Alexander J. E. Foss

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.

Endothelial cells of tumor vessels : Abnormal but not absent

The question of whether some blood vessels in tumors of non-vascular origin are lined by cancer cells has been discussed for many years because of the relevance to metastasis, access of drugs to tumor cells, and the effectiveness of angiogenesis inhibitors. Most evidence favoring the existence of tumor cell-lined vessels has come from observations of standard histopathological tissue sections or from transmission and scanning electron microscopic studies. However, it has been difficult to determine convincingly just how abundant these vessels are in tumors. On the one hand, virtually the entire microvasculature is supposedly lined by tumor cells in aggressive uveal melanomas, assuming the presence of vasculogenic mimicry where tumor cells masquerading as endothelial cells create the channels for blood flow. On the other hand, morphometric studies using immunohistochemistry and green fluorescent protein-transfected tumor cells suggest that human colon cancer cells constitute only 3% of the vessel surface in tumors grown orthotopically in mice. This commentary weighs evidence that cancer cells are located in the wall of tumor vessels and discusses the pitfalls in identifying such vessels. Published data along with new observations illustrate the challenges of making an unequivocal identification of tumor cells in vessel walls. Taken together, current evidence suggests that cancer cells contribute at most only a small proportion of the lining of blood vessels in tumors and may be migrating through vessel walls or exposed by defects in the endothelium. Even in aggressive uveal melanomas, blood flow probably occurs mainly through channels lined by endothelial cells, not tumor cells, and most existing data do not support a functionally significant contribution of vasculogenic mimicry. Innovative new approaches that distinguish pleomorphic tumor cells from abnormal endothelial cells in vessel walls will help to define the incidence and importance of tumor cell-lined blood vessels in drug delivery and metastasis via the bloodstream.

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.

The Importance of Acuity, Stereopsis, and Contrast Sensitivity for Health-Related Quality of Life in Elderly Women with Cataracts

PURPOSE To investigate the relative contribution of visual and other factors to quality of life among elderly women with bilateral cataract. METHODS Data were analyzed from a trial of first-eye cataract surgery. Visual parameters, general health, and social variables, and disease-specific (VF-14 Index of Visual Function), generic (Euroqol: EQ-5D, London Handicap Scale, Barthel), and intermediate (anxiety, depression, and activity) outcomes were measured at baseline and 6 months later, when approximately half the group had had surgery. RESULTS Three hundred six participants provided data at baseline, and 289 at 6 months. At baseline, acuity, stereopsis, and contrast sensitivity were all associated with quality of life. Acuity and stereopsis were most strongly and consistently associated. Change in VF-14 was associated with changes in stereopsis and contrast sensitivity, while change in handicap was associated with change in stereopsis. CONCLUSIONS Acuity, stereopsis, and contrast sensitivity each contributed to quality of life, across a range of measures, in elderly women with cataract. Acuity was marginally the most consistently and generally the most strongly associated, but in some analyses stereopsis was more important. Change in quality of life was associated with change in stereopsis and contrast sensitivity.

Establishment of a human in vitro model of the outer blood-retinal barrier

The outer blood–retinal barrier is composed of a monolayer of retinal pigment epithelium, Bruchs membrane and the choriocapillaris which is fenestrated. Endothelial proliferation and breaching of Bruchs membrane leads to the neovascular form of age‐related macula degeneration (ARMD). The aim of this study was to generate an in vitro model that mimics more faithfully the phenotype of the choriocapillaris and the trilayer architecture in vitro. A trilayer culture model was generated with retinal pigment epithelium (ARPE‐19) cell cultures on the epithelial surface of amniotic membrane and with human umbilical vein‐derived endothelial cells on the other surface. A control model for the effect of retinal pigment epithelium on endothelial changes was generated with corneal epithelial cells replacing the ARPE‐19. Both human umbilical vein‐derived endothelial and ARPE‐19 cells formed confluent monolayers on respective surfaces of the amnion. The human umbilical vein‐derived endothelial cells in the trilayer became fenestrated when co‐cultured with the ARPE‐19 cells, but not with corneal epithelial cells, or when grown as monolayers on the amnion, showing a loss of fidelity of origin in the presence of ARPE‐19 cells. These cells also revealed VE‐cadherin and ZO‐1 at cell–cell contacts from 24 h in the trilayer. The tight junctional molecules, occludin and ZO‐1, were localized to cell–cell contact regions in the retinal pigment epithelium, both in the monolayer and in the trilayer system. Permeability of the trilayer was tested by using fluorescein and fluorescein‐conjugated tracers under flow. At 72 h the trilayer severely restricted transfer of sodium fluorescein (NaF) (ten‐fold reduction) whilst transfer of a 4 kDa FITC‐conjugated dextran was virtually occluded, confirming a restrictive barrier. Ultrastructural studies showed the retinal pigment epithelium monolayer was polarized with microvilli present on the apical surface. Paracellular clefts showed numerous tight junctional‐like appositions, similar to that seen on amnion alone. This study demonstrates that ARPE‐19 and human umbilical vein‐derived endothelial cells can be co‐cultured on the amniotic membrane and that the resultant cross‐talk leads to formation of a fenestrated endothelium, whilst maintaining a polarized restrictive epithelial layer. The fenestrated endothelial phenotype achieved in this human in vitro trilayer model is a first and offers an outer‐retinal barrier which approaches the in vivo state and has potential for studies into induced junctional disruption, endothelial proliferation and migration: features of ARMD.

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.

Falls and health status in elderly women following first eye cataract surgery: an economic evaluation conducted alongside a randomised controlled trial

Aim: To evaluate the cost-effectiveness of first eye cataract surgery compared with no surgery from a health service and personal social services perspective. Methods: An economic evaluation undertaken alongside a randomised controlled trial of first eye cataract surgery in secondary care ophthalmology clinics. A sample of 306 women over 70 years old with bilateral cataracts was randomised to cataract surgery (expedited, approximately four weeks) or control (routine, 12 months wait); 75% of participants had baseline acuity of 6/12 or better. Outcomes included falls and the EuroQol EQ-5D. Results: The operated group cost a mean £2004 (bootstrapped) more than the control group over one year (95% confidence interval (CI), £1363 to £2833) (p<0.001), but experienced on average 0.456 fewer falls, an incremental cost per fall prevented of £4390. The bootstrapped mean gain in quality adjusted life years (QALYs) per patient was 0.056 (95% CI, 0.006 to 0.108) (p<0.001). The incremental cost–utility ratio was £35 704, above the currently accepted UK threshold level of willingness to pay per QALY of £30 000. However, in an analysis modelling costs and benefits over patients’ expected lifetime, the incremental cost per QALY was £13 172, under conservative assumptions. Conclusions: First eye cataract surgery, while cost-ineffective over the trial period, was probably cost-effective over the participants’ remaining lifetime.

Differences in the vascular patterns of basal and squamous cell skin carcinomas explain their differences in clinical behaviour

Tumour angiogenesis is essential for tumour growth and appears to play an important role both at the transition from hyperplasia to invasive growth and at a late stage in the dissemination process. Basal cell carcinomas (BCCs) and trichoepitheliomas (TEs) are related tumours that share the properties of invasive growth but without the capacity to metastasize. Squamous cell carcinomas (SCCs) of the skin are derived from a similar cell type and they have both invasive and metastatic potential. The aim of this study was to investigate whether the behaviour of these tumours could be explained by differences in their microvasculature. The study looked both qualitatively and quantitatively at the microvasculature of BCCs (n = 50) and TEs (n = 33) and compared them with normal skin (n = 6) and with SCCs of the skin (n = 22). Vessel counts were performed using a standard graticule count method after immunohistochemical staining for CD31. Counts were made of blood vessels in the stroma surrounding the tumour and also for vessels in the body of the tumour. The stromal counts for all the tumour groups differed significantly from normal skin. The SCC counts differed significantly from the counts for the BCCs and TEs. There was no significant difference between the counts for different subtypes of BCC or TE groups. While vessels could be found in the body of the SCCs, none was seen in the nodular BCC or the TE groups. There was no correlation between the vascular density and the depth of invasion. Overall, invasive growth correlated with an angiogenic response in the stroma, while metastatic potential correlated with microvessels being present in the body of the tumour. Copyright

Predictive power of screening tests for metastasis in uveal melanoma.

Purpose Uveal melanoma undergoes haematogenous dissemination, particularly to the liver. It is routine practice to screen for metastatic disease. The purpose of this study was to evaluate such screening tests and to determine their value in detecting metastatic disease at presentation.Methods In this study of a series of 245 patients with uveal melanoma of whom 55 (22%) died, the sensitivity, specificity, positive and negative predictive powers and likelihood ratio of the blood tests, chest radiographs and liver ultrasound investigations performed at diagnosis were determined.Results All the screening investigations were found to have a low yield, but the most sensitive were those for gamma-glutamyl transpeptidase (γGT;sensitivity 21%) and alkaline phosphatase (sensitivity 25%), with 7GT being more specific (specificity 92%). No blood test had a positive predictive power greater than 50%. The chest radiograph and liver ultrasonography were both 100% specific but had sensitivities of 2% and 14% respectively.Conclusions Only the chest radiograph and liver ultrasonography had positive predictive powers greater than 50% and these tests had very poor sensitivity. We conclude that there is no good test available for screening for metastatic uveal melanoma.

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.