Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization.

The aim of this study was to test the selectivity, in-vivo effectiveness, and potential mechanism of action of a linomide analogue (N-phenyl-1,2-dihydro-4-hydroxyl-2-oxo-quinoline-3-carboxamide, Lin05) for inhibition of choroidal neovascularization. The selectivity of Lin05 was tested in cell proliferation assays with human umbilical vein endothelial cells (HUVEC) and a retinal pigmented epithelial cell line(ARPE-19). In-vivo anti-angiogenic effect of Lin05 was investigated utilizing an experimental laser-induced choroidal neovascularization (ECNV) model in adult Brown Norway rats. Western blot and/or reverse transcriptase-PCR was used to test the effect of Lin05 on potential targets. Our results indicate that Lin05 is at least an 8-fold more selective inhibitor of endothelial cell proliferation compared to RPE cells. Systemic administration of Lin05 in an ECNV model was associated with a significant decrease in both vascular leakage on fluorescein angiography and lesion size by histopathology (p = 0.02). No systemic toxicity was detected for Lin05 in major organs such as the liver, lung and kidneys. Lin05 did not inhibit VEGF-induced VEGFR2 (KDR) phosphorylation in HUVEC nor was associated with decreased VEGF gene expression. Also it did not inhibit insulin-like growth factor (IGF-1) and Epidermal Growth Factor (EGF) induced activation of p42/p44 MAPK activation. It inhibited both PDGF- and bFGF-induced p42/p44 MAPK phosphorylation. However, the effect on PDGF was variable in different HUVEC cells. In conclusion, Lin05 is a potential anti-angiogenic agent for the treatment of eye diseases associated with pathological neovascularization. The anti-angiogenic effect of Lin05 is likely through inhibition of bFGF but not through inhibition of the VEGF/KDR pathway.

Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The extent of the contribution of familial/hereditary predisposition to the development of uveal melanoma is largely unknown. Thus we sought to ascertain the frequency of cancers in patients with UM and their family members to identify the prevalence of hereditary/familial predisposition to cancer in these patients. An unselected series of 121 patients with UM seen in a university-based tertiary referral program were consented to the study. Cancer histories (site and age of diagnosis) were obtained for all first- and second-degree relatives. Patients/families were classified as being potentially at high risk for hereditary predisposition if they met any of the following criteria: (1) Diagnosis of UM at age 30 or under, (2) Two or more cases of UM in the family, (3) UM plus at least one other primary cancer in the same patient (excluding non-melanoma skin and cervix cancers due to their strong environmental etiological link). (4) Family history meeting high risk criteria for a known hereditary cancer predisposition syndrome as defined by Hampel et al. (J Med Genet 41(2): 81-91, 2004). One patient had a family history of UM (0.8%). Ten patients (8.3%) had a personal and/or family history consistent with predisposition to a known hereditary cancer syndrome including six with possible hereditary breast, two with hereditary colon and two with hereditary melanomas. Twenty three patients (19%) had a personal history of a second cancer after exclusion of non-melanoma skin and cervical cancers. The frequency of cutaneous melanomas was significantly higher in UM patients than the general population (RR: 2.97, 95% CI: 1.00-6.94). Patients with a family history suggestive of a high risk predisposition to a known cancer syndrome had a significantly higher risk for having a second cancer than the remaining UM patients (P = 0.02). Our results indicate that the frequency of UM patients with high risk for a hereditary cancer predisposition is much higher than earlier estimates (0.6%) and that it could be as high as 11.6%. Our results suggest that cancer phenotypes in these patients are diverse and include cancers other than UM. Thus, alerting ophthalmologists to the need for expanding their cancer family history intake to include other cancers is warranted. It also suggests that patients with a hereditary predisposition to UM have a higher risk for the development of other cancers and that characterization of the germline genetic alterations in these patients is highly warranted.

Bungee cord-associated ocular injuries.

PURPOSE: To report ocular injuries associated with the use of bungee cords. METHOD: Four patients with bungee cord-associated ocular trauma are presented. RESULTS: Four eyes of four patients demonstrated severe contusion injuries associated with bungee cord trauma. Ocular injuries in the four eyes included a variable combination of corneal abrasion, hyphema, iridodialysis, anterior chamber angle recession, secondary glaucoma, lens subluxation, vitreous hemorrhage, and retinal detachment. Three of the four eyes required ophthalmic surgery. All eyes had anterior chamber angle recession and required continuing ophthalmic care. CONCLUSION: Bungee cords may be associated with severe ocular injury and should be used with caution.

Interferon alfa-associated retinopathy.

Interferon alfa and its related compounds have been used for more than 10 years in the treatment of a number of conditions including viral illnesses, childhood hemangiomas, various cancers, and leukemia. The potential applications for this class of medication continue to grow. The use of interferon alfa in experimental protocols has also increased, thus making it more likely that new indications will be discovered. It is probable that primary care physicians will be called on to initiate therapy or will see patients being treated with interferon in their practice. We report the development of interferon-related retinopathy in a 43-year-old man while he was receiving experimental treatment with interferon alfa for hepatitis B virus and hepatitis C virus infection. The vision loss was acute and only partially reversible. Interferon, its mechanism of action, and the past literature are briefly discussed.

False-positive magnetic resonance imaging of a metastatic carcinoma simulating a malignant melanoma.

Previous studies have shown the value of magnetic resonance imaging (MRI) in the diagnosis of malignant melanoma of the choroid. We describe the case of a patient with a choroidal mass whose MRI study was characteristic of malignant melanoma. Subsequently the eye was enucleated. However, on histopathologic examination, the mass was a metastatic carcinoma to the choroid. This false-positive study makes us question the value of MRI in the diagnosis of malignant melanoma of the choroid.

Retinoblastoma, microphthalmia, coloboma, and neuroepithelioma of the pineal body.

A one-month-old infant boy was examined early in life because his mother had bilateral retinoblastoma and his father had bilateral microphthalmia. The ophthalmologist found his right eye was normal size with a coloboma of the iris, choroid, and retina. The left eye was microphthalmic with a coloboma of the uveal tract and retina. A vascularized fluffy white mass in the posterior pole was diagnosed clinically as a retinoblastoma. The tumor regressed with radiation. When the patient was four years of age, a large tumor was found in the region of the pineal recess, causing hydrocephalus and seizures. A biopsy showed an undifferentiated malignant neuroepithelial neoplasm. The patient died within three months of diffuse central nervous system tumor. The unusual findings of a retinoblastoma in a microphthalmic eye with bilateral colobomas and a neuroepithelial neoplasm of the pineal gland are discussed.

Systemic immunostimulation after retinal laser treatment in retinitis pigmentosa.

Systemic immunostimulation followed an experimental treatment trial of scatter argon laser photocoagulation directed to the retina of one eye of 10 patients with heredo-degenerative retinitis pigmentosa (RP). Significantly increased RP lymphocyte CD25, CD26, and CD4/CD26 activation epitope expressions over prelaser values and controls were found with a normalization of soluble interleukin-2 receptor secretion after laser treatment. Serum interferon-gamma was low both pre- and postlaser. Interestingly, when a panel of viral antibodies was tested, only those to rubella virus were elevated in the early postlaser period. The character of RP immunostimulation after laser-induced inflammation could be consistent with an antigenic stimulus from laser-released retinal proteins which might be of autoimmune or latent infectious origin. Enhanced immune responses may be a common but unrecognized sequellae of retinal laser.

Modified vitrectomy for impending macular holes.

We report a consecutive series of 13 eyes (11 patients) treated with pars plana vitrectomy, in which surgical manipulation of the prefoveal layer of cortical vitreous was avoided, for stage I (eight eyes) and stage II (five eyes) macular hole formation. Average follow up was 8.1 months (range, 2 to 13 months). There was no significant improvement in vision in the patients with stage II macular holes; however, vision in these patients stabilized and did not fall below 20/400. Visual acuity improved in seven of the eight patients with stage I holes. The results for both these groups achieved by our modified vitrectomy, which is relatively easy to perform and involves minimal intraoperative manipulation of the fovea, are consistent with those obtained by methods involving more aggressive cortical vitreous stripping of the fovea.

A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma.

A randomized controlled clinical trial of methanol-extracted residue of bacille Calmette-Guerin adjuvant treatment of posterior uveal melanoma was undertaken. Of 113 patients, 34 patients received adjuvant immunotherapy and 79 patients received no treatment. No difference in survival was observed between the adjuvant-treated group and the control group of patients. This study found that the size of the tumor was a highly significant risk factor for death caused by metastasis of uveal melanomas. The standard deviation of the nucleolar area of the neoplastic cells was a significant risk factor, even though patients with tumors composed of Callender's spindle-type cells were not included in the study.

Ocular toxicity of vitreal pluronic polyol F-127.

To evaluate pluronic polyol F-127 (PF-127) as a vitreous substitute and an intraocular drug delivery system, a total vitrectomy was performed on 18 New Zealand rabbits (18 eyes). The vitreous was replaced with either PF-127 (9 eyes) or balanced salt solution (9 eyes). There was little difference clinically between the eyes containing PF-127 and the control eyes. Both groups showed mild postoperative inflammation, with no differences in intraocular pressures. Histopathologic findings for the control group showed no significant retinal alteration, and serial ERG findings were within normal limits. In contrast, the eyes containing PF-127 showed marked destruction of the retina by 2 weeks after surgery. The ERG amplitudes decreased dramatically to a flat tracing by 24 hours after surgery. Although it is attractive as a potential vitreous substitute, PF-127 is not safe for human use, at least at the concentration used.

Magnetic resonance imaging of uveal melanomas.

A series of 31 patients who presented with uveal mass lesions was studied with magnetic resonance imaging (MRI). Uveal melanoma was the presumed clinical diagnosis in 23 of the cases. Ten (43%) of these suspected melanomas provided useful images on both spin-lattice (T1)- and spin-spin (T2)-weighted studies and these had characteristic features. The features include a high-intensity image on T1-weighted studies with progressively decreasing relative intensity on T2-weighted images. These findings are consistent with short T1 and T2 relaxation times. In contrast, three cases of carcinoma metastatic to the choroid demonstrated a relatively high signal intensity on both T1- and T2-weighted images. The short relaxation times exhibited by uveal melanomas are in contrast with the relatively long T1 and T2 times found in other malignant neoplasms. These characteristics may provide a noninvasive method for differentiation of malignant melanoma from other mass lesions within the uveal tract.

Radiotherapy for choroidal melanoma. An 18-year experience with radon.

Twenty-three patients were treated with radon therapy for choroidal melanoma at the Ohio State University Hospitals, Columbus, between 1968 and 1976. We present an 18-year experience, including follow-up of at least eight years, in all those receiving therapy. Three patients (13%) died of metastatic disease. Four patients (17.4%) died of other causes. Sixteen patients (69.6%) were alive, with no signs of metastatic disease. Eight patients subsequently required enucleation due to inadequate tumor response. Of the 15 patients who demonstrated successful tumor destruction and retained their eyes, 13 (86.7%) developed substantial irradiation-induced retinopathy, including hard exudates, telangiectasias, neovascularization, microaneurysms, intraretinal and vitreous hemorrhages, secondary glaucoma, and irradiation-induced cataract. Our long-term results indicate a high incidence of both vascular complications and decreased visual acuity.

Incidence of misdiagnosed and unsuspected choroidal melanomas. A 50-year experience.

The eye pathology files at Ohio State University, Columbus, were examined for a 50-year period to determine the percentage of misdiagnosis of uveal melanomas in three separate time periods (1931 through 1959, 1960 through 1969, and 1970 through 1981) and the percentage of unsuspected melanomas during these same periods. Of 395 eyes enucleated for choroidal melanoma, 369 had clear media. Histologic examination of these eyes showed that 13 (3.5%) did not contain a melanoma. The incidence of misdiagnosis decreased from 10.9% in 1931 through 1959 to 1.7% in 1960 through 1981. Of 411 choroidal melanomas present on histologic examination, 37 (9%) were unsuspected. All had opaque media. This percentage, when categorized by the aforementioned periods, decreased from 19.6% to 13.3% to 2.4%, respectively. These results confirm the reliability of indirect ophthalmoscopy, widely used since the 1960s, in the diagnosis of melanoma in the presence of clear media and the reliability of ultrasonography, used since 1970, in the diagnosis of melanoma in eyes with opaque media.

Ossoinig's angle of ultrasonic absorption and its role in the diagnosis of malignant melanoma.

Using standardized A-scanning, we have defined a method of quantitating the attenuation of ultrasound through intraocular mass lesions. In a retrospective study using 43 histologically proven melanomas, the attenuation of ultrasound through these tumors was characterized by an angle that we termed "Ossoinig's angle of ultrasonic absorption." This angle was measured on the static Ascans, and the values for melanomas clustered nicely in the 40 to 65 degrees range. The series of tumors also was used to illustrate previously published criteria for the ultrasound diagnosis of malignant melanomas, emphasizing their echographic differences from other lesions.