1996 Jules Gonin Lecture of the Retina Research Foundation. Long-term results after proton irradiation of uveal melanomas.
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Adolescent↗
Biomedical subjects
E S Gragoudas
Publications and source records attributed to E S Gragoudas.
Choroidal metastases from renal cell carcinoma.
BACKGROUND: Choroidal metastases from renal cell carcinoma are uncommon. The authors investigated the clinical characteristics of patients with renal cell carcinoma in whom choroidal metastases developed. METHODS: The clinical records of five patients with histopathologically confirmed renal cell carcinoma and choroidal metastases were reviewed retrospectively. RESULTS: In four patients, choroidal metastases were either the sole initial manifestation of disease or were the initial manifestation of metastatic disease. The interval from nephrectomy to the onset of ocular signs ranged from 6 to 18 years. A reddish-orange appearance of the tumor was present in two patients, but no pathognomonic features distinguishing these tumors from other choroidal metastases were identified. CONCLUSIONS: Ocular metastases may precede the diagnosis of renal cell carcinoma or may follow it by years or decades. This interval between its ocular and systemic presentation may be so prolonged as to obscure the relation between the choroidal metastases and the primary tumor. In patients with amelanotic or reddish choroidal lesions without known metastatic disease, evaluation of the kidney may be warranted as part of a metastatic workup to exclude metastatic renal cell carcinoma.
Aged↗
Localization of lipoprotein-delivered benzoporphyrin derivative in the rabbit eye.
PURPOSE: Photodynamic therapy (PDT) using the photosensitizer Benzoporphyrin derivative monoacid (BPD-MA or verteporfin) is currently under investigation for the treatment of choroidal neovascularization. We investigated the localization of this photosensitizer using fluorescence microscopy and quantified its presence in ocular tissues after porphyrin extraction using fluorescence spectroscopy. METHODS: Albino rabbits were administered 2mg/kg BPD-MA pre-complexed with low density lipoprotein (LDL) intravenously, or given no treatment. The eyes were enucleated at intervals between 5 minutes and 24 hours after dye injection and were studied with light and fluorescence microscopy, or dissected for porphyrin extraction. RESULTS: At 5 minutes after dye injection, there was bright fluorescence from the choroid and retinal pigment epithelium (RPE) with trace retinal outer segment fluorescence. After 20 minutes, there was increased photoreceptor outer segment and RPE fluorescence but decreased choroidal fluorescence. By 2 hours no fluorescence remained in either the choroid or the photoreceptors and there was diminished fluorescence of the RPE. Trace RPE fluorescence was still visible at 24 hours. Fluorescence localization of liposomal BPD (2mg/kg) at the earliest (5 minutes) time point was indistinguishable from that of the BPD-LDL complex. Using spectrofluorimetry, the highest BPD-MA levels from the eye were measured in the retina/RPE/uvea complex with lower levels measured from the sclera and other tissues. CONCLUSIONS: BPD-MA with LDL rapidly accumulates in the choroid, RPE, and photoreceptors after intravenous injection. Future studies of PDT with BPD-MA for the treatment of fundus disorders may need to address the relationship between dye localization and photodynamically-mediated injury.
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An evaluation of tumour vascularity as a prognostic indicator in uveal melanoma.
Experimental and clinical evidence suggests that tumour angiogenesis plays a role in the tendency for certain neoplasms, including cutaneous melanomas, to metastasize. We evaluated whether tumour vasculature is associated with the rate of metastases in patients with melanoma of the choroid or ciliary body. The study was based on a group of 63 patients enucleated between 1976 and 1984 with paraffin-embedded tissue blocks available for sectioning and with known survival status as of December 1988. Vessel endothelial cells were highlighted with Ulex europaeus agglutinin I (UEA-I) conjugated with peroxidase. UEA-I-stained microvessels were counted at varying levels in the tumour (apex, centre and base) without knowledge of patient outcome. Patients with (n = 30) and without (n = 33) metastases had similar total vessel counts (P = 0.31). There was no evidence of greater vessel density in tumours that had metastasized, by level within the tumour. Similar results were obtained in multivariate analyses. Findings of this study suggest that tumour microvessel density is unrelated to patient survival in uveal melanoma.
Adult↗
Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate.
OBJECTIVE: To determine if the angiogenic peptide vascular endothelial growth factor (VEGF) is required for retinal ischemia-associated iris neovascularization in a nonhuman primate. METHODS: Laser retinal vein occlusion was used to produce retinal ischemia in 16 eyes of eight animals (Macaca fascicularis). Eyes were randomized to treatment every other day with intravitreal injections of either a neutralizing anti-VEGF monoclonal antibody or a control monoclonal antibody of the same isotype. Serial iris fluorescein angiograms were assessed using a standardized grading system and masked readers. Retinal VEGF and placental growth factor expression were assessed by Northern blotting. The specificity of the antibodies was determined in capillary endothelial cell proliferation assays prior to intravitreal injection. RESULTS: Zero of eight eyes receiving the neutralizing anti-VEGF antibodies developed iris neovascularization. Five of eight control antibody-treated eyes developed iris neovascularization. The difference was statistically significant (P = .03). Intravitreal antibody injection did not impair the ability of the ischemic retina to increase VEGF messenger RNA expression. The anti-VEGF antibodies specifically inhibited VEGF-driven capillary endothelial cell proliferation in vitro. CONCLUSION: These data demonstrate that VEGF is required for iris neovascularization in an adult nonhuman primate eye. The inhibition of VEGF is a new potential therapeutic strategy for the treatment of ocular neovascularization.
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Photodynamic therapy of pigmented choroidal melanomas using a liposomal preparation of benzoporphyrin derivative.
OBJECTIVE: To evaluate the effectiveness of photodynamic therapy of pigmented choroidal melanoma using a liposomal preparation of benzoporphyrin derivative monoacid (BPD), verteporfin. DESIGN: Pigmented choroidal melanomas were established in 25 New Zealand albino rabbit eyes. The animals were treated with daily injections of cyclosporine, and tumor growth was monitored with funduscopic examination and ultrasonography. Fifteen minutes after intravenous injection of BPD (2 mg/kg), the tumors were irradiated at 692 nm through an argon-pumped dye laser with the delivered fluence ranging between 40 and 150 J/cm2. Control animals were treated with light only, photosensitizer only, or observation only. Tumor growth was monitored by indirect ophthalmoscopy, fundus photography, fluorescein angiography, and ultrasonography. Histologic examination was performed. RESULTS: Eighteen tumor-bearing rabbits were treated with light and BPD; 16 were followed up for 1 month, and two were killed immediately for histologic examination. Tumors regressed in all eyes treated with 60 J/cm2 or more. With fluence of 40 J/cm2, tumor regrowth was observed in one animal within 10 days of treatment. In the three control groups, all animals showed continuous tumor growth. Histologic examination of the eyes treated with photosensitizer and light immediately after treatment showed prominent vascular occlusion throughout the full thickness of the tumor. One month after treatment, tumor necrosis and infiltration of mononuclear cells and pigment-laden macrophages were the predominant findings. CONCLUSIONS: Photodynamic therapy with BPD may have a role in the treatment of pigmented choroidal melanomas.
Animals↗
Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate.
OBJECTIVE: To determine whether the angiogenic peptide vascular endothelial growth factor (VEGF) is sufficient to produce iris neovascularization in a nonhuman primate (Macaca fascicularis). METHODS: Eight eyes of 4 animals were studied. The 165-amino acid isoform of human recombinant VEGF (VEGF165) was injected into the vitreous of 5 cynomolgus monkey eyes (doses ranging from 0.25-2.5 micrograms per injection). Equal amounts of inactivated human recombinant VEGF (2 eyes) or vehicle (1 eye) were injected into contralateral control eyes. Eyes were assessed by slitlamp biomicroscopy, tonometry, iris color photography, fluorescein angiography, histopathologic examination, and immunostaining with antibodies against proliferating cell nuclear antigen. RESULTS: All 5 bioactive VEGF-injected eyes developed neovascularization with dilated and tortuous iris vessels that leaked fluorescein. None of the 3 control eyes exhibited any iris vascular changes. Inflammation was absent in both treatment groups. A dose response to VEGF was observed in the single animal that received 2.5 micrograms and 0.25 microgram in the right and left eyes, respectively. Iris vessel endothelial cells were positive for proliferating cell nuclear antigen in the bioactive VEGF-injected eyes only. Injections of 1.25 micrograms of VEGF every 3 days during a 30-day period produced advanced iris neovascularization, ectropion uvea, and neovascular glaucoma. CONCLUSIONS: Intravitreal injections of recombinant human VEGF165 in amounts comparable with those measured in eyes with active neovascularization are sufficient to produce noninflammatory iris neovascularization in a nonhuman primate. Prolonged exposure to VEGF165 can produce ectropion uveae and neovascular glaucoma.
Animals↗
Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal neovascularization.
OBJECTIVE: To compare the effectiveness of photodynamic therapy to close experimental choroidal neovascularization using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin) with previous work using a rapid intravenous injection, before initiating clinical trials. METHODS: Choroidal neovascularization was induced in cynomolgus monkey eyes using argon laser. Liposomal benzoporphyrin derivative was delivered by an intravenous infusion pump for 10 or 32 minutes at a dose of 0.375 mg/kg. Irradiation was performed with 689- or 692-nm laser light (600-mW/cm2 irradiance and 150-J/cm2 fluence) in 7 normal eyes and 11 eyes with choroidal neovascularization between 30 and 105 minutes after the start of dye infusion. Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy. RESULTS: Irradiation within 32 to 50 minutes of the start of the fast (10 minutes) or slow (32 minutes) dye infusion resulted in closure of choroidal neovascularization. In normal eyes, this technique caused choriocapillaris closure and retinal pigment epithelium damage with minimal damage to surrounding tissues. CONCLUSION: Photodynamic therapy using intravenous infusion of liposomal benzoporphyrin derivative selectively closed experimental choroidal neovascularization. This may be a suitable modality for clinical use.
Animals↗
Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors.
Benzoporphyrin derivative (BPD), a sensitizer currently in clinical trials, was evaluated for the treatment of experimental Greene melanoma implanted in the rabbit iris. To improve tumor targeting, BPD was complexed with low-density lipoprotein (LDL) representing an endogenous carrier system for BPD as previously described. Twelve tumors were irradiated at a sensitizer dose of 2 mg kg-1 body weight using a dye laser at 692 nm. Tumor responses were documented by photography, angiography and light and electron microscopy. All tumors treated with 80 J cm-2 regressed irreversibly. The principal mechanism of tumor necrosis was thrombosis following disruption of endothelial membranes. Ultrastructure data suggested tumor cell damage, although evidence for this being the result of direct PDT-mediated tumor cell death was less clear. These data suggest that BPD-LDL may be used to improve the selectivity of photodynamic tumor therapy possibly by the increased uptake of lipoprotein-delivered sensitizer to neovascular endothelial cells.
Animals↗
Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness.
PURPOSE: The purpose of the study is to determine the effect of photodynamic therapy in the destruction of experimental pigmented choroidal melanomas > or = 3 mm in thickness using a liposomal preparation of benzoporphyrin derivative, verteporfin. METHODS: Pigmented choroidal tumors were established in 32 New Zealand albino rabbit eyes. Animals were treated with daily injections of cyclosporine, and tumor growth was followed by serial fundus examinations and ultrasonography. When a tumor exceeded 3 mm in thickness (tumor height ranged from 3.1-4.6 mm), the authors administered benzoporphyrin derivative intravenously (1 mg/kg) and irradiated the tumor at 692-nm through an argon-pumped dye laser at different total light doses ranging from 60 to 120 J/cm2. Control animals were treated with light or benzoporphyrin derivative only. Each animal then was followed-up for 4 to 6 weeks by fundus photography, fluorescein angiography, and ultrasonography. RESULTS: All animals treated with benzoporphyrin derivative and light at fluences of > or = 80 J/cm2 showed complete tumor arrest. In contrast, both control groups showed continuous tumor growth in all animals with tumors filling most of the vitreous cavity by 3 weeks. Histologic examination results of tumors treated with dye plus light immediately after treatment showed prominent vascular closure. No vascular changes were noted in the control eye treated with light or dye alone. Examination results of the eyes that showed tumor regression after a 4-week follow-up period showed tumor necrosis and extensive infiltration of mononuclear cells and pigment-laden macrophages at the tumor site. CONCLUSIONS: These data suggest that photodynamic therapy may have a role in the management of pigmented choroidal melanomas.
Animals↗
Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate.
PURPOSE: The purpose of the study is to determine the effect of exogenous vascular endothelial growth factor (VEGF) on the primate retina and its vasculature. METHODS: Ten eyes of five animals were studied. Physiologically relevant amounts of the 165 amino acid isoform of human recombinant VEGF were injected into the vitreous of six healthy cynomolgus monkey eyes. Inactivated human recombinant VEGF or vehicle was injected into four contralateral control subject eyes. Eyes were assessed by slit-lamp biomicroscopy, tonometry, fundus color photography, fundus fluorescein angiography, light microscopy, and immunostaining with antibodies against proliferating cell nuclear antigen and factor VIII antigen. RESULTS: All six bioactive VEGF-injected eyes developed dilated, tortuous retinal vessels that leaked fluorescein. Eyes receiving multiple injections of VEGF developed progressively dilated and tortuous vessels, venous beading, edema, microaneurysms, intraretinal hemorrhages and capillary closure with ischemia. The severity of the retinopathy correlated with the number of VEGF injections. None of the four control eyes exhibited any abnormal retinal vascular changes. The endothelial cells of retinal blood vessels were proliferating cell nuclear antigen positive only in the bioactive VEGF-injected eyes. CONCLUSION: Vascular endothelial growth factor is sufficient to produce many of the vascular abnormalities common to diabetic retinopathy and other ischemic retinopathies, such as hemorrhage, edema, venous beading, capillary occlusion with ischemia, microaneurysm formation, and intraretinal vascular proliferation.
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Liposomal benzoporphyrin derivative verteporfin photodynamic therapy. Selective treatment of choroidal neovascularization in monkeys.
PURPOSE: The authors have previously shown that photodynamic therapy (PDT) using lipoprotein-delivered benzoporphyrin derivative mono-acid (BPD) effectively closed experimental choroidal neovascularization (CNV). In the current study, the authors used a clinical preparation, liposomal BPD verteporfin in the same model, with experiments designed to establish optimal dye and light doses, and the timing of laser light irradiation after dye injection, for effective and selective closure of CNV. METHODS: Experimental CNV was induced in the maculae of cynomolgus monkeys. Liposomal BPD verteporfin was injected intravenously at doses of 1.0, 0.5, 0.375, and 0.25 mg/kg. Laser light at 692 nm then was applied to CNV, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2, at various times after dye injection, ranging from 5 to 120 minutes. Treatment effect was assessed by fundus photography and fluorescein angiography and confirmed by light and electron microscopy. The PDT of experimental CNV was studied to assess efficacy; PDT performance on normal eyes was studied to investigate selectivity. RESULTS: The CNV closure was demonstrated by fluorescein angiography and histopathologic findings at all tested dye doses. A dye dose of 0.375 mg/kg, with laser light irradiation applied 20 to 50 minutes after dye injection, optimized CNV closure with minimal retinal and choroidal damage. No major local adverse effects were noted, and the drug was well tolerated systematically. CONCLUSIONS: Liposomal BPD verteporfin is a potent photosensitizer, and PDT using this dye is a potentially effective and selective treatment for CNV.
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Visual-field deficits associated with proton beam irradiation for parapapillary choroidal melanoma.
PURPOSE: A large series of patients treated with proton irradiation for parapapillary choroidal melanoma were reviewed retrospectively to determine the frequency of radiation papillopathy and visual-field loss after treatment. METHODS: Among 249 patients with proton irradiation for parapapillary choroidal melanoma, the authors identified 59 patients who had visual-field testing performed before treatment and at least 18 months after treatment. The visual fields, color fundus photographs, and charts were reviewed to determine the prevalence of radiation papillopathy and visual-field loss after treatment. RESULTS: Nineteen of the 59 patients reviewed (31%) received a clinical diagnosis of radiation papillopathy. Progressive visual-field loss, defined as enlargement of absolute scotoma of greater than [corrected] or equal to 30 degrees as compared with the pretreatment visual field, was noted in 67% of patients with radiation papillopathy and 73% of patients without papillopathy. In both groups, visual-field loss correlated with the area of the retina predicted to be exposed to irradiation in the majority of patients. CONCLUSIONS: Progressive visual-field loss is common after proton irradiation for parapapillary choroidal melanoma. However, the scotoma usually correlates with the area of the retina exposed to irradiation. The development of radiation papillopathy does not appear to be associated with additional visual-field defects in most cases.
Adult↗
The subretinal fibrosis and uveitis syndrome.
The subretinal fibrosis and uveitis syndrome is a rare posterior uveitis characterized in the early stages by a multifocal choroiditis, followed by progressive subretinal fibrosis. It usually is seen in otherwise healthy, young myopic women with no systemic disease. Symptoms include acute, unilateral visual loss, scotomas, metamorphopsia, and photopsias. Ophthalmic examination reveals a mild anterior or posterior uveitis, and transient, multiple, small, whitish-yellow RPE or choroidal lesions in the posterior pole and midperiphery. These lesions fade or enlarge and coalesce to create areas of white subretinal fibrosis, a progression that occurs over weeks to months. The visual prognosis generally is poor, and recurrences are common. Treatment is controversial, with some authors finding an early beneficial effect of steroids and chemotheraphy in severe cases. The etiology is not known, but is believed to be a localized autoimmune reaction to the RPE.
Blindness↗
Rhegmatogenous retinal detachment in eyes with uveal melanoma.
PURPOSE: To describe the clinical features, surgical management, and outcome of patients with uveal melanoma who presented with or later developed a rhegmatogenous retinal detachment. METHODS: We retrospectively identified four patients who presented with uveal melanoma and rhegmatogenous retinal detachment simultaneously and six patients in whom a rhegmatogenous retinal detachment developed 11-100 months (mean, 44.8 months) after radiotherapy for a choroidal melanoma. RESULTS: All four patients with simultaneous presentation of uveal melanoma and retinal detachment underwent successful retinal detachment repair (cases 1 and 4, scleral buckle; case 2, pars plana vitrectomy, and case 3, pneumatic retinoplexy). Rhegmatogenous retinal detachment occurring after proton beam or plaque radiotherapy of uveal melanoma was repaired successfully in five of six patients with scleral buckling alone or in combination with pars plana vitrectomy. In the short follow-up period of this study, we did not observe tumor recurrence either before or after retinal detachment repair. CONCLUSION: Rhegmatogenous retinal detachment associated with uveal melanoma may be treated successfully using conventional retinal surgical techniques. The benefits of retinal detachment repair must be weighed against any theoretical increased risk of extra-scleral extension of the melanoma. Long-term follow-up evaluation will be required to determine the safety of various retinal detachment repair techniques in these eyes.
Aged↗
Constitutional alterations in p16 in patients with uveal melanoma.
Chromosome 9p21 contains a susceptibility gene for cutaneous melanoma. Recent studies suggest that the gene responsible may be CDK41, since it encodes a putative cell cycle inhibitor, p16, and is frequently lost or rearranged in melanoma cell lines. In this study we examined whether germline alterations in CDK41 could be identified in patients with melanoma of the uveal tract. From an archive of bloods collected from patients with uveal melanoma, we identified 13 samples drawn from patients with a history in a family member of uveal (n = 6) or cutaneous (n = 7) melanoma. An additional 24 'control' bloods (without melanoma or any other primary malignancy in a family member), similar to the 'cases' in age and number of first-degree relatives, were also selected for study. For each sample, DNA was extracted from the red blood cell fraction. Using the polymerase chain reaction-single strand conformation polymorphism method, we screened for alterations in p16. Specific changes were characterized by DNA sequencing. Six nucleotide changes were detected in five (13.5%) of the 37 samples examined. An altered gene was found in one (7.7%) of the 13 patients with a family history (of intra-ocular melanoma) and four (16.7%) of the 24 patients with no family history (P = 0.64) of melanoma. In this series the group with a positive family history was predominantly female and most pedigrees involved matrilineal descent. In these data prevalence of germline alteration in p16 was similar in familial and sporadic cases. The results provide evidence against a significant role for p16 in familial clustering of intra-ocular and cutaneous melanomas.
Adult↗
Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin.
OBJECTIVE: To investigate photodynamic therapy of experimental choroidal neovascularization using benzoporphyrin derivative monoacid (Verteporfin). METHODS: Photodynamic therapy using benzoporphyrin derivative monoacid was investigated in cynomolgus monkeys. Following intravenous injection of benzoporphyrin derivative monoacid (1 to 2 mg/kg) complexed with low-density lipoprotein, the eyes were irradiated with 692-nm light at a fluence of 50 to 150 J/cm2 and irradiance of 150 to 600 mW/cm2. Choroidal neovascularization was documented before photodynamic therapy and closure was demonstrated by fundus photography, fluorescein angiography, and light and electron microscopic examination. RESULTS: Following photodynamic therapy, vessels within choroidal neovascularization were occluded, and there was damage to the choroidal neovascularization endothelium and the subjacent choriocapillaris. Damage to the retinal pigment epithelium and photoreceptors was also observed. CONCLUSION: Photodynamic therapy with lipoprotein-delivered benzoporphyrin derivative monoacid was effective in this animal model of choroidal neovascularization and may be a promising, potentially selective, therapy for choroidal neovascularization.
Animals↗