was implemented in August 2010 for year 3 ophthalmology trainees in the East Midlands Deanery North Rotation (United Kingdom). Trainees participated in extra-ocular surgery and 50 h of virtual reality cataract surgery simulator training over a 2-year period. Their third year comprised 6 months of intensive phacoemulsification training in a tertiary centre followed by a 6-month period of consolidation in a district general hospital. The complication rates and case numbers were evaluated after the first 2 years of implementation. RESULTS: At 2 years, three trainees had completed a full year of intensive training. In the first 6 months of training, Trainee 1 completed 156 cases, Trainee 2 completed 194 cases, and Trainee 3 completed 151 full cases as primary surgeons with an average rate of posterior capsule rupture (PCR) of 1%. At 12 months, Trainee 1 completed 291, Trainee 2 completed 318, and Trainee 3 completed 294 cases, with an average PCR rate of 0.66%. The trainees required 84 lists on average to complete 150 full cataract procedures. CONCLUSION: The combination of simulation and the new intensive training programme is safer than the traditional programme for cataract surgery training.