A Systematic Comparison of Dose Distributions Delivered in 125I Plaque Brachytherapy and Proton Radiation Therapy for Ocular Melanoma.

PURPOSE: To characterize dose distributions with 125I plaque brachytherapy compared with proton radiation therapy for ocular melanoma for relevant clinical scenarios, based on tumor base diameter (d), apical height (h), and location. METHODS AND MATERIALS: Plaque and proton treatment plans were created for 4 groups of cases: (1) REF: 39 instances of reference midsize circular-base tumor (d = 12 mm, h = 5 mm), in locations varying by retinal clock hours and distance to fovea, optic disc, and corneal limbus; (2) SUP: 25 superiorly located; (3) TEMP: 25 temporal; and (4) NAS: 25 nasally located tumors that were a fixed distance from the fovea but varying in d (6-18 mm) and h (3-11 mm). For both modalities, 111 unique scenarios were characterized in terms of the distance to points of interest, doses delivered to fovea, optic disc, optic nerve at 3 mm posterior to the disc (ON@3mm), lens, and retina. Comparative statistical evaluation was performed with the Mann-Whitney U test. RESULTS: Superior dose distributions favored plaque for sparing of (1) fovea in large (d + h ≥ 21 mm) NAS tumors; (2) ON@3mm in REF cases located ≤4 disc diameters from disc, and in NAS overall. Protons achieved superior dose sparing of (1) fovea and optic disc in REF, SUP, and TEMP; (2) ON@3mm in REF >4 disc diameters from disc, and in SUP and TEMP; and (3) the lens center overall and lens periphery in REF ≤6 mm from the corneal limbus, and in TEMP with h = 3 mm. Although protons could completely spare sections of the retina, plaque dose was more target conformal in the high-dose range (50% and 90% of prescription dose). CONCLUSIONS: Although comparison between plaque and proton therapy is not straightforward because of the disparity in dose rate, prescriptions, applicators, and delivery techniques, it is possible to identify distinctions between dose distributions, which could help inform decisions by providers and patients.

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment.

IMPORTANCE: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. OBJECTIVE: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. DESIGN: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). RESULTS: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. CONCLUSIONS: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.

Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal. (i.p.) injection of 17-AAG or vehicle. Twenty-four hours later, the retinas were extracted and assayed for leukocyte adhesion; blood-retinal barrier breakdown; VEGF, TNF-alpha, IL-1beta, and CD14 protein levels; NF-kappaB and HIF-1alpha activity; hsp90 and 70 levels and expression and phosphorylation of the tight junction proteins ZO-1 and occludin. 17-AAG treatment significantly suppressed the LPS-induced increase in retinal leukocyte adhesion; vascular leakage; NF-kappaB, HIF-1alpha, p38, and PI-3K activity; and VEGF, TNF-alpha, and IL-1beta levels. 17-AAG also suppressed phosphorylation of ZO-1 and occludin by inhibiting their association with p38 and PI-3K. Although 17-AAG treatment did not reduce the LPS-induced increase in total CD14 levels in leukocytes, it significantly decreased membrane CD14 levels. These data suggest that Hsp90 inhibition suppresses several cardinal manifestations of endotoxin-induced uveitis in the rat. 17-AAG has demonstrated a favorable safety profile in clinical trials in cancer patients and represents a promising therapeutic agent for the treatment of inflammatory eye diseases.

MRI of blood volume with superparamagnetic iron in choroidal melanoma treated with thermotherapy.

Functional magnetic resonance imaging (MRI) with a new intravascular contrast agent, monocrystalline iron oxide nanoparticles (MION), was applied to assess the effect of transpupillary thermotherapy in a rabbit model of choroidal melanoma. 3D-spoiled gradient recalled sequences were used for quantitative assessment of blood volume. The MRI-parameters were 5/22/35 degrees (time of repetition (TR)/echo delay (TE)/flip angle (FA)) for T(1)- and 50/61/10 degrees for T(2)-weighted sequences. Images were collected before and at different times after MION injection. In all untreated tissues studied, MION reduced the T(2)-weighted signal intensity within 0.5 h and at 24 h (all p <== 0.012), whereas no significant changes were detected in treated tumors. T(1)-weighted images also revealed differences of MION-related signal changes between treated tumors and other tissues, yet at lower sensitivity and specificity than T(2). The change of T(2)-weighted MRI signal caused by intravascular MION allows early distinction of laser-treated experimental melanomas from untreated tissues. Further study is necessary to determine whether MRI can localize areas of tumor regrowth within tumors treated incompletely.

MRI of blood volume with MS 325 in experimental choroidal melanoma.

Functional magnetic resonance imaging (MRI) allows quantitative blood volume imaging in vivo at high tissue resolution. The purpose is to apply this technique for untreated and hyperthermia-treated experimental choroidal melanoma. MS 325 was used as new intravascular albumin-bound gadolinium-based contrast agent. Pigmented choroidal melanomas were established in albino rabbits. MRI was performed in 7 untreated eyes and 7 eyes treated with a Neodymium:Yttrium-Lanthanum-Fluoride-laser at 1047 nm. 3D-spoiled gradient echo pulse sequences were used to acquire T' weighted axial images. First, a set of images was collected without contrast agent. MS 325 was then injected i.v. and images were obtained within 12 min after injection. Signal intensities were measured within tumor, ciliary body, choroid, and iris and relative signal intensities were determined for these tissues in relation to vitreous. In untreated tumors, the relative signal intensity was higher after injection of MS 325 (5.61+0.70) than without MS 325 (2.90+0.33; p = 0.0002). In contrast, the relative signal intensity of treated tumors did not differ significantly before and after MS 325 (6.19+1.59 and 6.13+1.64). Histopathological sections indicated vascular occlusion in treated tumors. All other studied tissues of untreated and treated eyes showed a significant increase of relative signal intensities in the presence of MS 325. An animal model for the research on contrast agents in MRI is presented. Blood volume measurement with MS 325 was adapted for experimental choroidal melanomas. Reduced change of relative signal intensity indicates compromised blood volume after vascular occlusion in hyperthermia-treated melanoma. Further studies are needed to investigate whether this technique allows the evaluation of tumor viability following treatments.

Treatment of experimental choroidal melanoma with an Nd:yttrium-lanthanum-fluoride laser at 1047 nm.

OBJECTIVE: To evaluate the effect of a new infrared laser in the destruction of pigmented choroidal melanomas. METHODS: B16F10 melanomas were implanted in the subchoroidal space of 64 rabbits (tumor height, 2.0-4.0 mm). Laser radiation from an Nd:yttrium-lanthanum-fluoride laser (1047 nm) was delivered as a focused (beam waist, 25 micro m; irradiance, 100 kW/cm( 2)) raster-scanned transpupillary beam. To investigate melanin heating, treatment with focused light was compared with collimated light (beam waist, 2 mm; irradiance, 16 W/cm(2)). Fine-wire thermocouples were implanted at the base of 3 tumors for in vivo temperature measurements. Untreated animals were used as controls. RESULTS: Of 64 animals, 27 received a single treatment with focused 1047-nm light. The rate of complete tumor eradication was 91% (10 of 11 animals) at a dosage of 125 J/cm(2) and 75% (9/12) at 63 J/cm(2) to 87 J/cm(2). The eradication rate dropped to 25% (1 of 4) at 38 J/cm(2) or less (P<.001). Continuous tumor growth was observed in all animals treated with collimated radiation and in untreated controls. Temperature measurements indicated that tissue heating at the tumor base was more rapid at 1047 nm than at 805 nm. CONCLUSIONS: These data suggest that a single treatment with a focused, raster-scanned beam at 1047 nm may play a role in the destruction of pigmented choroidal melanoma. Focused irradiation at 1047 nm may provide more effective submillisecond heating of melanin than collimated irradiation, resulting in immediate photothermal disruption of tumor cells.