Iris and Ciliary Body Melanocytomas Are Defined by Solitary GNAQ Mutation Without Additional Oncogenic Alterations.

OBJECTIVE: To analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication. DESIGN: Retrospective case-control study. SUBJECTS: Patients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea. METHODS: Targeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features. MAIN OUTCOME MEASURES: Presence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence. RESULTS: Hotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized. CONCLUSIONS: In this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.

Trends in Radiation Practices for Female Ocular Oncologists in North America: A Collaborative Study of the International Society of Ocular Oncology.

BACKGROUND: The aim of this study was to determine the known radiation exposure, attitudes, and consequent risk modifications among female ocular oncologists in North America who routinely administer radioactive plaque brachytherapy treatment and are members of the International Society of Ocular Oncology. METHODS: Nineteen female ocular oncologists completed an anonymous 17-question radiation exposure survey. RESULTS: Eleven of the participants chose to routinely wear lead protection during surgery; 8 did not. Fifteen of 19 participants reported using an unloaded "nonactive" template to prepare for plaque implantation. During pregnancy, 11 of 13 participants continued to perform plaque brachytherapy. Eight of these 11 undertook measures to decrease radiation exposure self-reported as lead wear and other. The average reported anxiety regarding fertility was 2.1 (SD, 2.2) on a scale from 1 to 10. CONCLUSION: This study corroborates prior literature that surgeons' exposure to radiation during plaque brachytherapy is minimal. Nonetheless, there remains some anxiety regarding exposure risk to women, due to potential effects on fertility and fetal health. We found variability in exposure monitoring, required training, and precautions during pregnancy amongst this group of surgeons. Improved education and clearer pregnancy guidelines may equip female ocular oncologists with optimal knowledge regarding risk of radiation exposure.

Proptosis Caused by Rhabdomyomatous Mesenchymal Hamartomata Occurring in the Orbit.

Two infants were referred for progressive orbital proptosis. MRI in both cases demonstrated a homogenous mass in the orbit adherent to and isointense with a rectus muscle. Histopathology in both cases demonstrated a bland proliferation of spindle cells with entrapped skeletal muscle. Immunochemistry demonstrated that the abnormal tissue was of skeletal muscle origin, consistent with rhabdomyomatous mesenchymal hamartoma (RMH). Observation was elected due to the reported benign nature of RMH. In contrast to RMH of the cutaneous tissues that typically follows a benign course, RMH of the orbit may present with rapid growth.

Histology of Müller's muscle observed in quiescent Graves' orbitopathy.

OBJECTIVE: Histologic examination of Müller's muscle (MM) in patients with clinically significant upper eyelid retraction secondary to Graves' orbitopathy (GO). DESIGN: Prospective, single-blinded, comparative experimental study at a single institution. PARTICIPANTS: Patients from a single San Francisco Bay Area practice (RZS). METHODS: Consecutive patients with upper eyelid retraction secondary to GO who underwent surgical correction by transcutaneous mullerectomy were recruited between January and December 2011. An equal number of control MM specimens were gathered in consecutive patients undergoing conjunctivo-MM resection for ptosis correction. A total of 10 specimens in each group was available for analysis. The proportion of fat and fibrosis, as well as inflammatory markers, was studied and graded in both the study and the control group by a masked pathologist. These data were compared between groups using the Student t-test. RESULTS: No significant difference between the 2 groups of MM specimens was detected. CONCLUSIONS: Patients with quiescent GO with clinically significant eyelid retraction exhibit normal MM histology.

Defective retinal vascular endothelial cell development as a consequence of impaired integrin αVß8-mediated activation of transforming growth factor-ß.

Deletions of the genes encoding the integrin αVß8 (Itgav, Itgb8) have been shown to result in abnormal vascular development in the CNS, including prenatal and perinatal hemorrhage. Other work has indicated that a major function of this integrin in vivo is to promote TGFß activation. In this paper, we show that Itgb8 mRNA is strongly expressed in murine Müller glia and retinal ganglion cells, but not astrocytes. We further show that Itgb8 deletion in the entire retina severely perturbs development of the murine retinal vasculature, elevating vascular branch point density and vascular coverage in the superficial vascular plexus, while severely impairing formation of the deep vascular plexus. The stability of the mutant vasculature is also impaired as assessed by the presence of hemorrhage and vascular basal lamina sleeves lacking endothelial cells. Specific deletion of Itgb8 in Müller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with αVß8's role in TGFß1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGFß signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGFßRII gene recapitulates the major deficits observed in the Itgb8 and TGFß1 mutants. Of special interest, the retinal vascular phenotypes observed in each mutant are remarkably similar to those of others following inhibition of neuropilin-1, a receptor previously implicated in TGFß activation and signaling.

The expression of STAT-1 and phosphorylated STAT-1 in conjunctival granulomas.

PURPOSE: Sarcoidosis is a granulomatous inflammatory disease whose cause is unknown. Based on gene expression profiles of peripheral blood and on immunostaining of lymph nodes from sarcoidosis patients, the authors recently implicated the transcription factor STAT-1 in the pathogenesis. They explored the potential contribution of STAT-1 in an ocular manifestation of this disease. METHODS: Conjunctival biopsies from 4 subjects with known sarcoidosis and from 8 subjects with conjunctival granulomas presumed from causes other than sarcoidosis were immunostained for STAT1. RESULTS: STAT-1 was readily detectable in all biopsies from patients with sarcoidosis and in 3 controls. The activated form of STAT-1, phosphorylated STAT-1, was also more frequently detected in tissue from subjects with sarcoidosis relative to controls. CONCLUSIONS: The activities of STAT-1 in regulating the inflammatory response suggest that it contributes to the conjunctival granulomas characteristic of sarcoidosis, but its expression is not specific for either sarcoidosis or all granulomatous conjunctival disease.

Blindness from orbital varices: case report.

A 41-year-old woman presented with a 21-year history of a left orbital mass. She reported 3 distinct episodes of sudden proptosis, periorbital bruising, pain, nausea and vomiting with resulting stepwise deterioration in her vision. Her symptoms resolved spontaneously over several days, with the exception of loss in vision, which persisted. Examination was notable for ipsilateral enophthalmos in primary gaze. With Valsalva she developed proptosis. Magnetic resonance imaging (MRI) demonstrated a left orbital apex malformation consistent with a varix. She had no light perception on the left with end-stage optic atrophy. This case illustrates the severity of visual loss that can occur with orbital varices.

Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma.

CONTEXT: Treatment recommendations assume that repeated mass antibiotic distributions can control, but not eradicate or even locally eliminate, the ocular strains of chlamydia that cause trachoma. Elimination may be an important end point because of concern that infection will return to communities that have lost immunity to chlamydia after antibiotics are discontinued. OBJECTIVE: To determine whether biannual treatment can eliminate ocular chlamydial infection from preschool children and to compare results with the World Health Organization-recommended annual treatment. DESIGN, SETTING, AND PARTICIPANTS: A cluster-randomized clinical trial of biannual vs annual mass azithromycin administrations to all residents of 16 rural villages in the Gurage Zone, Ethiopia, from March 2003 to April 2005. INTERVENTIONS: At scheduled treatments, all individuals aged 1 year or older were offered a single dose of oral azithromycin either annually or biannually. MAIN OUTCOME MEASURE: Village prevalence of ocular chlamydial infection and presence of elimination at 24 months in preschool children determined by polymerase chain reaction, correcting for baseline prevalence. Antibiotic treatments were performed after sample collections. RESULTS: Overall, 14,897 of 16,403 eligible individuals (90.8%) received their scheduled treatment. In the villages in which residents were treated annually, the prevalence of infection in preschool children was reduced from a mean of 42.6% (range, 14.7%-56.4%) to 6.8% (range, 0.0%-22.0%) at 24 months. In the villages in which residents were treated biannually, infection was reduced from 31.6% pretreatment (range, 6.1%-48.6%) to 0.9% (range, 0.0%-4.8%) at 24 months. Biannual treatment was associated with a lower prevalence at 24 months (P = .03, adjusting for baseline prevalence). At 24 months, no infection could be identified in 6 of 8 of those treated biannually and in 1 of 8 of those treated annually (P = .049, adjusting for baseline prevalence). CONCLUSION: Local elimination of ocular chlamydial infection appears feasible even in the most severely affected areas, although it may require biannual mass antibiotic distributions at a high coverage level. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00221364.