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After inoculation into the upper lip of mice, HSV1 established latency in several nervous system structures that have direct or indirect connections with ocular tissues. These results suggest that after an oral primary infection, the most frequent in humans, HSV1 may establish latency in several sites connected to the eye and may finally result in herpetic ocular disease involving the cornea, the iris, or even the retina.

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We previously reported that intratumoral injection of AdK3, a recombinant adenovirus encoding human angiostatin kringle (K) 1 to 3, inhibits tumor vascularization and tumor growth. To reduce the serum clearance of this factor, we constructed an adenovirus (AdK3-HSA) that carries a chimeric gene encoding a fusion protein between angiostatin K1-3 and human serum albumin (HSA). This conjugate inhibited endothelial cell proliferation as efficiently as K1-3. K3-HSA serum concentrations in immunodeficient mice systemically injected with AdK3-HSA were dramatically higher than in AdK3-injected mice. Furthermore, the growth of MDA-MB-231 tumors grafted into nude mice that had been injected intravenously with AdK3-HSA was inhibited by 79% (versus 17% with AdK3). In TRP-1/SV40 Tag transgenic mice, which spontaneously develop eye tumors with brain metastases, intravenous injections of AdK3-HSA in newborn mice blocked metastatic dissemination efficiently and significantly, and prolonged survival by 3 weeks. After 2 months, only 46% of AdK3-HSA-treated animals developed micrometastases, whereas 94% of the AdCO1-injected group displayed numerous macrometastases. Nevertheless, ocular tumor growth was not modified because of impaired diffusion of the conjugate in the eye compartment. Our results show that HSA genetic coupling is an efficient way to increase the pharmacokinetics of circulating angiogenic inhibitors and thus their antitumoral activity.

To evaluate the efficacy and safety of proton beam therapy for complicated circumscribed choroidal hemangiomas. Methods: The study was a retrospective nonrandomized investigation. Seventeen consecutive patients, referred to the Institut Gustave-Roussy, Villejuif, France, for circumscribed choroidal hemangioma associated with serous retinal detachment were studied. Each eye received a total dose of 20 cobalt gray equivalents (CGEs) delivered in 15-second fractions of 5 CGEs over 4 days. Functional tests included the initial and final bestcorrected visual acuity, slitlamp examination, intraocular pressure, fundus examination, fluorescein angiography, and indocyanine green angiography. Tumor thickness was determined on B-scan ultrasonography. Results: The macula was involved in 7 eyes and the lesion was juxtapapillary in 2 eyes. The mean (SD) tumor thickness was 3.06 (9.0) mm. The mean initial tumor diameter was 6.82 mm (range, 3.2-12.1 mm). The right eye was involved in 7 cases and the left eye in 10 cases. The mean (SD) follow-up period was 52 (58) months (range, 36-90 months). Retinal reattachment was obtained in all cases after a mean period of 2 months (range, 1-12 months; median, 1 month). Tumor regression was obtained in all cases. One recurrence occurred 1 year after the initial treatment in an undertreated area. After re-treatment, however, resolution of the retinal detachment occurred, and flattening of the choroidal lesion was obtained. Final visual acuity improved to 2 Snellen lines or more in 16 eyes (94%), was stable in 1 eye, and attained 20/40 or more in 12 eyes (70.6%). No radiation therapy complications occurred during follow-up. Conclusions: Proton beam therapy for choroidal hemangiomas seems to be an effective and safe alternative option. A total dose of 20 CGEs delivered in 4 daily 15second fractions of 5 CGEs seems adequate for local control of both the tumor and serous retinal detachment.

Herpetic retinitis in humans is characterized by a high frequency of bilateral localization. In order to determine the possible mechanisms leading to bilateral retinitis, we studied the pathways by which herpes simplex virus type 1 (HSV-1) is propagated from one retina to the other after intravitreal injection in mice. HSV-1 strain SC16 (90 p.f.u.) was injected into the vitreous body of the left eye of BALB/c mice. Animals were sacrificed 1, 2, 3, 4 and 5 days post-inoculation (p.i.). Histological sections were studied by immunochemical staining. Primary retinitis in the inoculated eye (beginning 1 day p.i.) was followed by contralateral retinitis (in the uninoculated eye) starting at 3 days p.i. Infected neurons of central visual pathway nuclei (lateral geniculate nuclei, suprachiasmatic nuclei and pretectal areas) were detected at 4 days p.i. Iris and ciliary body infection was minimal early on, but became extensive thereafter and was accompanied by the infection of connected sympathetic and parasympathetic pathways. The pattern of virus propagation over time suggests that the onset of contralateral retinitis was mediated by local (nonsynaptic) transfer in the optic chiasm from infected to uninfected axons of the optic nerves. Later, retinopetal transneuronal propagation of the virus from visual pathways may have contributed to increase the severity of contralateral retinitis.

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.