Impact of gene expression profiling on diagnosis and survival after metastasis in patients with uveal melanoma.

Surveillance frequency for metastasis is guided by gene expression profiling (GEP). This study evaluated the effect of GEP on time to diagnosis of metastasis, subsequent treatment and survival. A retrospective study was conducted of 110 uveal melanoma patients with GEP (DecisionDx-UM, Castle Biosciences, Friendswood, Texas, USA) and 110 American Joint Committee on Cancer-matched controls. Surveillance testing and treatment for metastasis were compared between the two groups and by GEP class. Rates of metastasis, overall survival and melanoma-related mortality were calculated using Kaplan-Meier estimates. Baseline characteristics and follow-up time were balanced in the two groups. Patients' GEP classification was 1A in 41%, 1B in 25.5% and 2 in 33.6%. Metastasis was diagnosed in 26.4% ( n  = 29) in the GEP group and 23.6% ( n  = 26) in the no GEP group ( P  = 0.75). Median time to metastasis was 30.5 and 22.3 months in the GEP and no GEP groups, respectively ( P  = 0.44). Median months to metastasis were 34.7, 75.8 and 26.1 in class 1A, 1B and 2 patients, respectively ( P  = 0.28). Disease-specific 5-year survival rates were 89.4% [95% confidence interval (CI): 81.0-94.2%] and 84.1% (95% CI: 74.9-90.1%) in the GEP and no GEP groups respectively ( P  = 0.49). Median time to death from metastasis was 10.1 months in the GEP group and 8.5 months in the no GEP group ( P  = 0.40). There were no significant differences in time to metastasis diagnosis and survival outcomes in patients with and without GEP. To realize the full benefit of GEP, more sensitive techniques for detection of metastasis and adjuvant therapies are required.

VLA-4 blockade suppresses endotoxin-induced uveitis: in vivo evidence for functional integrin up-regulation.

Leukocyte adhesion to the vascular wall is a critical early step in the pathogenesis of inflammatory diseases and is mediated in part by the leukocyte integrin, VLA-4, which binds to endothelial vascular cell adhesion molecule (VCAM) -1. Here, we investigate VLA-4's role in endotoxin-induced uveitis (EIU). At various time points (6-48 h) after EIU induction, the severity of the inflammation was evaluated by quantifying cell and protein content in the aqueous fluid, firm leukocyte adhesion in the retinal vessels, and the number of extravasated leukocytes into the vitreous. Functional activation of VLA-4 in vivo was investigated in our previously introduced autoperfused micro flow chamber assay. Firm adhesion of EIU leukocytes to immobilized VCAM-1 under physiological blood flow conditions was significantly increased compared with normal controls (P<0.05), suggesting an important role for VLA-4 in EIU. VLA-4 blockade in vivo significantly suppressed all uveitis-related inflammatory parameters studied, decreasing the clinical score by 45% (P<0.01), protein content in the aqueous fluid by 21% (P<0.01), retinal leukostasis by 68% (P<0.01), and leukocyte accumulation in the vitreous by 75% (P<0.01). Our data provide novel evidence for functional up-regulation of VLA-4 during EIU and suggest VLA-4 blockade as a promising therapeutic strategy for treatment of acute inflammatory eye diseases.

Patterns of tumor initiation in choroidal melanoma.

This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001). Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

A computerized image analysis method for measuring elastic tissue.

A computerized image analysis technique for quantifying area fractions of elastic tissue in light microscopic sections is presented that considers the nonuniform distribution of the elastic tissue. The method uses Verhoeff-van Gieson stained sections. The analysis is stratified vertically in three uniform layers starting at the dermo-epidermal junction and horizontally by two schemes. A standard method consists of five equally spaced measurements. The densest method uses the three areas that contain the most elastic tissue. The area fractions are determined by counting the positive and total pixels (thresholding). A validity test utilizing independent physical measurements demonstrated differences of no more than 1.7%. Reliability tests for reading the same section on different days and adjacent sections showed no significant differences (p less than 0.05) between the readings. Reliability tests of sections using different stain lots and adjacent biopsy sites also did not have significant differences. This method may be particularly useful for studies in which the distribution of the material to be measured may be very uneven, such as in solar elastosis.

Relative biological effectiveness of modulated proton beams in various murine tissues.

The relative biological effectiveness (RBE) of proton beams produced by Harvard University 160 MeV synchrocyclotron was studied in various murine tissues. Reference radiation was Cobalt-60 gamma-rays from a teletherapy unit at the Massachusetts General Hospital. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Test tissues are: lens, lung, testes and tail vertebrae. The RBE of the third generation isotransplants of a spontaneous mouse mammary carcinoma was also investigated. The proton and Cobalt-60 irradiations were carried out simultaneously by 2 teams. The dose response curves obtained for testes weight loss and growth stunting of tail vertebrae indicated that the RBE for our protons was independent of radiation dose in the range of 0.4 to 16 Gy. This finding was identical to our previous studies of the murine fibrosarcoma, skin and small intestine. The RBE values for lens and lung tissues were obtained by determining radiation dose to result in a complete cataract in half the irradiated eyes in 210 days and a 50% mortality in 180 days respectively. We have studied proton RBE in 7 normal tissues and 2 tumors including previously reported results. The RBE values for these tissues were found to fall between 1.09 and 1.32. No significant differences in the proton RBE were found between the several normal and tumor tissues studied.

Conservative treatment of uveal melanoma: probability of eye retention after proton treatment.

Enucleation was performed after proton treatment in 57 of 1006 (5.7%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986. Only 2% of 99 patients with small tumors and 4% of 566 patients with intermediate size tumors underwent enucleation after treatment; 10% of 341 patients with large tumors lost the treated eye. No eyes were removed after 52 months, with 89% of enucleations performed during the first 36 months after treatment. Eye retention rates at 60 months were 89.1 +/- 3.0% for the entire group, and 97 +/- 3.7%, 92.7 +/- 3.1%, and 78.3 +/- 7.0% in patients with small, intermediate, and large tumors, respectively. Significantly greater enucleation rates were observed in patients with large tumors than in those with intermediate tumors (p = less than .0001), in patients with tumor height greater than 8 mm relative to those with tumors less than or equal to 8 mm, p = (less than .0001), with tumor diameter greater than 16 mm compared to less than or equal to 16 mm, (p = less than .0001), and with tumor involvement of the ciliary body compared to involvement of the choroid only (p = less than .0001). Possible strategies to decrease the likelihood of enucleation in patients at apparently increased risk of losing the eye after conservative therapy, that is, those with large tumors involving the ciliary body, might include a lower total dose, a more protracted treatment course, or a lower radiation dose and adjuvant treatment with chemotherapy and/or immunotherapy, with hyperthermia, or with other radiation sensitizers.

Conservative treatment of uveal melanoma: local recurrence after proton beam therapy.

Twenty-three of 1006 (2.3%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986 received additional treatment for documented (15 patients) or suspected (eight patients) tumor growth in the irradiated eye. Growth within the initially irradiated volume was documented at Massachusetts Eye and Ear Infirmary in 12 patients. Documented growth occurred in nine of 665 (1.4%) patients with small and intermediate size tumors, at times after treatment ranging from 6 to 48 months (median 16 months), and in three of 341 (.9%) patients with large tumors at 7, 11, and 12 months after treatment. Melanoma growing totally outside the treated volume was also documented in three additional patients at 7, 9, and 45 months; two of these were thought to be "ring melanomas". Eight patients had the treated eye removed elsewhere for suspected tumor growth. The additional treatment in these 23 patients was conservative in nine patients (repeat proton irradiation in five and laser photocoagulation in four). Thirteen underwent immediate enucleation and one had orbital exenteration. Ultimately, 17 of the 23 eyes (74%) were removed. Estimated probability of local control of the melanoma within the irradiated eye at 60 months was 96.3 +/- 1.5%. Dose distributions to the 12 patients with documented local failure within the irradiated volume were analyzed. Ten tumors recurred marginally in an area receiving less than the prescribed dose of 70 CGE (CGE = Cobalt Gray Equivalents = proton Gy X RBE 1.1), whereas only two recurred in the volume receiving full dose. Based on these data, it appears that a dose of 70 CGE in five fractions is associated with very high rates of local control in human uveal melanoma. It is reasonable to consider initiating studies using a lower total dose or a more protracted course, to determine if some of the observed complications are dose-related.

Photodynamic therapy using Lu-Tex induces apoptosis in vitro, and its effect is potentiated by angiostatin in retinal capillary endothelial cells.

PURPOSE: To examine the effect of combining angiostatin with photodynamic therapy (PDT) using Lutetium Texaphyrin (Lu-Tex; Alcon, Fort Worth, TX) as a photosensitizer in bovine retinal capillary endothelial (BRCE) and retinal pigment epithelial (RPE) cells and to determine the mode of PDT-induced cell death in these cell lines. METHODS: Cultured BRCE and RPE cells were incubated with angiostatin (500 ng/ml) for 18 hours and subjected to Lu-Tex/PDT, using treatment parameters previously optimized (3 microgram/ml Lu-Tex for 30 minutes followed by timed irradiation at 732 nm). Cellular survival was assessed after a 1-week cellular proliferation. Data were analyzed using Student's t-test. Caspase 3 activity was monitored in cells after PDT using a fluorogenic substrate, (Asp-Glu-Val-Asp)-AFC (7-amino-4-trifluoromethyl coumarin) [DEVD-AFC], of caspase 3. After PDT, expression of Bcl-2, Bcl-x(L), Bax, and Bak was also examined in cell lysates by Western blot analysis. RESULTS: A synergistic cytotoxic effect of angiostatin and Lu-Tex/PDT was observed in BRCE cells at all fluences used (5, 10, and 20 J/cm(2); P

Evaluation of an iris color classification system. The Eye Disorders Case-Control Study Group.

A system for classification of iris color based on standard photographs, developed for use in a multicenter study, is described. Categories of iris color are distinguished based on predominant color (blue, gray, green, light brown, or brown) and the amount of brown or yellow pigment present in the iris. Two trained readers independently graded 339 iris photographs; discrepancies in grades were adjudicated. Measures of interobserver reliability were 0.76 by kappa for exact agreement and 0.97 for weighted kappa. The distribution of iris color grades demonstrates that the system achieved an appropriate level of detail within the authors' study population, which included patients with various racial backgrounds from five urban clinical centers. This simple, reliable classification system for iris color is offered for use in clinical research.

Dynamic sodium chemical shift imaging for the study of aqueous humor flow.

Ocular images were obtained using sodium chemical shift imaging (CSI) and 1,4,7,10-tetraazacyclododecane-N,N'N",N"'-tetramethylenephospho nate thulium (III) [Tm(DOTP)5-], a paramagnetic chemical shift reagent. After injecting the shift reagent into the anterior chamber of rabbits, serial imaging was done, monitoring the change in chemical shift with time. Sodium CSI produced images of the eye in three dimensions, quantitatively depicting the spatial and temporal changes in the concentration of a paramagnetic tracer substance. The Tm(DOTP)5- is eliminated from the anterior chamber by first-order kinetics with a half-life of 49 min. These data suggest that this substance is eliminated from the anterior chamber at the same rate as aqueous humor is replaced. Sodium CSI shows promise as a valuable technique for monitoring fluid dynamics in the living eye.

Evaluation of skin microtopography as a measure of ultraviolet exposure.

A pilot study was conducted to investigate the use of skin microtopography as a semiquantitative noninvasive method for estimating cumulative sun exposure in epidemiologic studies of eye disease. The subjects received a kit through the mail containing materials needed to make a replica of the skin texture of a sun-exposed area of the hand. Each subject previously had undergone a skin biopsy around the same site to evaluate elastotic degeneration, and all were interviewed about past sun exposures. A gradable skin impression was obtained from 96 of 115 (83%) participants after two mailings. The impressions were graded according to the degree of skin texture alteration using standard photographs; interobserver reliability was 0.73 using a weighted kappa statistic. The impression score was correlated most strongly with age (r = 0.53). Independent predictors of higher impression scores (more skin texture changes) were older age, cigar or pipe smoking, less education, lighter iris color, lighter skin color, male gender, and tendency to sunburn. After adjustment for age and the other predictor variables, the biopsy score was not correlated with the impression grade (r = 0.18, P = 0.13). Behaviors indexing sun exposure were not correlated with microtopography. These results suggest that skin microtopography as done in this study reflects aging from intrinsic parameters more than from actinic damage.

Diffusion of high molecular weight compounds through sclera.

PURPOSE: To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size. METHODS: Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera. RESULTS: Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera. CONCLUSIONS: Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.

Transscleral delivery of bioactive protein to the choroid and retina.

PURPOSE: To investigate the feasibility of transscleral drug delivery to the choroid and retina. METHODS: An osmotic pump was used to deliver IgG across the sclera of pigmented rabbits, and levels were measured in the choroid, retina, vitreous humor, aqueous humor, orbit, and plasma over 28 days. This method was then used to deliver an anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb), and its effect on inhibiting vascular endothelial growth factor (VEGF)-induced leukostasis in the choroid and retina was determined by measuring tissue myeloperoxidase (MPO) activity. RESULTS: Levels of retinal and choroidal IgG were significantly higher than baseline at all points up to 28 days (P < or = 0.01). IgG levels in the orbit, vitreous humor, aqueous humor, and plasma were negligible (P > 0.05). MPO activity in the choroid of eyes treated with anti-ICAM-1 mAb was 80% less (P = 0.01) than in eyes receiving an equal rate of delivery of an isotype control antibody. Inhibition of MPO activity in the retina was 70% (P = 0.01). The plasma concentration of anti-ICAM-1 mAb was 31,000-fold less than the concentration in the osmotic pump. CONCLUSIONS: Minimally invasive transscleral delivery can be used to deliver therapeutic levels of bioactive drugs to the choroid and retina with negligible systemic absorption. This method of ocular drug delivery may be used in the treatment of a variety of chorioretinal disorders.

An NMR blood test for uveal melanoma?

In a recent article a simple nuclear magnetic resonance (NMR) blood test was suggested for the detection of the presence of cancer. The test's sensitivity to uveal melanoma of both pre- and posttreatment status has been investigated. Cases in this study were 95 patients with uveal melanoma, and controls were 70 participants in an ongoing case control study of retinal eye disease being conducted at the Massachusetts Eye and Ear Infirmary. Proton NMR evaluations at 4.7 T (200 MHz) were performed on plasma obtained from EDTA and citrated blood samples. The average line-width values were calculated from each spectrum. Statistical analysis revealed that mean proton NMR line widths were essentially equal for patients with treated (18.7 Hz) and untreated tumors (18.4 Hz) and for controls (18.5 Hz). Results based on this data set suggest that proton NMR spectroscopy has little predictive power in the detection of uveal melanoma or in the monitoring of therapy.

Photodynamic therapy of pigmented choroidal melanomas.

PURPOSE: To evaluate the effectiveness of photodynamic therapy with chloroaluminum sulfonated phthalocyanine in the treatment of pigmented choroidal melanomas in a rabbit model. METHODS: Pigment containing B16F10 murine melanoma cells were implanted transclerally into the subchoroidal space of 28 immunosuppressed New Zealand albino rabbits. The animals were treated with daily injections of cyclosporine and were followed up until tumors at least 2 mm in height were detected by ultrasonography. Twenty-four hours after the intravenous injection of chloroaluminum sulfonated phthalocyanine (CASPc, 5 mg/kg), tumors were irradiated at 675 nm through an argon-pumped dye laser at estimated total light doses of 25 to 70 J/cm2. Control animals were treated with light only or photosensitizer only. The animals were followed up for 4 1/2 to 8 weeks with regular fundus examinations. RESULTS: Twenty tumor-bearing rabbits were treated with light and dye. The tumor regressed in 12 animals. Five of these animals were followed up for at least 4 1/2 weeks and the other seven for 8 weeks after treatment. At light doses under 40 J/cm2, tumor regrowth was observed in five animals within 10 days of treatment. In all control groups, the tumor-bearing eyes were filled with tumor cells by the third week after implantation. Histologic examination of tumors treated with photosensitizer and light revealed prominent vascular damage early after treatment that resulted in vascular occlusion. Tumor necrosis was evident within 24 hours of treatment. CONCLUSIONS: Results suggest that photodynamic therapy may have a role in the treatment of pigmented choroidal melanomas.

A feasibility study of 23Na magnetic resonance imaging of human and rabbit vitreal disorders.

PURPOSE: To assess the clinical feasibility of sodium magnetic resonance imaging for the visualization and characterization of intraocular tissues. METHODS: 23Na magnetic resonance images were obtained of enucleated human eyes and of rabbit eyes in vivo. The magnetic resonance imaging technique used in this study provided slices of < 2 mm thickness and in-plane resolution of < 2 x 2 mm. From each of these slices local values of spin-spin relaxation time (T2*) were calculated from pixel intensities in each of the eight echoes. RESULTS: The images clearly display normal anatomic details of the lens and vitreous humor, and important pathologic details such as intravitreal and subretinal hemorrhages, ocular melanoma, and retinal detachments. Intraocular tissue identifications based on relative spin-spin relaxation time values and pixel intensities correlate with those made by standard diagnostic techniques. CONCLUSIONS: 23Na magnetic resonance imaging may be used for the visualization and characterization of intraocular tissues. Differentiation among vitreous humor, lens, aqueous humor, subretinal fluid, or hemorrhage and tumor may be based on image intensity and/or spin-spin relaxation times.

Effects of photodynamic therapy using verteporfin on experimental choroidal neovascularization and normal retina and choroid up to 7 weeks after treatment.

PURPOSE: To study the long-term effects of photodynamic therapy (PDT), using liposomal benzoporphyrin derivative (BPD) or Verteporfin, on experimental choroidal neovascularization (CNV) and on normal retina and choroid (with no CNV) in the cynomolgus monkey eye. METHODS: Photodynamic therapy was performed in 8 cynomolgus monkey eyes with experimental CNV induced by laser injury. The effect of PDT on normal retina and choroid (with no CNV) was studied in 9 monkey eyes. Liposomal BPD was administered intravenously (0.375 mg/kg) either as a bolus, as a slow infusion over 32 minutes, or as a fast infusion over 10 minutes. Photodynamic therapy was performed using light at a wavelength of 689 or 692 nm, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2. Follow-up studies, including fundus photography and FA, were performed at 24 hours after PDT and then weekly. Indocyanine green and BPD angiography were performed in selected cases. Tissues were examined with light and electron microscopy at the end of follow-up. RESULTS: Twenty-three of the 32 areas of CNV treated with PDT showed absence of angiographic leakage at 24 hours. Twenty-eight areas of CNV were followed for 4 weeks; 22 of 28 showed absence of angiographic leakage at 2 weeks; and 20 of 28 at 4 weeks of follow-up. Forty spots on the normal retina and choroid were treated with PDT and were followed for 4 to 7 weeks. These spots showed pigment-laden cells in the outer retina, variably pigmented retinal pigment epithelium (RPE) in the treated area, intact neurosensory retina, and reperfusion of the choriocapillaris. CONCLUSIONS: Photodynamic therapy leads to absence of angiographic leakage for at least 4 weeks in experimental CNV in the monkey model. In the normal monkey eye the RPE and choriocapillaris show generalized recovery with preservation of the neurosensory retina 7 weeks after PDT.

Serum zinc and serum lipid profiles in 778 adults.

There has been increasing use of high-dosage zinc supplementation in the population, in particular as a potential treatment for age-related macular degeneration. We examined the relationship between fasting serum zinc and serum lipid levels in 778 adults, aged 22 to 80 years, who were control subjects in a multicenter, clinic-based case-control study. The samples were taken during 1987 to 1990, a time when vitamin/mineral supplementation was becoming increasingly common. We found that higher serum zinc levels, most notably those above the highest quintile, were associated with higher levels of total serum cholesterol, low-density-lipoprotein cholesterol, and triglycerides. No significant trend was noted for high-density-lipoprotein cholesterol. Previous studies demonstrated that high-dosage zinc supplements raise serum zinc levels. The possibility that use of such supplements can adversely affect serum lipid profiles suggests that chronic ingestion of such supplements should not be done without adequate medical supervision.

Case-control study of idiopathic retinal detachment.

A case-control study of idiopathic, rhegmatogenous retinal detachment (IRD) was conducted to investigate potential risk factors for developing IRD. These included some factors reported previously, such as cardiovascular disease, and some not under suspicion, such as cigarette smoking and iris colour. Cases (n = 198) were incident cases of IRD who were hospitalized for surgical repair of their detachments. Controls (n = 655) were patients hospitalized for conditions unrelated to suspected risk factors for IRD. The risk of IRD appeared to increase with increasing age, and the relative risk for self-reported myopes, compared with non-myopes, was elevated (RR = 3.4, 95% CI = 2.3 - 5.0). The relative risk of IRD was decreased in current smokers (RR = 0.5, 95% CI = 0.3 - 0.8); although there was not a significant trend of decreasing relative risk with increasing amount smoked, the estimate was lowest in those who smoked most heavily. Risk did not appear to be related to gender, eye colour, history of myocardial infarction, or history of hypertension.

Peripapillary subretinal neovascularization in presumed sarcoidosis.

Peripapillary subretinal neovascularization developed in both eyes of two young women with bilateral chronic granulomatous uveitis. Despite intensive medical therapy, central vision was lost in two eyes owing to disciform scarring that extended to the macula. The neovascularization in the other two eyes was treated successfully with argon laser photocoagulation. Neither of the patients had the clinical or roentgenographic findings typical of sarcoidosis. Both, however, showed elevated serum angiotensin-converting enzyme activity, which provides indirect evidence for the diagnosis of sarcoid uveitis.