Proton beam therapy and iris neovascularisation in uveal melanoma.

PURPOSE: Local treatment of uveal melanoma by radiotherapy involves the use of brachytherapy with radioactive plaques attached to the sclera, or proton irradiation. Both treatments induce growth arrest within the tumour and its slow involution over several years. Although ocular retention rates are excellent, regrowth of tumours due to resistance and neovascular glaucoma leads to enucleation of up to 10% of affected eyes. Proton irradiation involves part of the iris in most cases and we noticed that neovascularisation only occurred in the part of the iris that was not irradiated. We therefore conducted this study to determine the relationship between the development of iris neovascularisation and iris irradiation. METHODS: A total of 21 enucleation specimens from patients who had previously had proton irradiation were collected from the files of the Department of Pathology, Moorfields Eye Hospital during the 5-year period from 1994 to 1999. Sections of these eyes were assessed for VEGF-A, bFGF, and von Willebrand Factor (vWF) by immunohistochemistry. Ophthalmic notes and radiotherapy records were reviewed to assess the extent of iris irradiation. RESULTS: In all, 11 cases showed clinical evidence of iris neovascularisation and were selected for further study. Three of these eyes also showed clinical evidence of regrowth of the tumour. Histological evidence of iris neovascularization was noted in all 11 of the eyes examined, and was only present in the nonirradiated side of the iris in 8/11 eyes. NVI was present on both sides of the iris in three cases, but was less severe in the irradiated part. Expression of VEGF-A was at most weak within the tumour, but was present in the detached retina and in the epithelium of both ciliary body and iris. Some bFGF staining was noted around vessels in the iris stroma. CONCLUSIONS: Our results suggest that irradiation leads to iris atrophy, and that atrophic, irradiated iris is resistant to the development of neovascularisation.

Uveal melanomas express vascular endothelial growth factor and basic fibroblast growth factor and support endothelial cell growth.

BACKGROUND: Tumour microvascularity is a significant determinant of prognosis for a large number of different tumours, including uveal melanoma. The development of blood vessels within these and other tumours is partly controlled by soluble pro-angiogenic cytokines, of which basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) are the best described. METHODS: Because VEGF has been inconsistently found within uveal melanomas and bFGF is described as an autocrine growth factor in cutaneous melanoma, the authors looked at the expression of these cytokines in uveal melanomas using immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). The cross talk between uveal melanoma cells and endothelial cells was then assessed in an in vitro co-culture model. RESULTS: While most tumour cells expressed bFGF at the protein level by immunohistochemistry (89%), relatively few (22%) expressed VEGF, and this was of limited extent. All 20 tumours tested by RT-PCR contained mRNA for both bFGF and VEGF. Co-culture experiments using an ATP based bioassay showed that uveal melanomas could support the growth of a rat brain endothelial cell line (GPNT) and human umbilical vein endothelial cells (HUVEC), and that this could be modulated by cytokines and anti-cytokine antibodies. CONCLUSION: These results suggest that angiogenesis within uveal melanoma may be the result of a complex interplay between endothelial and tumour cells, and that bFGF and VEGF could play a part.

Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window.

BACKGROUND: Improved local treatment of uveal melanoma makes it possible for many patients to retain the affected eye, but a proportion will develop secondary complications such as neovascularisation of the iris (NVI) and require enucleation. Although vascular endothelial growth factor A (VEGF-A) is known to correlate with NVI and can cause NVI in experimental models, this pro-angiogenic cytokine is consistently reported to be absent in uveal melanoma. Novel anti-VEGF therapies are now in clinical trial, and the authors therefore wished to determine whether VEGF-A was indeed elevated in melanoma bearing eyes. METHODS: VEGF-A concentrations were measured in aqueous and vitreous from 19 and 30 enucleated eyes respectively. RESULTS: Elevated VEGF-A concentrations (up to 21.6 ng/ml) were found in melanoma bearing eyes compared with samples from patients undergoing routine cataract extraction (all had values below 0.96 ng/ml). Immunohistochemistry showed VEGF-A protein in the iris and/or ciliary body of 54% and basic fibroblast growth factor (bFGF) in 82% of the eyes examined. VEGF was found to a limited extent and at very low levels in only 9% of these tumours. Aqueous or vitreous VEGF levels showed no apparent correlation with retinal detachment, tumour size, vascularity, or immunohistochemistry. Though limited in number, the highest VEGF levels correlated with previous radiation therapy, and with the presence neovascularisation of the iris or optic nerve head. bFGF was not significantly elevated in ocular fluids: it is known to be a pro-angiogenic agent and was detected in the majority of primary uveal melanomas. CONCLUSION: Based on this study, though the source of VEGF within eyes harbouring uveal melanoma is not clear, these data suggest that anti-VEGF therapy might prove useful in the management of some patients with NVI secondary to uveal melanoma.

Immunopathology of the noninfectious posterior and intermediate uveitides.

The posterior and intermediate uveitides share an underlying immune etiology; however, they can be clinically and immunopathologically distinguished. Although the initiating stimuli for posterior and intermediate uveities are not known, it is believed that an exogenous agent (such as a bacterium or a virus) or an endogenous molecule may induce disease. In either case, T-helper lymphocytes in conjunction with human leukocyte antigens are likely to be involved. This review examines the epidemiology, histology, immunopathology, and theories of pathogenesis of several posterior and intermediate uveitides, including sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, Behçet's disease, sarcoidosis, intermediate uveitis, white dot syndromes, and birdshot retinochoroidopathy.

Panretinal photocoagulation during cataract extraction in eyes with active proliferative diabetic eye disease.

PURPOSE: Cataract surgery in the presence of active proliferative diabetic eye disease carries a high risk of progression of retinopathy and neovascular glaucoma. Lens opacities may prevent panretinal photocoagulation (PRP) before surgery, and applying PRP in the immediate post-operative period can be difficult. The purpose of this study is to report results of cataract extraction combined with per-operative indirect laser PRP in a group of these patients. METHODS: Nine eyes of 9 diabetic patients with active retinal or iris neovascularisation in which lens opacities prevented adequate pre-operative PRP underwent cataract surgery combined with indirect laser PRP after cortex aspiration and before intraocular lens implantation. RESULTS: Regression of neovascularisation with this combined procedure alone was achieved in 5 eyes, 3 responded to further PRP, and 1 developed neovascular glaucoma. Visual acuity improved in all eyes, 4 achieving > or = 6/12. Four patients developed increased post-operative uveitis. One developed clinically significant macular oedema. CONCLUSIONS: The method described has definite practical advantages over PRP attempted in the immediate post-operative period, when many factors can prevent its application or reduce its effectiveness, and when neovascularisation may be progressing rapidly. In addition, adjunctive per-operative indirect laser PRP appears to improve the outcome of cataract surgery in eyes with active proliferative diabetic eye disease.

Ocular manifestations of diabetes mellitus.

The ocular complications of diabetes mellitus are numerous and include retinopathy, cataract, uveitis, and neurophthalmic disorders. A review of the current literature shows that the emphasis has changed from the laser and surgical management of pre-existent retinopathy to the development of cohesive multidisciplinary screening and education programs, and to a better understanding of the cellular and molecular mechanisms that underlie disease. The role of associated and potentially modifiable systemic factors is also now recognized. Early intervention with systemic and local therapies may soon provide hope for the better management of diabetic eye disease.

Haemophilus aphrophilus bleb infection after a mitomycin trabeculectomy.

BACKGROUND: Haemophilus aphrophilus is a rare cause of ocular infection. It has been reported once as a cause of late-onset endophthalmitis in a patient with an inadvertent bleb after cataract surgery. We present a case of Haemophilus aphrophilus bleb infection after a mitomycin trabeculectomy. METHODS: A 56-year-old woman presented with a bleb infection 10 weeks after a mitomycin C augmented trabeculectomy at a University tertiary referral practice of one of the authors (GET). The causative organism was Haemophilus aphrophilus, identified by the Toronto Public Health Laboratory, Ontario, Canada. RESULTS: The bleb infection resolved following topical, subconjunctival and intravenous antibiotic therapy. A formal bleb revision was required to repair a persistent bleb leak. CONCLUSION: Patients who have had trabeculectomies augmented with mitomycin C may be predisposed to bleb infection with unusual organisms. Prompt diagnosis and treatment is necessary to control the infection. Increased awareness and communication with laboratory personnel may increase the isolation of this fastidious organism.

Intralenticular foreign bodies: case reports and surgical review.

Management of intralenticular foreign bodies (ILFBs) is controversial. Correlation between visual outcome, foreign body characteristics, the need for surgical intervention, and the choice of surgical technique are not well established. We report five cases of traumatic ILFBs all managed surgically. Three ILFBs were metal, one was presumably also metal, and one was wood. We chose to proceed with foreign body removal and simultaneous cataract extraction with intraocular lens implantation as a single-staged procedure in four cases. In one case of planned extracapsular cataract extraction, a foreign body was identified only after the expressed nucleus was sent for pathological examination. Visual outcomes were 20/30 or greater in all cases at 5 to 18 month follow up.

Compartmentalization of the embryonic striatum after intraocular transplantation.

In order to assess the intrinsic potential of the isolated embryonic striatum to develop its adult patch and matrix compartments, embryonic day 16 striata were transplanted into the anterior eye chamber of adult host rats. After 2-12 weeks of survival the transplants showed heterogeneous and in the majority of cases complementary distributions of opiate receptor binding and acetylcholinesterase staining, which mark the patch and matrix compartments of the adult striatum, respectively. The complementarity of patch and matrix markers in the transplants shows that the transplants do compartmentalize. However, the density of the markers in the transplants did not reach the levels seen in the adult striatum. The results suggest that the commitment of cells to a striatal compartment is a very early event in the embryonic development of the forebrain.