Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n. =. 20) and patients with GPA (n. =. 6), NSOI (n. =. 25), sarcoidosis (n. =. 7), or thyroid eye disease (TED) (n. =. 20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays.Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>. 1.5-fold difference, false discovery rate adjusted p. <. 0.05). The immunoglobulin family of genes had the most dramatic increase in expression. Although gene expression in GPA could be readily distinguished from gene expression in TED, sarcoidosis, or controls, a comparison of gene expression in GPA versus NSOI found no statistically significant differences.Thus, forms of orbital inflammation can be distinguished based on gene expression. NSOI/pseudotumor is heterogeneous but often may be an unrecognized, localized form of GPA.

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

Copyright © 2020 The Authors, Liver metastases often progress from primary cancers including uveal melanoma (UM), breast, and colon cancer. Molecular biomarker imaging is a new non-invasive approach for detecting early stage tumors. Here, we report the elevated expression of chemokine receptor 4 (CXCR4) in liver metastases in UM patients and metastatic UM mouse models, and development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive MRI detection of UM liver metastases. ProCA32.CXCR4 exhibits high relaxivities (r1 = 30.9 mM−1 s−1, r2 = 43.2 mM−1 s−1, 1.5 T; r1 = 23.5 mM−1 s−1, r2 = 98.6 mM−1 s−1, 7.0 T), strong CXCR4 binding (Kd = 1.10 ± 0.18 μM), CXCR4 molecular imaging capability in metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables detecting UM liver metastases as small as 0.1 mm3. Further development of the CXCR4-targeted imaging agent should have strong translation potential for early detection, surveillance, and treatment stratification of liver metastases patients.

© 2016 International Journal of Ophthalmology (c/o Editorial Office). All rights reserved. Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the fn wtocontrol release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.

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Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. PURPOSE: This study tested the hypothesis that highly targeted intrastromal delivery of bevacizumab using coated microneedles allows dramatic dose sparing compared with subconjunctival and topical delivery for treatment of corneal neovascularization.METHODS: Stainless steel microneedles 400 μm in length were coated with bevacizumab. A silk suture was placed in the cornea approximately 1 mm from the limbus to induce corneal neovascularization in the eyes of New Zealand white rabbits that were divided into different groups: untreated, microneedle delivery, topical eye drop, and subconjunctival injection of bevacizumab. All drug treatments were initiated 4 days after suture placement and area of neovascularization was measured daily by digital photography for 18 days.RESULTS: Eyes treated once with 4.4 μg bevacizumab using microneedles reduced neovascularization compared with untreated eyes by 44% (day 18). Eyes treated once with 2500 μg bevacizumab using subconjunctival injection gave similar results to microneedle-treated eyes. Eyes treated once with 4.4 μg subconjunctival bevacizumab showed no significant effect compared with untreated eyes. Eyes treated with 52,500 μg bevacizumab by eye drops three times per day for 14 days reduced the neovascularization area compared with untreated eyes by 6% (day 18), which was significantly less effective than the single microneedle treatment. Visual exam and histological analysis showed no observable effect of microneedle treatment on corneal transparency or microanatomical structure.CONCLUSIONS: This study shows that microneedles can target drug delivery to corneal stroma in a minimally invasive way and demonstrates effective suppression of corneal neovascularization after suture-induced injury using a much lower dose compared with conventional methods.

Retinoblastoma (RB) is an ocular tumor of early childhood. Current treatments attempt to preserve visual function, but may spare chemoresistant tumor cells. One potential therapeutic target for RB is HER2, (ERBB2), expressed in RB in truncated form. In this study, we tested the hypothesis that Her2 DNA and RNA are expressed in RB tumors and adjacent retina. We examined 24 human RB tumors as well as normal-appearing adjacent retinal tissues for Her2 DNA and RNA expression by in situ hybridization. We also examined 28 RB tumors for HER2 protein immunoreactivity. 21/22 RB tumors expressed Her2 DNA and 14/19 tumors expressed Her2 RNA. In 17 paired cases, there were three cases in which Her2 DNA was detected, but not RNA. We also saw Her2 RNA signal in six instances of "normal" adjacent retinal tissue. Heterogeneous HER2 protein expression in specific tumor regions also was confirmed by quantitative HER2 immunohistochemistry. In summary, Her2 DNA and RNA are expressed in many RB tumors, and in some adjacent ocular tissues, with hetereogenous protein expression throughout. These results may provide important insights regarding RB tumor progression, and drug targeting approaches designed to spare the eye, preserve vision and improve quality of life for RB patients.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Uveal melanoma is the most common primary intraocular malignancy in adults, with nearly half of all patients eventually developing metastases, which are invariably fatal. Manual assessment of the level of expression of the tumor suppressor BRCA1-associated protein 1 (BAP1) in tumor cell nuclei can identify patients with a high risk of developing metastases, but may suffer from poor reproducibility. In this study, we verified whether artificial intelligence could predict manual assessments of BAP1 expression in 47 enucleated eyes with uveal melanoma, collected from one European and one American referral center. Digitally scanned pathology slides were divided into 8176 patches, each with a size of 256 × 256 pixels. These were in turn divided into a training cohort of 6800 patches and a validation cohort of 1376 patches. A densely-connected classification network based on deep learning was then applied to each patch. This achieved a sensitivity of 97.1%, a specificity of 98.1%, an overall diagnostic accuracy of 97.1%, and an F1-score of 97.8% for the prediction of BAP1 expression in individual high resolution patches, and slightly less with lower resolution. The area under the receiver operating characteristic (ROC) curves of the deep learning model achieved an average of 0.99. On a full tumor level, our network classified all 47 tumors identically with an ophthalmic pathologist. We conclude that this deep learning model provides an accurate and reproducible method for the prediction of BAP1 expression in uveal melanoma.

Purpose: To report the clinical and histopathological findings associated with congenital fibrovascular pupillary membranes. Design: Case series. Participants: Seven infants; six with a unilateral congenital pupillary membrane and one with classic persistent fetal vasculature (PFV). Methods: Patients underwent a membranectomy, pupilloplasty and/or a lensectomy. Histopathological examination was performed on the excised membranes. Main Outcome Measures: Visual acuity and pupil size. Results: Four of the 6 patients with a unilateral congenital pupillary membrane had one or more recurrences after a membranectomy and pupilloplasty. The most recent pupil size ranged from 2 to 5 mm in the affected eye. When last tested, the vision in the affected eye was excellent in 4 of the 6 patients. The two patients without recurrences of the pupillary membranes underwent multiple iris spincterotomies at the time of the initial surgery. Histopathological examination of two primary pupillary membranes showed fibrovascular tissue that did not stain for neuron specific enolase. Smooth muscle actin was only present in vascular walls. In contrast, histopathology of a recurrent pupillary membrane revealed collagenized fibrovascular tissue that was immunoreactive for smooth muscle actin. Finally, histopathology of the retrolenticular membrane excised from an infant with classic PFV was similar to the latter aside from hypercellularity. Conclusions: Congenital fibrovascular pupillary membranes in infants are likely a variant of PFV that may recur if incompletely excised. The risk of these membranes recurring may be reduced by excising as much as the membrane as possible and enlarging the pupil with iris spincterotomies. A lensectomy should be avoided if possible.

Neovascular ('wet') age-related macular degeneration (AMD) is the leading cause of blindness among Caucasians over the age of 55 in the USA and is an important cause of ocular morbidity worldwide. Progress in oncology, and more recently ophthalmology, led to the development of VEGF antagonists, three of which are now approved for the treatment of wet AMD. Recent discoveries in ophthalmology and vascular biology, however, suggest that combined inhibition of VEGF and platelet-derived growth factor (PDGF) may be more beneficial than inhibition of VEGF alone. Accordingly, numerous studies are underway to evaluate the role of anti-VEGF/PDGF combination therapies for the treatment of wet AMD. This review discusses the biology of VEGF and PDGF and current preclinical and clinical data exploring the use of combined VEGF/PDGF inhibitors in the treatment of neovascular age-related macular degeneration. © Informa UK, Ltd.