Vitreous microparticles contain apoptotic signals suggesting a diabetic vitreopathy.

AIM: To evaluate differences in microparticle profiles in vitreous samples between diabetic and non-diabetic eyes undergoing vitrectomy. METHODS: Un-masked cross-sectional series of 34 eyes undergoing vitrectomy. Vitreous specimens were collected and processed to evaluate for membrane integrity (DAPI), apoptosis (Annexin-V), and endothelial-cell origin (V-Cadherin). A BD LSR II flow cytometer was used for analysis and standardized sub-micron-sized beads were used for size comparison. RESULTS: Thirty-four specimens underwent analysis. Greater levels of Annexin-V were found on microparticles from specimens in which blood had entered the vitreous (n=12) compared to those without blood (n=22; 52.3%±30.7% vs 19.6%±27.2%, P=0.002). Patients with diabetes having surgery with hemorrhage (n=7) had greater expression of Annexin-V than those without hemorrhage (n=8; 62.1%±31.7% vs 18.9%±20.9%, P=0.009). However, in patients with non-diabetic vitreous hemorrhage, the level of Annexin-V expression was not significantly different compared to other disease processes (38.6%±25.7%, n=5 vs 20.0%±30.9%, n=14, P=0.087). CONCLUSION: Increased expression of the apoptotic marker, Annexin-V is detected on vitreous microparticles in diabetes-related vitreous hemorrhage. When evaluating vitreous hemorrhage in patients without diabetes, the apoptotic signal is not significantly different. Vitrectomy in patients with diabetes, and improvement in visual outcomes, may be related to the removal of a serum-derived, pro-apoptotic vitreous. Further investigation is warranted in order to identify the molecular characteristics of microparticles that regulate disease.

BILATERAL CHOROIDAL DETACHMENTS SECONDARY TO IPILIMUMAB AND PEMBROLIZUMAB USE.

PURPOSE: To report the occurrence of bilateral choroidal detachments due to the use of ipilimumab and pembrolizumab immunochemotherapeutics to treat widely metastatic cutaneous melanoma and to raise awareness about this potentially vision-threatening adverse drug event. METHODS: A 77 year-old man presented with acute onset, painless, and bilateral blurry vision. He had started ipilimumab and pembrolizumab 2 weeks prior for Stage IV metastatic cutaneous melanoma. RESULTS: Clinical examination revealed bilateral choroidal detachments. After discussion with the patient's medical oncologist, the patient discontinued both medications and began oral prednisone to expedite visual recovery. The choroidal detachments subsequently resolved, and visual acuity improved 2 weeks later. CONCLUSION: Ipilimumab and pembrolizumab have been reported both in monotherapy and in combination to cause a wide variety of ophthalmic adverse events. This is the first report of choroidal detachments as a complication.

Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells.

Constitutively active G protein α subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. We found that constitutively active Gαq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate-for-guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gαq in inactive, GDP-bound Gαßγ heterotrimers. Allosteric inhibition of other Gα subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active Gαq, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors (GPCRs) where targeting a single receptor is ineffective.

Patterns of care and survival outcomes after treatment for uveal melanoma in the post-coms era (2004-2013): a surveillance, epidemiology, and end results analysis.

PURPOSE: The Collaborative Ocular Melanoma Study (COMS) established modern treatment recommendations for uveal melanoma. We aim to evaluate patterns of care and survival outcomes in the time after COMS. MATERIAL AND METHODS: The retrospective study population includes 2,611 patients in the SEER database treated for uveal melanoma between 2004-2013. Patients stage were T1-4N0M0. Data analyzed included age, clinical stage, tumor size, race, and treatment. Treatments included enucleation (EN) and globe preserving therapy (GPT), which consisted of limited surgical resection or ablation (LSRA), external beam radiation (EBRT), or brachytherapy (BT). Patients treated with radiation may receive radiation therapy alone (RTA) or radiation therapy and supplemental laser therapy (RT+SLT). We evaluated disease specific survival (DSS) and overall survival (OS) using log-rank statistics, and Cox univariate and multivariate analysis. RESULTS: The median follow-up was 44 months. Treatment strategy was EN in 538 (20.6%) patients, LSRA in 80 (3.1%), EBRT in 609 (23.3%), and BT in 1,384 (53.0%). 1,876 patients received RTA and 117 received RT+SLT. Enucleation was associated with inferior DSS and OS compared to GPT in multivariate analysis (MVA) (p < 0.01). Limited surgical resection or ablation and radiation had similar DSS and OS. Brachytherapy and EBRT had similar DSS and OS. Radiation therapy and supplemental laser therapy was associated with improved DSS compared to RTA in UVA (p = 0.03), but not MVA. The 5-year DSS for enucleation, RTA, and RT+SLT were 66.7%, 87.0%, and 94.7% (p < 0.01), respectively. CONCLUSIONS: Globe preserving treatments such as limited surgery or radiation are commonly utilized alternatives to enucleation, and resulted in favorable survival outcomes. Additional research is required to compare the outcomes of the various globe preserving treatment strategies.

Patterns of care and outcomes of proton and eye plaque brachytherapy for uveal melanoma: Review of the National Cancer Database.

PURPOSE: To examine national practice patterns and outcomes of eye plaque brachytherapy compared to proton external beam radiotherapy in the treatment of choroid melanoma. METHODS AND MATERIALS: Demographic and clinical data for 1224 patients with choroid melanoma treated with either brachytherapy or proton beam therapy from 2004 to 2013 were obtained from the National Cancer Database. Logistic regression and propensity score matching was used to create a 1:1 matched cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate survival in brachytherapy and proton groups. RESULTS: Median followup was 37 and 29 months for brachytherapy and protons, respectively. Most patients were treated with brachytherapy (n = 996) vs. protons (n = 228). Proton patients came from more urban, affluent, and educated zip codes, and they were more likely to be treated at an academic center (all p < 0.004). In the propensity-score matched cohort, 2-year overall survival was 97% vs. 93%, and 5-year overall survival was 77% vs. 51% for brachytherapy and protons, respectively (p = 0.008). Multivariate Cox regression found older age (hazard ratio [HR] = 1.06, 95% confidence interval (CI) = 1.03-1.09), larger tumor diameter (12-18 mm, HR = 2.48, 95% CI = 1.40-4.42, >18 mm, HR = 6.41, 95% CI = 1.45-28.35), and protons (HR = 1.89, 95% CI = 1.06-3.37) were negative prognosticators of survival. CONCLUSIONS: Patients selected for proton treatment have inferior survival outcomes compared to brachytherapy in this retrospective analysis. There may be unaccounted variables that influence survival, warranting further prospective studies.

Presumed ocular histoplasmosis.

PURPOSE OF REVIEW: To update the knowledge on the risk factors and treatment options for choroidal neovascular membrane due to ocular histoplasmosis and to provide a treatment algorithm. RECENT FINDINGS: Smoking has been shown to be a strong risk factor in the development of choroidal neovascularization. Alleles that have been identified as a risk factor for the development of choroidal neovascularization in age-related macular degeneration have not shown to be associated with Presumed Ocular Histoplasmosis Syndrome-related choroidal neovascularization. Treatment has largely moved away from submacular surgery and macular photocoagulation to antivascular endothelial growth factor therapy. SUMMARY: This review highlights the devastating vision loss that may occur in ocular histoplasmosis from the development of an atrophic scar at the fovea or following choroidal neovascularization. Many therapies have been tried with varied amounts of success. Antivascular endothelial growth factor therapy appears to be the gold-standard treatment with the possibility of combined photodynamic therapy in refractory cases.

Ocular manifestations of systemic lupus erythematosus.

PURPOSE OF REVIEW: To describe the ophthalmic manifestations of systemic lupus erythematosus and to review recent advances in our understanding of the pathogenesis and treatment of this condition. RECENT FINDINGS: Significant vision loss and associated ocular morbidity are possible in systemic lupus erythematosus, particularly in cases of retinal or central nervous system involvement. Considerable progress has been made in our understanding of the immunologic mechanisms of disease. Approaches to treatment include the use of systemic immunosuppressive medications. Biologic agents are being developed to target specific aspects of the immune response. SUMMARY: Ocular involvement is not uncommon in systemic lupus erythematosus. Aggressive systemic therapy is often needed to control the disease. Several new immunomodulatory treatment strategies are being developed which may show great promise in the future.