Purpose: To describe the natural history and management of a rare case of iris melanoma in a pediatric patient. Observations: A Caucasian female presented with left pupillary abnormalities at age 7, progressive iris changes at age 9, and markedly elevated intraocular pressure with advanced optic nerve cupping at 11 years of age. She was found to have a pigmented lesion overlying her iris and invading her angle. Trans-corneal fine needle aspirate biopsy demonstrated malignant melanoma of the iris. The patient subsequently underwent Iodine-125 plaque brachytherapy for the tumor. Conclusions: and Importance: Early identification and treatment of iris melanoma may be associated with decreased risk of local progression and metastatic disease. Treatment of glaucoma in conjunction with uveal melanoma is complicated by tumor specific considerations, including treatment of the tumor and prevention of metastasis.

© 2018 The Authors. PURPOSE. To evaluate BRAF, NRAS, and GNAQ mutations in surgical specimens of common and blue conjunctival melanocytic nevi. METHODS. Surgical specimens from 25 conjunctival melanocytic nevi (23 common and 2 blue) of 25 patients were evaluated. All common nevi were analyzed immunohistochemically for the expression of BRAF V600E or NRAS Q61R. One lesion with negative immunoreactivity and for all blue nevi, a hybridization capture-based next-generation sequencing method was employed for mutation analysis. For common nevi, genetic features were compared with clinical and histopathologic findings. Continuous variables (age at excision and largest basal diameter) were compared with a Students’s t-test and all categoric variables were compared with Fisher’s Exact Test. RESULTS. Of common melanocytic nevi, 9 (39.1%) were immunoreactive for NRASQ61R and 13 (56.5%) were immunoreactive for BRAFV600E. One common nevus, which was immunonegative for both BRAFV600E and NRASQ61R was found to harbor an NRASQ61K mutation by sequence analysis. Patients with NRAS-mutated nevi were more likely to report occurrence of the lesion prior to 18-years old and more likely to have intrinsic cysts. The mean largest basal diameter was 6.0 and 3.5 mm for NRAS- and BRAF-immunoreactive lesions, respectively (P = 0.003). GNAQ mutations were identified in each of the two blue nevi of this study. CONCLUSIONS. These findings document that common conjunctival melanocytic nevi have mutually exclusive mutations in BRAF and NRAS. The two conjunctival blue nevi harbored GNAQ mutations. This suggests the driver mutations of conjunctival nevi are similar to those of nevi of the skin. At the molecular level, conjunctival nevi appear more like cutaneous nevi than choroidal nevi.

Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR-targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd3+ binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM-1s-1 at 1.5 T and 25 °C) and strong Gd3+ selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects.

We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 distinct growth patterns of UM metastasis: infiltrative (n = 12) and nodular (n = 3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell–like phenotype were present and formed aggregates of stage I < 50-μm-diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes, and form stage II 51- to 500-μm-diameter and then stage III > 500μm-diameter metastases, which were encapsulated by collagenized fibrous septae. In the nodular growth pattern, CD133+ melanoma cells aggregated adjacent to portal venules and subsequently appeared to grow and efface the adjacent hepatocytes to form stage II 51- to 500-μm-diameter nodules that surrounded the portal venu le. These avascular nodules appeared to further expand to form stage III > 500-μm-diameter nodules that exhibited vascularization with minimal fibrosis. The tumor stem cell–like phenotype seen in individual UM cells was lost as the tumors progressed. There were CD56+ natural killer cells in sinusoidal spaces and CD3+ lymphocytes in periportal areas. The nodular growth pattern showed UM cells expressing MMP9 and VEGF. UM cells in both above-described growth patterns exhibited variable BAP1 expression. We propose that changes in the liver microenvironment are related to metastatic UM growth. We hypothesize that these changes include immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF/PEDF ratio for the nodular pattern.

Background/Aims: To clarify the pathogenesis of fibrosis in inflammatory orbital diseases, we analysed the gene expression in orbital biopsies and compared our Results: with those reported for idiopathic pulmonary fibrosis. Methods: We collected 140 biopsies from 138 patients (58 lacrimal glands; 82 orbital fat). Diagnoses included healthy controls (n=27), non-specific orbital inflammation (NSOI) (n=61), thyroid eye disease (TED) (n=29), sarcoidosis (n=14) and granulomatosis with polyangiitis (GPA) (n=7). Fibrosis was scored on a 0-3 scale by two experts, ophthalmic pathologists. Gene expression was quantified using Affymetrix U133 plus 2.0 microarray. Results: Within orbital fat, fibrosis was greatest among subjects with GPA (2.75±0.46) and significantly increased in tissue from subjects with GPA, NSOI or sarcoidosis ( p<0.01), but not for TED, compared with healthy controls (1.13±0.69). For lacrimal gland, the average score among controls (1.36±0.48) did not differ statistically from any of the four disease groups. Seventy three probe sets identified transcripts correlating with fibrosis in orbital fat (false discovery rate <0.05) after accounting for batch effects, disease type, age and sex. Transcripts with increased expression included fibronectin, lumican, thrombospondin and collagen types I and VIII, each of which has been reported upregulated in pulmonary fibrosis. Conclusions: A pathologist's recognition of fibrosis in orbital tissue correlates well with increased expression of transcripts that are considered essential in fibrosis. Many transcripts implicated in orbital fibrosis have been previously implicated in pulmonary fibrosis. TED differs from other causes of orbital fat inflammation because fibrosis is not a major component. Marked fibrosis is less common in the lacrimal gland compared with orbital adipose tissue.

Although effective drugs that lower intraocular pressure (IOP) in the management of glaucoma exist, their efficacy is limited by poor patient adherence to the prescribed eye drop regimen. To replace the need for eye drops, in this study we tested the hypothesis that IOP can be reduced for one month after a single targeted injection using a microneedle for administration of a glaucoma medication (i.e., brimonidine) formulated for sustained release in the supraciliary space of the eye adjacent to the drug's site of action at the ciliary body. To test this hypothesis, brimonidine-loaded microspheres were formulated using poly(lactic acid) (PLA) to release brimonidine at a constant rate for 35 days and microneedles were designed to penetrate through the sclera, without penetrating into the choroid/retina, in order to target injection into the supraciliary space. A single administration of these microspheres using a hollow microneedle was performed in the eye of New Zealand White rabbits and was found to reduce IOP initially by 6 mm Hg and then by progressively smaller amounts for more than one month. All administrations were well tolerated without significant adverse events, although histological examination showed a foreign-body reaction to the microspheres. This study demonstrates, for the first time, that the highly-targeted delivery of brimonidine-loaded microspheres into the supraciliary space using a microneedle is able to reduce IOP for one month as an alternative to daily eye drops.

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.

Purpose: To evaluate outcomes of choroidal melanoma patients treated with 125 I or 103 Pd plaque brachytherapy. Methods and Materials: From 1993 to 2012, our institution treated 160 patients with 103 Pd (56.1%) and 125 patients with 125 I (43.9%) plaque brachytherapy. Tumor outcomes, visual acuity (VA), and toxicity were compared. Multivariate analyses (MVAs) and propensity score analysis were used to help address differences in baseline characteristics. Results: Median followup was longer for 125 I patients, 52.7 vs. 43.5 months (p < 0.01). At baseline, 103 Pd patients had lower rates of VA worse than 20/200 (4.4% vs. 16%, p = 0.002), T3–T4 tumors (17.5% vs. 32.8%, p = 0.03), and transpupillary thermotherapy use (3.1% vs. 9.6%, p = 0.001). Both 103 Pd and 125 I provided > 90% 3-year overall survival and > 93% 5-year secondary enucleation-free survival. On MVA, radionuclide was not predictive for tumor outcomes. A higher percentage maintained vision better than 20/40 with 103 Pd (63% vs. 35%, p = 0.007) at 3 years. MVA demonstrated 103 Pd radionuclide (odds ratio [OR]: 2.12, p = 0.028) and tumor height ≤5 mm (OR: 2.78, p = 0.017) were associated with VA better than 20/40. Propensity score analysis matched 23 125 I with 107 103 Pd patients. 103 Pd continued to predict better VA at 3 years (OR: 8.10, p = 0.014). On MVA for the development of VA worse than 20/200 or degree of vision loss, radionuclide was not significant. Lower rates of radiation retinopathy were seen with 103 Pd than 125 I (3 years: 47.3% vs. 63.9%, p = 0.016), with radionuclide significant in MVA. Conclusions: Both 125 I and 103 Pd achieve excellent tumor control. An increased probability of long-term VA better than 20/40 and reduced risk of radiation retinopathy is associated with 103 Pd.

Background Endogenous endophthalmitis secondary to Nocardia species is extremely rare but often portends a poor visual prognosis often owing to the advanced nature of disease at presentation and delay in diagnosis. Patients who are systemically immunosuppressed are at greatest risk and early suspicion of the role of this organism in patients with acute panuveitis is paramount. Findings A 66-year-old cardiac transplant patient on oral prednisone, Myfortic, and tacrolimus developed unilateral panuveitis with a focal white subretinal and retinal lesion. His past medical history was notable for Aspergillus pneumonia and cytomegalovirus retinitis in the contralateral eye 12 months prior. Aqueous humor sampling for eubacterial, eufungal, and viral PCR testing, as well as vitreous cultures for bacteria and fungi were unsuccessful in the identification of a causative organism. Progressive enlargement of the lesion was noted despite intravitreal foscarnet, vancomycin, ceftazidime, and voriconazole. A pars plana vitrectomy and retinal and subretinal biopsy led to the identification of Nocardia veterana, a recently identified Nocardia species. A combination of linezolid, meropenem, azithromycin, ceftriaxone, and intravitreal amikacin resulted in eradication of the infection. Conclusion This is the first reported case of N. veterana endogenous endophthalmitis in an immunosuppressed patient. Pars plana vitrectomy with a subretinal biopsy was required to establish a diagnosis, as other testing including aqueous PCR and vitreous cultures were negative. The poor visual outcome in our patient highlights the importance of early consideration of Nocardia in the differential diagnosis of panuveitis with subretinal disease in the context of immunosuppression.