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Purpose: This review aims to summarize the current knowledge concerning the clinical features, diagnostic work-up, and therapeutic approach of bilateral diffuse uveal melanocytic proliferation (BDUMP)., Methods: A meticulous literature search was performed in the PubMed database. A supplementary search was made in Google Scholar to complete the collected items. Our search strategy utilized the following keywords: "bilateral diffuse uveal melanocytic proliferation", "BDUMP", and "Paraneoplastic Syndrome". Articles were considered based on their relevance, with the search spanning publications up to 2023. Studies were excluded if they did not contribute pertinent information or lacked methodological rigor. A critical appraisal of included studies was conducted, assessing study design, sample size, methodology, and potential bias, ensuring a thorough and transparent review process., Results: BDUMP is a rare and potentially sight-threatening condition characterized by the bilateral proliferation of melanocytes within the uvea. BDUMP is typically observed in middle-aged or elderly individuals and is often associated with an underlying malignancy, most commonly of gastrointestinal origin. BDUMP is frequently misdiagnosed as a benign nevus or choroidal metastasis, leading to delayed diagnosis and treatment. The ophthalmic symptoms and signs typically precede the diagnosis of a systemic malignancy, emphasizing the crucial role of ophthalmologists in the recognition of BDUMP. Several diagnostic modalities can aid in the diagnosis of BDUMP, including ophthalmic examination, imaging studies such as optical coherence tomography, fluorescein angiography, and indocyanine green angiography, and biopsy of the uveal tissue. Treatment of BDUMP is directed towards the underlying malignancy and may include chemotherapy, radiotherapy, or surgical resection. Additionally, strict monitoring with regular follow-ups may contribute to the detection of new lesions and the reduction in the size of existing ones., Conclusions: BDUMP can be considered a potential biomarker in the management of malignancies, especially when the primary underlying tumor has not been detected. Further research is needed to better understand the pathogenesis of BDUMP and its association with malignancy., (© 2024. Crown.)

Purpose: To investigate the ultrasonographic features in patients with primary uveal mucosa-associated lymphoid tissue (MALT) lymphoma., Methods: Medical records of 12 patients (13 eyes) diagnosed with primary uveal MALT lymphoma between September 2014 and September 2021 were retrospectively reviewed. Ultrasonography, B-scan ultrasonography, color Doppler flow imaging, and ultrasound biomicroscopy findings were retrieved from the medical records., Results: Mean age of the included patients was 59.4 ± 8.6 years. Typical ultrasonographic features of the choroidal infiltrates were flat, diffuse, and thickened, with low and homogenous internal reflectivity and with rich arterial blood flow from posterior ciliary arterioles. The mean thickness of the choroidal infiltrates was 1.34 ± 0.68 mm (n = 13). Most of the affected eyes had posterior episcleral extensions, with a mean thickness of 1.66 ± 1.21 mm (n = 12). Typical crescent-like posterior episcleral extensions were detected in nine eyes (69.2%). In six eyes, the blood flow from the choroidal infiltrates communicated with the episcleral extensions. In the ciliary body, the mean thickness of the infiltrates was 1.08 ± 0.43 mm (n = 9), and seven eyes (77.8%) had 360° ring-like infiltrations. The initial best-corrected visual acuity (BCVA) was significantly correlated with the final BCVA after treatment (p < 0.001)., Conclusion: Multipurpose ultrasonographic imaging revealed the unique characteristics of the primary uveal MALT lymphoma and is helpful in the diagnosis of this rare disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Gross, histopathological, and immunohistochemical characteristics of uveal melanocytic neoplasms in dogs and cats were investigated., Samples: Thirty-two enucleated globes with uveal melanocytic neoplasms, 27 from dogs and 5 from cats, were examined., Procedures: Morphological characteristics of uveal melanocytic neoplasms in dogs and cats were evaluated with anti-PNL2, anti-Melan-A, anti-Ki-67, anti-caspase-3, and anti-BAP1 immunomarkers. Statistical analysis was performed to compare canine melanocytomas and melanomas., Results: The 32 uveal neoplasms were classified as melanocytomas (19/27 in dogs) or melanomas (8/27 in dogs, 5/5 in cats). Most tumours (84%) were located in the anterior uvea. Neoplastic cells were classified as epithelioid, spindle-shaped, mixed, or special type (balloon and signet ring cells). The percentage of cells with melanin, melanin concentration within cells, anisocytosis and anisokaryosis, mitotic count, lymphocytic inflammation, necrosis, vascular invasion, and glaucoma were also characterized. Anisocytosis, percentage of neoplastic cells with melanin, mitotic count, and indices (proliferation and apoptotic) varied significantly between canine uveal melanomas and melanocytomas; in general, melanomas had greater cell variability, were less pigmented, and had a higher mitotic count. The melanocytic origin of the neoplasms was confirmed by positive anti-PNL2 immunolabelling (29/32) and positive anti-Melan-A immunolabelling (3/32). In canine uveal melanomas, anisocytosis and anisokaryosis correlated with less pigmentation and minimal pigmentation correlated with a high percentage of immunolabelling for caspase-3., Conclusions: Uveal melanocytomas were more common in dogs, and uveal melanomas were more frequent in cats. Anisocytosis, percentage of neoplastic cells with melanin, and mitotic count are important histologic characteristics of malignancy to evaluate in uveal melanocytic neoplasms. The proliferation and apoptotic indices are relevant when comparing malignant tumours with benign tumours., (© 2022 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Purpose: While early treatment of posterior uveal melanoma can save the eye, the effect of early treatment on survival remains unknown. Therefore, we aimed to determine whether the tumour size at diagnosis has changed over time, and if this has affected survival rates of patients with posterior uveal melanoma in Denmark., Methods: Nationwide retrospective cohort study linking data from registry-based resources to data from clinical charts and pathology records. Including all Danish patients diagnosed with posterior uveal melanoma from 1943 to 2017. Incidence rates were estimated as annual percentage change (APC) overall and by American Joint Committee on Cancer (AJCC) tumour sizes. The age-period-cohort model was applied to estimate the relative risk of calendar period. The cox proportional hazards model, relative survival Kaplan-Meier curves and cumulative incidence curves were applied to estimate the effect of calendar period on survival., Results: An overall increase in incidence rate of uveal melanoma was found (APC = 0.25%, 0.08-0.42; 95% CI). This was due to increasing incidence rate of AJCC T1 + T2 tumours (APC = 0.97%, 0.57-1.37; 95% CI), whereas no increase in incidence rates of AJCC T3 + T4 tumours was found (APC = -0.01%, -0.26 to 0.25; 95% CI). The disease-specific survival improved with calendar period for all tumour sizes (HR = 0.988; 0.984-0.993; 95% CI)., Conclusion: Increasing incidence rate and improved survival rate for uveal melanoma was found concordantly with a decrease in tumour size during a 70-year period., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: In spite of clear differences in tissue function and significance to ocular disease, little is known about how immune responses differ between the retina and uveal tract. To this end we compared the effects of acute systemic inflammation on myeloid cells within the mouse retina, iris-ciliary body, and choroid., Methods: Systemic inflammation was induced in Cx3cr1gfp/gfp and CD11c-eYFP Crb1wt/wtmice by intraperitoneal lipopolysaccharide (LPS). In vivo fundus imaging was performed at two, 24, and 48 hours after LPS, and ocular tissue wholemounts were immunostained and studied by confocal microscopy. Flow cytometry was used to investigate the expression of activation markers (MHC class II, CD80, CD86) on myeloid cell populations at 24 hours. For functional studies, retinal microglia were isolated from LPS-exposed mice and cocultured with naïve OT-II CD4+ T-cells and ovalbumin peptide. T-cell proliferation was measured by flow cytometry and cytokine assays., Results: Systemic LPS altered the density and morphology of retinal microglia; however, retinal microglia did not upregulate antigen presentation markers and failed to stimulate naïve CD4+ T-cell proliferation in vitro. In contrast, uveal tract myeloid cells displayed a phenotype consistent with late-activated antigen-presenting cells at 24 hours. Systemic LPS induced remodeling of myeloid populations within the uveal tract, particularly in the choroid, where dendritic cells were partially displaced by macrophages at 24 hours., Conclusions: The disparate myeloid cell responses in the retina and uveal tract after systemic LPS highlight differential regulation of innate immunity within these tissue environments, observations that underpin and advance our understanding of ocular immune privilege.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males and uro-gynaecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterised. Herein, we present a female in her 70s with diagnosis of stage IV vaginal clear-cell carcinoma and metastatic melanoma of unknown primary that developed progressive bilateral loss of visual acuity compatible with 'B-DUMP'. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP be termed 'diffuse integumentary melanocytic proliferation (DIMP)'., (© 2021 The Australasian College of Dermatologists.)

Purpose: The purpose of this study was to determine classification criteria for sarcoidosis-associated uveitis., Design: Machine learning of cases with sarcoid uveitis and 15 other uveitides., Methods: Cases of anterior, intermediate, and panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed including cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used in the training sets to determine a parsimonious set of criteria that minimized the misclassification rate among the uveitides. The resulting criteria were evaluated in the validation sets., Results: A total of 1,083 cases of anterior uveitides, 589 cases of intermediate uveitides, and 1,012 cases of panuveitides, including 278 cases of sarcoidosis-associated uveitis, were evaluated by machine learning. Key criteria for sarcoidosis-associated uveitis included a compatible uveitic syndrome of any anatomic class and evidence of sarcoidosis, either 1) tissue biopsy results demonstrating non-caseating granulomata or 2) bilateral hilar adenopathy on chest imaging. The overall accuracy of the diagnosis of sarcoidosis-associated uveitis in the validation set was 99.7% (95% confidence interval: 98.8-99.9). The misclassification rates for sarcoidosis-associated uveitis in the training sets were 3.2% in anterior uveitis, 2.6% in intermediate uveitis, and 1.2% in panuveitis; in the validation sets, the misclassification rates were 0% in anterior uveitis, 0% in intermediate uveitis, and 0% in panuveitis., Conclusions: The criteria for sarcoidosis-associated uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To determine classification criteria for tubulointerstitial nephritis with uveitis (TINU)., Design: Machine learning of cases with TINU and 8 other anterior uveitides., Methods: Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set., Results: One thousand eighty-three cases of anterior uveitides, including 94 cases of TINU, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for TINU included anterior chamber inflammation and evidence of tubulointerstitial nephritis with either (1) a positive renal biopsy or (2) evidence of nephritis (elevated serum creatinine and/or abnormal urine analysis) and an elevated urine β-2 microglobulin. The misclassification rates for TINU were 1.2% in the training set and 0% in the validation set., Conclusions: The criteria for TINU had a low misclassification rate and seemed to perform well enough for use in clinical and translational research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose : To report bilateral anterior uveitis and corneal punctate epitheliopathy in children with multisystem inflammatory syndrome (MIS-C) secondary to coronavirus disease (COVID-19). Participants and methods : Five patients who were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies and diagnosed with MIS-C were evaluated. Ophthalmologic examinations were performed in order to reveal ocular findings in MIS-C disease. Results : Slit lamp examinations showed bilateral non-granulomatous acute anterior uveitis in all patients and severe corneal punctuate epitheliopathy in three of the patients. These ocular findings mostly disappeared with treatment in about one week. Conclusion : Bilateral non-granulomatous acute anterior uveitis and dry eye can be detected in patients diagnosed with MIS-C secondary to COVID-19. Even if generally, COVID-19 is not a life threatening disease in children by itself, inflammatory ocular manifestations can be detected in MIS-C secondary to COVID-19.

Purpose : Herein, we report a case of bilateral neuroretinitis and panuveitis in a patient recovered from coronavirus disease 2019 (COVID-19). Case presentation : A 37-year-old male patient with a history of recovered COVID-19, which was confirmed with nasopharyngeal reverse transcriptase polymerase chain reaction (RT-PCR) for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), about one-month ago was referred with one-week history of bilateral severe vision loss. Visual acuity was counting fingers, and bilateral retinitis and panuveitis were revealed in ocular examination. The result of the vitreous sample using RT-PCR was positive for SARS-CoV-2 and negative for Herpesviridae viruses and mycobacterium tuberculosis . The patient was successfully treated with corticosteroid. Conclusion : We report a case of bilateral neuroretinitis and panuveitisin a recovered COVID-19 patient and positive RT-PCR of the vitreous sample. It is suggested to apply intraocular sampling and evaluation for COVID-19 in patients with the new-onset of uveitis and/or retinitis during the pandemic.

A20 is a negative regulator of inflammation and immunity and plays a role in several autoimmune and inflammatory diseases. Here, we demonstrate that A20 overexpression significantly ameliorates severity of EAU by inhibiting the infiltration of Th1 and Th17 cells, and by protecting integrity of the blood retinal barrier. In vitro studies showed that A20 silencing could promote CD4+T cells toward a Th1 and Th17 phenotype. A decreased expression of A20 in CD4+T cells was noticed in active BD patients but not in VKH patients. Furthermore, silencing of A20 in hRPE cells induced the production of IL-6, IL-8, and MCP-1 and downregulated ZO-1 and occludin expression which is mediated by inhibition of MAPK and NF-κB pathways. This study reveals a mechanism by which A20 prevents autoimmune uveitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Yi, Wang, Zhang, Tang, Huang, Yang, Yang and Li.)

Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73 + BMDCs play a critical role in cascading Th17 responses, and CD73 + BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73 -/- mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73 + DCs is critically involved in augmented Th17 responses. We conclude that CD73 + DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ko, Shao, Kaplan and Sun.)

Experimental autoimmune uveitis (EAU) is a CD4 + T cell-mediated organ-specific autoimmune disease and has been considered as a model of human autoimmune uveitis. Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. DH suppressed the production of inflammatory cytokines through the recruitment of myeloid-derived suppressor cells (MDSCs) to the liver. However, it remains elusive whether DH can directly regulate CD4 + T cell biology and hence ameliorates the development of CD4 + T cell-mediated autoimmune disease. In the current study, we found that DH extract significantly suppressed the production of pro-inflammatory cytokines by CD4 + T cells. Further study showed that DH didn't affect the activation, differentiation, and apoptosis of CD4 + T cells. Instead, it significantly suppressed the proliferation of conventional CD4 + T cells both in vitro and in vivo . Mechanistic study showed that DH-treated CD4 + T cells were partially arrested at the G2/M phase of the cell cycle because of the enhanced inhibitory phosphorylation of Cdc2 (Tyr15). In addition, we demonstrated that treatment with DH significantly ameliorated EAU in mice through suppressing the proliferation of autoreactive antigen specific CD4 + T cells. Taken together, the current study indicates that DH-mediated suppression of CD4 + T cell proliferation may provide a promising therapeutic strategy for treating CD4 + T cell-mediated diseases., (Copyright © 2020 Bian, Wang, Wang, Wang, Wang, Shi and Ruan.)

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis. EAU spontaneously resolves and is marked by ocular autoantigen-specific regulatory immunity in the spleen. Kallikrein binding protein (KBP) or kallistatin is a serine proteinase inhibitor that inhibits angiogenesis and inflammation, but its role in autoimmune uveitis has not been explored. We report that T cells activation is inhibited and EAU is attenuated in human KBP (HKBP) mice with no significant difference in the Treg population that we previously identified both before and after recovery from EAU. Moreover, following EAU immunization HKBP mice have potent ocular autoantigen specific regulatory immunity that is functionally suppressive., (Copyright © 2020 Muhammad, Avalos, Mursalin, Ma, Callegan and Lee.)

Twenty-eight patients were identified with large B-cell lymphoma of the uvea. Uveal involvement was iris (1 case), ciliary body (1 case), or choroidal in 14 cases. Panuveal involvement was observed in 12 cases. The clinical presentation could be categorized into uveitis (8), intraocular mass (9), neovascular glaucoma (4), and vascular disorders (4). The majority (21 cases, 77%) were diagnosed at autopsy (11) or after enucleation (10). Only 7 were diagnosed with conservative techniques. Histopathologically, 3 distinct subgroups of large B-cell lymphoma could be identified: 15 were characterized as diffuse large B-cell lymphoma, 11 as intravascular large B-cell lymphoma, and 2 as plasmablastic lymphoma. All cases had a poor prognosis, with a median survival of 14 months. Most cases (19, 67%) represented secondary uveal involvement with widespread systemic lymphoma at ophthalmic presentation. Six cases were treated with radiotherapy, most of these diagnosed before the 1990s (4). Subsequent cases (9) received systemic or local chemotherapy and adjunct radiotherapy, depending on the organs affected. Two cases were treated only with enucleation, and systemic treatment was not specified in 13 cases. Large B-cell lymphoma can rarely involve the uvea. The presenting features are nonspecific, often leading to enucleation. Effective therapy is not known. In all 3 variants, the aggressive nature and widespread involvement at ophthalmic presentation is associated with short survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare paraneoplastic syndrome, with most cases reported as secondary to female urogenital and male lung malignancies. We reported this case of BDUMP patient whose primary malignancy was gastric adenocarcinoma verified with gastroscopy and subsequent pathological test., Case Presentation: A patient complaining blurred vision was suspected of bilateral diffuse uveal melanocytic proliferation (BDUMP), due to bilateral round oval patches at the posterior pole and cardinal signs in retinal angiography. Malignancy screening was suggested, and pathological report from gastroscopy confirmed the primary lesion as gastric adenocarcinoma. The patient chose palliative care due to late stage and unresectable nature of the malignancy., Conclusions: Identifying BDUMP warrants further investigation of a primary malignancy. Our case provided evidence for the link between gastric adenocarcinoma and BDUMP.

Purpose: To investigate the relationship between surgical approach for intraocular tumor biopsy of uveal melanoma and tumor morphologic features such as size and intraocular location and the effect of these variables on diagnostic yield and biopsy outcome., Methods: Consecutive patients from nine Ocular Oncology centers with uveal melanoma (UM) undergoing tumor biopsy immediately preceding I 125 plaque brachytherapy with tissue sent for gene expression profiling (GEP) testing were reviewed retrospectively., Results: Three hundred sixty patients were included (50% men, mean age 60.2 years). Overall biopsy yield was 99% and 83% for GEP and cytopathology, respectively. Surgeon choice of biopsy approach (trans-vitreal vs. trans-scleral) was found to associate with both tumor location and tumor thickness. A trans-scleral rather than trans-vitreal approach was used more commonly for anteriorly located tumors (92% vs. 38% of posterior tumors, p < 0.001) and thicker tumors (86% vs. 55% of thin tumors, p < 0.001). When performing trans-vitreal biopsies, ocular oncologists with previous vitreoretinal surgery fellowship training were more likely to use wide-field surgical viewing systems, compared with indirect ophthalmoscopy (82.6% vs. 20.6%, p < 0.001). Surgical complications were rare and occurred more frequently with trans-vitreal biopsies (3.6% vs. 0.46%, p = 0.046)., Conclusions: In this multi-center analysis of UM tumor biopsy, surgical yield was high for obtaining tumor tissue for GEP and cytopathology analysis with both trans-scleral and trans-vitreal techniques. Fellowship-trained ocular oncologists' preferred intraocular biopsy techniques associated strongly with tumor location, tumor thickness, and fellowship training of the surgeon. Short-term complication rates were low.

Background: Melanoma is a life-threatening group of cancers mainly affecting the skin (cutaneous melanoma, CM) and the eyes (uveal melanoma, UM). Nearly half of patients with UM develop liver metastases regardless of the primary treatment. For this reason, adjuvant therapy to prevent disease progression is essential to improve survival of patients with melanoma. Beta-adrenoceptors (β-AR) have emerged as novel targets to inhibit tumor growth and dissemination in CM, but have not been investigated in UM., Methods: The aim of this study was to comprehensively evaluate the effects of a non-selective β-blocker in UM and CM. Propranolol was tested on four UM and two CM cell lines to determine the effects of this beta-blocker. The expression of β-AR in UM was assessed in enucleated eyes of 36 patients., Results: The results showed that propranolol exerts potent anti-proliferative effects, attenuates migration, reduces VEGF and induces cell cycle arrest and apoptosis in both UM and CM in a dose-dependent manner. Furthermore, levels of cell-free DNA released from the cells correlated to propranolol treatment and may be an indicator of treatment response. Finally, immunohistochemical analysis revealed the expression of β1 and β2 adrenoceptors in all UM patients, with higher expression seen in the more aggressive epithelioid versus less aggressive spindle cells., Conclusions: Collectively our data suggest that a nonselective beta-blocker may be effective against melanoma. For the first time, we show potent anti-tumor effects in UM cells following propranolol administration and expression of β1 and β2 adrenoceptors in patient tissue., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To compare the efficacy of systemic and intravitreal infliximab treatments in an experimental endotoxin-induced uveitis (EIU) model. Methods: Twenty-eight white New Zealand rabbits were equally divided into 4 groups. Group 1 received an intravitreal injection of 0.1 cc saline, group 2 received an intravitreal injection of 2 µg/0.1 cc lipopolysaccharide (LPS), group 3 received an intravitreal injection of 2 µg/0.1 cc LPS and 2 mg/0.1 cc infliximab, and group 4 received intravitreal injection of 2 µg/0.1 cc LPS and intravenous injection of 5 mg/kg infliximab. Clinical, biochemical (aqueous and vitreous humour protein levels and TNF-α concentrations), and histopathological evaluations were performed. Results: The clinical examination score was lower in group 4 than in group 2 ( p  = 0.006); but there was no significant difference between groups 2 and 3 (Bonferroni correction, p  = 0.016). No statistically significant difference was found among groups 2, 3, and 4 for aqueous humour protein levels ( p  > 0.05). Significantly higher aqueous humour concentrations of TNF-α was measured in group 3 comparing to both group 1 and 4 ( p  = 0.003 and p  = 0.002, respectively). No significant difference was found in vitreous protein levels or TNF-α concentrations among all study groups (Bonferroni correction, p  = 0.026 and p  = 0.101, respectively). Histopathological evaluation of the uveal tissue and anterior chamber reaction revealed the highest inflammation in group 3 ( p  < 0.001). In group 4, histopathological evaluation of uveal tissue was lower than in groups 2 and 3 ( p  < 0.001 and p  = 0.001, respectively); whereas there was no difference in anterior chamber inflammation between groups 2 and 4 ( p  = 1.00). Conclusion: Intravitreal 2 mg/0.1 cc infliximab injection exacerbated inflammation in an EIU model; whereas systemic infliximab treatment at a dose of 5 mg/kg suppressed inflammation effectively and rapidly.

Typical blood capillaries and vessels in uveal melanoma were shown and different types of uveal melanoma stromal cells were determined by electron microscopy and immunohistochemical analysis. Macrophages, fibroblasts of varying degrees of differentiation and endothelial-like cells with numerous caveolae in the cytoplasm were found in the channels of the extracellular matrix surrounding accumulations of tumor cells. The presence local structures positively stained for markers of the blood and lymphatic vessels (CD31 and podoplanin) in channels of the extracellular matrix suggests that the described endothelial-like cells can be the structural basis for blood and lymphatic vessels of the tumor.

Background: Qinghuo Rougan Formula (QHRGF) is a traditional Chinese medicine (TCM) that has been widely apllied to treat uveitis for several decades. However, the inhibitory mechanism of QHRGF in uveitis has remained to be an enigma., Methods: The Chinese herbal medicine pharmacology data and analysis platform wereused to search and screen for the effective components of the QHRGF compound injection and to analyse possible therapeutic targets based on network topology. In addition, various known disease target databases were enraolled, the therapeutic target proteins in uveitis were screened, and a protein-protein interaction (PPI) network was constructed. Enrichment analysis was performed on key nodes. Finally, the inhibitory effect of QHRGF on uveitis was verified by experiments., Results: We identified 259 major candidate targets of QHRGF and successfully constructed a 'QHRGF-compound-target-uveitis' network. Above-mentioned targets revealed by Gene enrichment analysis have played an significant role in the cell cycle, autoimmune disease, apoptosis and related signal pathways. We demonstrated that QHRGF attenuates local inflammation in experimental autoimmune uveoretinitis (EAU) rats by regulating natural killer T (NKT) cells and inhibiting MAPK signal pathways., Conclusion: QHRGF may regulate the local immune response and inflammatory factors mainly through the MAPK signal pathway. For autoimmune uveitis, QHRGF may be a promising, long-lasting treatment strategy., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Lacking in previous studies on uveal metastasis is a robust statistical comparison of patient demographics, tumor features, and overall survival based on patient sex., Objective: The aim of this study was to evaluate demographics, clinical features, and overall survival of patients with uveal metastasis based on sex., Method: This is a retrospective analysis. All patients were evaluated on the Ocular Oncology Service, Wills Eye Hospital, PA between January 1, 1974 and June 1, 2017., Results: A total of 2214 uveal metastases were diagnosed in 1310 eyes of 1111 consecutive patients. A comparison (female versus male) revealed differences across several demographic and clinical features including, among others, mean age at metastasis diagnosis (58 vs 63 years, P < 0.001), bilateral disease (21% vs 11%, P < 0.001), and mean number of metastases per eye (1.8 vs 1.6 tumors per eye, P = 0.04). There were differences in overall mean survival (20 vs 13 months, P = 0.03) and 5-year survival (Kaplan-Meier estimate) (31% vs 21%, P < 0.001)., Conclusions: There are demographic, clinical, and survival differences when patients with uveal metastases are compared by sex. Understanding these differences can aid the clinician in better anticipating patient outcomes.

Importance: Bilateral diffuse uveal melanocytic proliferation is a rare sign of several systemic malignant neoplasms., Observations: A patient presenting with uveal melanocytic proliferation underwent a detailed physical examination and extensive imaging. No systemic malignant neoplasm was found. Chorioretinal biopsy was performed, and its immunohistochemical results revealed the presence of primary vitreoretinal lymphoma., Conclusions and Relevance: This patient's results suggest that diffuse uveal melanocytic proliferation may be associated not just with systemic malignant disease, but also with primary intraocular tumors, in this case a primary vitreoretinal lymphoma.

A patient with bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with endometrial cancer was treated with plasmapheresis, but failed therapy with progressive serous retinal detachment. We collected plasma before and after plasmapheresis therapy. Our goal was to determine if the cultured melanocyte elongation and proliferation (CMEP) factor and hepatocyte growth factor (HGF) was present in the IgG enriched fraction and understand why our patient failed plasmapheresis therapy. Melanocytes were cultured for 3-5 days in the presence of control medium, unfractionated pre-plasmapheresis BDUMP medium, IgG enriched or IgG depleted BDUMP medium, or unfractionated post-plasmapheresis BDUMP medium. Subretinal fluid was collected from patients with BDUMP and control retinal detachments and analyzed by electropheresis with immunoblotting. Medium with unfractionated BDUMP plasma stimulated melanocyte growth 1.4-1.5 fold compared to control medium on days 3-5 (p < 0.001 for all). Both IgG enriched and IgG depleted BDUMP medium mildly increased melanocyte growth 1.3 fold (p < 0.05 for enriched, p < 0.01 for depleted) compared to control. In comparison, unfractionated BDUMP medium caused a 1.7-fold increase in melanocyte growth, which was significantly more than the enriched (p < 0.01) and depleted (p < 0.05) fractions. Pre-plasmapheresis and post-plasmapheresis unfractionated BDUMP medium equally stimulated melanocyte growth 1.7-fold (p < 0.05) compared to control. HGF was present in IgG depleted, pre-plasmapheresis, and post-plasmapheresis samples, but absent in the IgG enriched fraction. There was no enrichment of IgG in the subretinal fluid from eyes with BDUMP. In conclusion, CMEP factor is not concentrated in the IgG enriched plasma fraction in our patient who failed plasmapheresis therapy. HGF levels have no correlation with melanocyte growth. Because plasmapheresis preferentially removes immunoglobulins from the plasma, our patient responded poorly to plasmapheresis treatment with worsening retinal detachment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Presentation of two typical cases with characteristic leopard retinopathy secondary to bilateral diffuse uveal melanocytic proliferation (BDUMP) and idiopathic uveal effusion syndrome (IUES) and brief review of the literature about leopard spot retinopathy., Case Report: A 43-year-old women, who was a known case of ovarian carcinoma, referred with gradual bilateral visual loss. In ophthalmic examination, subretinal fluid, multiple patchy subretinal hyperpigmented lesions and leopard spot chorioretinopathy were evident in her both eyes. Fluorescein angiography showed multiple nummular hyperfluorescent lesions surrounded by zones of hypofluorescence. Spectral domain optical coherence tomography revealed increased retinal thickness, subretinal fluid and RPE irregularities in both eyes. Enhanced depth imaging OCT (EDI-OCT) showed bilateral subfoveal choroidal thickening. During next 2-year follow-up, she underwent cataract surgery and later on developed neovascular glaucoma in her both eyes. The second case was a 45-year-old man who had developed decreased visual acuity in his left eye for 3 years. Anterior segment examination was unremarkable, and both eyes had normal intraocular pressure. No vitreous inflammation was observed. Fundoscopy revealed diffuse exudative retinal detachment in his left eye. Fluorescein angiography showed leopard spot retinopathy of posterior pole, and EDI-OCT disclosed subfoveal choroidal thickening. After exclusion of other causes of exudative retinal detachment and with diagnosis of IUES, he underwent intravitreal triamcinolone injection (2 mg) which improved his final vision to 20/40., Conclusion: Leopard spot retinopathy is an uncommon but clinically distinct manifestation of various disorders. BDUMP may present with leopard spot retinopathy, anterior uveal tract involvement and neovascular glaucoma. As EDI-OCT showed involvement and increased thickening of choroid in both cases of BDUMP and IUES, it may be better to consider such cases as leopard chorioretinopathy and categorize these entities as a member of pachychoroid pigment retinopathy disorders.

Inflammation in uveal melanoma (UM) is linked to a bad prognosis. It is rare type of cancer, of which the metastases are usually fatal within a year. Infiltration with an inflammatory infiltrate increases with disease progression but does not seem to inhibit metastasis. The Canonical NFκB (C-NFκB) pathway is known to play a crucial role in tumor inflammation. We therefore, studied the expression of canonical NFκB proteins and their prognostic relevance in UM. Our study evaluated the expression of C-NFκB proteins (p65, p50, and c-Rel) by using immunohistochemistry on sections from 75 formalin-fixed UM. Activation of the NFκB subunit was determined on fresh tumor specimens by measuring the DNA-binding activity in nuclei using an NFκB ELISA assay. Real-time PCR was performed on frozen material on 58 tumors. The presence of native C-NFκB heterodimers (p65/p50 and c-Rel/p50) was confirmed by co-immunoprecipitation followed by Western blotting. We observed a high nuclear immunoreactivity of p65, p50, and c-Rel proteins in 54, 60 and 41% UM cases, respectively. Expression of C-NFκB proteins significantly correlated with parameters which are related to the inflammatory environment of UM. Nuclear immunoreactivity of p65 and p50 was associated with lower patient survival (p = 0.041; p = 0.048) while c-Rel was not. Our finding reveals that C-NFκB proteins expressed are more often in UM with inflammation than those without inflammation. Activation of the canonical NFκB pathway is more frequent in high risk UM patients. These observations might help to understand the behaviour of high risk tumors, with upregulation of C-NFκB proteins contributing to tumor aggressiveness.

We reported uveal effusion and transient myopia as the initial presentation of systemic lupus erythematosus with pulmonary arterial hypertension. Choroidal retinopathy is rare but extremely destructive to visual function. Therefore, prompt diagnosis and effective treatments will result in complete resolution of the uveal effusion and functional restoration of vision.

Retigabine (RTG) is an antiepileptic drug approved as an adjunctive treatment for refractory partial-onset seizures in adults. In April 2013, the Food and Drug Administration issued a warning that RTG could cause changes in retinal pigmentation and discoloration of skin, resulting in a blue appearance. As part of a larger preclinical effort to gain a mechanistic understanding as to the origins of retinal pigment changes associated with RTG, we conducted a long-term repeat dosing study in rats. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was used to determine the distribution of RTG and its metabolites in the rat eye following 13 and 39 weeks of dosing. IMS revealed the presence of RTG, a previously characterized N-acetyl metabolite of RTG (NAMR), and several species structurally related through the dimerization of RTG and NAMR. These species were highly localized to the melanin-containing layers of the uveal tract of the rat eye including the choroid, ciliary body, and iris, suggesting that the formation of these dimers occurs from melanin bound RTG and NAMR. Furthermore, several of the RTG-related dimers have UV absorbance which give them a purple color in solution. We propose that the melanin binding of RTG and NAMR effectively concentrates the two compounds to enable mixed condensation reactions to occur when the binding provides the proper geometry in the redox environment of the uveal tissues. High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.

Uveitis is inflammation of the uvea which consists of the iris, ciliary body and the choroid of the eye. Uveitis can lead to impaired vision and is responsible for 10% of all cases of blindness globally. Using an endotoxin-induced uveitis (EIU) rodent model, our previous data implicated the endogenous cannabinoid system (ECS) in the amelioration of many of the components of the inflammatory response. Here, we test the hypothesis that the reduction in inflammatory mediators in the EIU model by the CB 2 agonist, HU308, is associated with changes in ECS endogenous ligands as well as related lipids, prostaglandins (PGs), 2-acyl glycerols, and lipoamines. Analysis of leukocytes and neutrophils, CB 2 mRNA, and 26 lipids in the eye of WT mice after EIU induction and HU308 treatment were compared to the same analyses in the CB 2 knock-out (CB 2 KO) mouse. Endothelial leukocyte adhesion and neutrophil migration were significantly increased in both WT and CB 2 KO after EIU. HU308 significantly reduced the leukocyte adhesion and neutrophil recruitment in the WT animals. HU308 also significantly reduced leukocyte adhesion in the CB 2 KO mouse, yet, had no effect on neutrophil infiltration suggesting an important off-target effect of HU308. Lipidomics profiles revealed significant increases in 6 non-ECS lipids after EIU in the WT and that HU308 effectively reduced these back to control levels; in addition, HU308 increased levels of 2-acyl glycerols and decreased all N-acyl glycines. CB 2 KOs with saline-injection compared to WT had significantly elevated levels of 2-acyl glycerols, whereas levels of N-oleoyl ethanolamine (OEA), N-stearoyl ethanolamine (SEA), and PGE 2 were reduced. CB 2 KOs with EIU had 13 lipids that were significantly lower than WT with EIU including 4 N-acyl glycines. HU308 had no effect on lipid concentrations in the CB 2 KOs with EIU, however, it did cause further reductions on 3 additional lipids compared to saline controls. HU308 appears to be acting at a non-CB 2 target for the reduction of leukocyte infiltration in the EIU model; however, our data suggest that HU308 is working through CB 2 to reduce neutrophil migration and for the regulation of multiple lipid signaling pathways including PGs, lipoamines, and 2-acyl glycerols. These data implicate ocular CB 2 as a key component of lipid signaling in the eye and part of the regulatory processes of inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. This review focuses on five most commonly used imaging modalities, i.e., positron emission tomography-computed tomography (PET/CT), single photon emission computed tomography (SPECT), optical coherence tomography (OCT), ultrasound (US), and magnetic resonance imaging (MRI). The principal of imaging modalities is briefly explained, along with their role in the diagnosis and management of the most common ocular tumors such as retinoblastoma and uveal melanoma. Further, the diagnostic features of ocular tumors corresponding to each imaging modality and possibilities of utilizing imaging techniques in the process of ocular drug development are included in this review.

The rate of advances in uveal melanoma has not kept pace with the rate of advances in cutaneous melanoma. Many patients lack access to or knowledge of specialty centers, and integrated multidisciplinary care between ophthalmology, radiation oncology, and medical oncology is far from the norm. This treatment isolation leads to limited communication about novel clinical trial opportunities. Clinical trials themselves are not widely available, and a lack of robust funding limits rapid and complete investigations. This review outlines the obstacles to success in uveal melanoma management and highlights strategies for overcoming these challenges. Cancer 2018;124:2693-2703. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: We evaluated the long-term biocompatibility and safety of a new modular posterior chamber intraocular lens (IOL) system in rabbit eyes., Methods: Seven New Zealand rabbits underwent bilateral phacoemulsification with placement of the modular IOL in OD and a control IOL (SA60AT) in OS. Slit-lamp examinations were performed at postoperative weeks 1, 2, 3, 4, 6 and 8 and months 3 and 6. All rabbits were then sacrificed and eyes enucleated. The eyes were examined grossly from the Miyake-Apple view. Selected IOLs were explanted and underwent surface staining for implant cytology. All globes were then sectioned and processed for histopathological examination., Results: The modular IOL remained stable in all seven rabbits through the entire follow-up period. Biocompatibility was better than the control lens at six months postoperatively, on account of less extensive synechiae formation as assessed by slit-lamp examination. At the six-week examination, posterior capsule opacification (PCO) was significantly better in the test group (scored as 1.71 ± 0.8 versus 3.28 ± 0.48 in the control group, p = 0.0008). On gross examination with the Miyake-Apple view, Soemmering's ring formation was significantly better in the test group, (5.14 ± 1.57 versus 10.85 ± 1.95 in the control group, p = 0.002)., Conclusion: Previous studies showed that explantation/exchange of the modular system optic was safer and easier than with a standard IOL. The new modular IOL system has demonstrated better long-term biocompatibility compared to the control lens at six months postoperatively in the rabbit model., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To compare long-term surgical outcomes and complications of pars plana (PP) tube implantation with conventional anterior chamber (AC) tube implantation., Materials and Methods: Records of patients undergoing glaucoma tube implant surgery at a single institution between 2007 and 2015 were retrospectively reviewed. Eyes were matched for glaucoma diagnosis and patient age. Demographics, baseline characteristics, and treatment outcomes were recorded. Surgical success was defined as intraocular pressure (IOP) between 6 and 21 mm Hg, no subsequent glaucoma surgeries performed, and at least light perception vision., Results: Fifty-seven eyes that underwent Ahmed or Baerveldt glaucoma drainage device surgery with PP tube placement were compared with 57 eyes with AC tube placement. Mean follow-up was 43.5 months in the PP group and 35.3 months in the AC group (P=0.02). Forty-nine (86.0%) PP eyes and 46 (80.7%) AC eyes achieved surgical success (P=0.45). At last follow-up, mean IOP decreased from 29.0 to 15.1 mm Hg in the PP group (P<0.01) and from 32.7 to 15.6 mm Hg in the AC group (P<0.01). Mean number of medications decreased from 2.9 to 1.1 in the PP group (P<0.01) and from 2.8 to 1.3 in the AC group (P<0.01). Mean IOP and number of medications were similar between PP and AC groups at baseline, last follow-up, and all interim time points (P>0.05 for all). There were 16 complications in the PP group and 14 in the AC group (P=0.67)., Conclusions: Long-term results of glaucoma tube implant surgery with PP versus AC implantation shows effective IOP control with similar rates of surgical success.

Purpose: To evaluate clinico-pathological and molecular prognostic factors in a well-defined series of posterior uveal melanoma (UM) with focus on chromosomal aberrations and mutations in the GNAQ, GNA11 and BRCA1-associated protein 1 (BAP1) genes., Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were obtained from 50 consecutive eyes enucleated for UM between 1993 and 2005. The material was tested for loss of chromosome 3 and gain of chromosome 8q gene signatures by selective molecular gene markers using multiplex ligation-dependent probe amplification (MLPA), and for DNA mutations in the GNAQ, GNA11 and BAP1 genes., Results: After a mean follow-up of 83 months (range, 8-205 months), 21 patients had died of metastatic UM and 16 patients of other causes. Tumour diameter, ciliary body involvement, mixed/epithelioid cell types, mitotic index, Ki-67 proliferation index, loss of chromosome 3 and gain of chromosome 8q showed statistically significant associations with metastatic disease. There were no significant differences in the prevalence of GNAQ and GNA11 mutations between patients with or without metastatic disease. Mutational analysis of the BAP1 gene was performed in 32 primary UM and in five UM liver metastases. Nine different BAP1 missense mutations were identified. BAP1 mutations were not more common in metastasizing than in nonmetastasizing UM., Conclusion: The molecular gene markers showing loss of chromosome 3 and gain of 8q gene signatures were associated with an increased risk of metastatic disease. BRCA1-associated protein 1 (BAP1) gene mutation status had no prognostic significance. The frequency and spectrum of BAP1 mutations in UM may be more dependent on ethnicity and demographic variables than hitherto considered., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The plasmacytoma variant translocation 1 gene (PVT1) plays an oncogenic role in the initiation and progression of multiple cancers. In this study, by using deep-sequencing data and follow-up data in the Cancer Genome Atlas-Uveal melanomas (TCGA-UVM), we assessed the association between the expression of PVT1 and clinicopathological characteristics of patients with uveal melanoma, the mechanism of its dysregulation and its prognostic value. Results showed that high PVT1 expression group had a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis) compared with the low PVT1 expression group. 61 out of 80 cases (76.3%) of primary uveal melanoma had PVT1 amplification in TCGA-UVM. In addition, PVT1 expression was strongly and negatively correlated with its methylation status (Pearson's r = -0.712, Spearman's r = -0.806). By performing univariate and multivariate analysis, we found that high PVT1 expression was an independent predictor of poor OS in patients with uveal melanoma (HR: 12.015, 95%CI: 1.854-77.876, p = 0.009). Based on these findings, we infer that PVT1 expression is modulated by both DNA amplification and methylation and its expression might serve as a valuable and specific prognostic biomarker in terms of OS in uveal melanoma.

The mechanisms underlying cutaneous melanogenesis have been widely studied; however, very little is known about uveal melanogenesis. Melanin is normally produced by uveal melanocytes and gives the color to the iris. A derangement from this normal production may occur, for instance, by iatrogenic events, such as glaucoma therapy with prostaglandins that may enhance cutaneous and iris pigmentation. In this study, we investigated the mechanisms that regulate uveal melanogenesis in human uveal melanoma cells (92.1) and murine cutaneous melanoma cells (B16-F1). In the first part of the study, we compared the effects of known cutaneous pigmenting agents on the B16-F1 and 92.1 cells, showing an opposite response of the two cell lines. Subsequently, using argan oil, a known depigmenting agent for murine cutaneous melanoma cells, on 92.1 cells, we found that in these cells, it also functioned as an inhibitor of melanogenesis and tyrosinase expression. From a molecular perspective, treatment of the 92.1 cells with argan oil decreased melanogenesis-associated transcription factor (MITF) gene expression by inducing MITF phosphorylation at Ser73, thus leading to MITF ubiquitination and disposal. It also led to the downregulation of the extracellular signal-regulated kinase (ERK)1/2 and Akt pathways, also known to be involved in cutaneous melanogenesis, although with an opposing function. Taken together, our data indicate that: ⅰ) some differences exist in the regulation of melanogenesis between cutaneous and uveal melanoma cells; and ⅱ) argan oil exerts a depigmenting effect on 92.1 cells through its action on the ERK1/2 and Akt pathways.

Background: We report a case of acute uveal effusion during phacoemulsification in an eye with preoperative chronic central serous chorioretinopathy (CSC)., Case Presentation: A 55-year-old man with a history of chronic CSC for >18 months presented with bilateral opaque lenses. A preoperative ophthalmic examination showed suspected lenticonus and risky anatomical features, including a thick ciliary body, and anterior rotation of the ciliary process and iris root in both eyes. Optical coherence tomography (OCT) detected CSC in the left eye, but the results of fundus photography and B-scan ultrasonography were unremarkable. The anterior chamber flattened during phacoemulsification. Anterior vitrectomy was quickly performed for suspected infusion misdirection syndrome, and was followed by uneventful surgery. On postoperative day 1, fundus photography, type B ultrasound, and OCT revealed uveal exudation in the macula of the left eye. On postoperative day 50, the patient's visual acuity recovered to 20/32, and fundus photography, ultrasonography, and OCT revealed complete resolution of the uveal effusion., Conclusions: This case suggests an association between preoperative CSC and uveal effusion during surgery, because choroidal hyperperfusion and hyperpermeability were present in the patient's CSC-affected eyes.

Purpose: There is currently no clinical risk-assessment tool allowing identification of patients at risk for developing uveal melanoma (UM) who might benefit from regular screening. As a first step toward the elaboration of such a tool, we systematically reviewed UM risk factors already established by meta-analysis., Methods: Two reviewers independently screened Pubmed, Medline, Embase, and Web of Science from their respective inception dates until July 2016 using a combination of keywords and MeSH terms. Eligible studies were meta-analyses or systematic reviews providing pooled odds ratios (ORs) of risk factors for UM development or sufficient information to calculate them. Methodological quality was evaluated using the Assessment of Multiple Systematic Reviews tool., Results: Four meta-analyses with a mean methodological quality score of 65.9% (min: 54.5%; max: 72.7%) were included. The following significant risk factors were identified: atypical cutaneous nevi (OR 2.82, 95% CI 1.10-7.26), welding (OR 2.05, 95% CI 1.20-3.51), occupational cooking (OR 1.81, 95% CI 1.33-2.46), fair skin color (OR 1.80, 95% CI 1.31-2.47), light eye color (OR 1.75, 95% CI 1.31-2.34), common cutaneous nevi (OR 1.74, 95% CI 1.27-2.39), propensity to sunburn (OR 1.64, 95% CI 1.29-2.09), iris nevi (OR 1.53, 95% CI 1.03-2.27), and cutaneous freckles (OR 1.27, 95% CI 1.09-1.49). Non-significant factors included outdoor leisure activity, occupational sunlight exposure, latitude of birth, and hair color., Conclusion: Moderate quality of evidence determined nine significant risk factors for developing UM. Knowledge of these variables will assist researchers in the elaboration of a formal risk-assessment tool allowing clinicians to estimate susceptibility to the disease and necessity of regular screening.

Background: The uveitis masquerade syndromes (UMS) are a group of ocular diseases that may mimic chronic intraocular inflammation. Many malignant entities such as non-Hodgkin's lymphomas may masquerade as uveitis. We report a case of an HIV-positive patient with masquerade syndrome presenting unilateral uveitis., Case Report: 45-year-old Caucasian man with a diagnosis of diffuse large B-cell lymphoma (DLBCL). The patient was diagnosed by a biopsy of an abdominal mass which showed fragments of gastric mucosa with diffuse growth of neoplastic cells. At diagnosis, the patient suffered from unilateral blurring of vision and a sudden decrease of left-eye visual acuity. A slit-lamp examination of the left eye revealed a diagnosis of anterior uveitis. The patient exhibited no signs of posterior uveitis. An anterior-chamber paracentesis was performed and analyzed by multiparameter flow cytometry (MFC), showing cells CD45, CD19, CD20, CD22, and CD38 positives, and moderate expression of CD10 with kappa light chain restriction, showing a monoclonal B-cell population. The patient received CHOP-R with intrathecal methotrexate followed by consolidation high dose methotrexate obtaining a complete response which is ongoing., Conclusion: Differential diagnosis between chronic uveitis and ocular lymphoma may be challenging. We advocate anterior-chamber paracentesis in cases of refractory uveitis in patients with hematologic malignancies. © 2016 International Clinical Cytometry Society., (© 2016 International Clinical Cytometry Society.)

Uveitis, defined as inflammation of the uveal tract, may cause blindness in both young and middle-aged people. Approximately 10-15% of blindness in the West is caused by uveitis. Therefore, a comprehensive investigation to determine the disease pathogenesis is urgent, as it will thus be possible to design effective treatments. Identification of the disease genes that cause uveitis is an important requirement to achieve this goal. To begin to answer this question, in this study, a computational method was proposed to identify novel uveitis-related genes. This method was executed on a large protein-protein interaction network and employed a popular ranking algorithm, the Random Walk with Restart (RWR) algorithm. To improve the utility of the method, a permutation test and a procedure for selecting core genes were added, which helped to exclude false discoveries and select the most important candidate genes. The five-fold cross-validation was adopted to evaluate the method, yielding the average F1-measure of 0.189. In addition, we compared our method with a classic GBA-based method to further indicate its utility. Based on our method, 56 putative genes were chosen for further assessment. We have determined that several of these genes (e.g., CCL4 , Jun , and MMP9 ) are likely to be important for the pathogenesis of uveitis.

The aim of the present study was to investigate differential modules (DMs) between uveal melanoma (UM) and normal conditions by examining differential networks. Based on a gene expression profile collected from the ArrayExpress database, the inference of DMs involved three steps: The first step was construction of a differential co‑expression network (DCN); second, the module algorithm was adapted to identify the DMs presented in DCN; finally, the statistical significance of DMs were assessed based on the null score distribution of DMs generated using randomized networks. A DCN with 309 nodes and 3,729 edges was obtained, and 30 seed genes from the DCN were examined. Subsequently, one DM, which had 179 nodes and 3,068 edges, was investigated. By utilizing randomized networks, the P‑value for DM was 0.034, therefore, the DM was statically significant between UM and baseline conditions. In conclusion, the present study successfully identified one DM in UM based on DCN and module algorithm, and this DM may be beneficial in revealing the pathological mechanism of UM and provide insight for future investigation of UM.

The purpose of this study is to examine the capability of photoacoustic (PA) imaging (PAI) in assessing the unique molecular and architectural features in ocular tumors. A real-time PA and ultrasonography (US) parallel imaging system based on a research US platform was developed to examine retinoblastoma in mice in vivo and human retinoblastoma and uveal melanoma ex vivo. PA signals were generated by optical illumination at 720, 750, 800, 850, 900 and 950 nm delivered through a fiber optical bundle. The optical absorption spectra of the tumors were derived from the PA images. The optical absorption spectrum of each tumor was quantified by fitting to a polynomial model. The microscopic architectures of the tumors were quantified by frequency domain analysis of the PA signals. Both the optical spectral and architectural features agree with the histological findings of the tumors. The mouse and human retinoblastoma showed comparable total optical absorption spectra at a correlation of 0.95 (p<0.005). The quantitative PAI features of human retinoblastoma and uveal melanoma have shown statistically significant difference in two tailed t-tests (p<0.05). Fully compatible with the concurrent procedures, PAI could be a potential tool complementary to other diagnostic modalities for characterizing intraocular tumors.

Epigenetic modifications can affect numerous mechanisms used by neoplastic cells to evade immune control. In melanoma epigenetic defects, caused by dysregulations in the expression of genome writers, erasers, or readers, play a significant role in the reduced expression of molecules required for efficient immune recognition as well as antigen presentation and processing. Alterations in gene expression were identified in tumor-associated antigens (TAAs), human leukocyte antigen (HLA) complex, co-stimulatory/accessory molecules, antigen processing machinery (APM), and NKG2D ligands that have shown to be silenced or down-regulated in melanoma. In agreement with the inherent reversibility of epigenetic silencing, epigenetic drugs such as inhibitors of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferase enhancer of Zeste homolog 2 (EZH2), and modifiers of microRNA (miRNA) dysregulation or antagomirs can restore the expression of these molecules, favouring the recognition of cancer cells by immune responses, reducing the resistance to Natural Killer (NK) and cytotoxic T cells (CTL), and enhancing the functions of antigen presenting cells. Moreover, inhibitors of reader proteins seem to preferentially affect the NF-kB-induced activation of pro-inflammatory cytokine genes. At present an increasing interest is shown toward new combined therapeutic approaches employing epidrugs or new molecular inhibitors and in vivo immunotherapies, such as vaccines and adoptive T-cell transfer (ACT). This review summarizes the current understanding of the role of epidrugs in the modulation of molecules involved in the melanoma immune response and focuses on their future clinical use in new therapeutic combinations for melanoma treatment.

The aim of the present study was to investigate the efficacy of luteolin on endotoxin-induced uveitis (EIU) in rats. EIU was induced in Lewis rats by subcutaneous injections of lipopolysaccharide (LPS). One hr before the LPS injection, 0.1, 1 or 10 mg/kg luteolin or 1 mg/kg prednisolone was intraperitoneally injected. We investigated its effect upon clinical scores, cellular infiltration and protein leakage, as well as on the level of tumor necrosis factor (TNF)-α, nitric oxide (NO) and prostaglandin (PG) E2 in the aqueous humor (AqH). Histologic examination and immunohistochemical analysis in the iris-ciliary body (ICB) were performed to determine the expressions of cyclooxygenase (COX)-2 and inducible NO synthase (iNOS), and then the activated nuclear factor (NF)-κB p65, I kappa B (IκB)-α degradation, phosphorylated (p)-IκB kinase (IKK) α/β and activator protein (AP)-1 c-Jun. Luteolin suppressed, in a dose-dependent manner, the clinical scores, number of inflammatory cells, the protein concentration, and the TNF-α, NO and PGE2 levels in the AqH and improved the histiologic status of the ocular tissue. Luteolin suppressed the expression of iNOS and COX-2 and the activated NF-κB p65, IκB-α degradation, p-IKKα/β and AP-1 p-c-Jun in the ICB. The anti-inflammatory potency of 10 mg/kg luteolin was as strong as that observed with 1 mg/kg prednisolone. These results demonstrate that luteolin attenuates ocular inflammation by inhibiting expression and release of inflammatory markers, along with the inhibition of the activated NF-κB pathway and at least partly AP-1 activity in the ICB.

Background: Ocular infections remain a major cause of blindness and morbidity worldwide. While prognosis is dependent on the timing and accuracy of diagnosis, the etiology remains elusive in ~50 % of presumed infectious uveitis cases. The objective of this study is to determine if unbiased metagenomic deep sequencing (MDS) can accurately detect pathogens in intraocular fluid samples of patients with uveitis., Methods: This is a proof-of-concept study, in which intraocular fluid samples were obtained from five subjects with known diagnoses, and one subject with bilateral chronic uveitis without a known etiology. Samples were subjected to MDS, and results were compared with those from conventional diagnostic tests. Pathogens were identified using a rapid computational pipeline to analyze the non-host sequences obtained from MDS., Results: Unbiased MDS of intraocular fluid produced results concordant with known diagnoses in subjects with (n = 4) and without (n = 1) uveitis. Samples positive for Cryptococcus neoformans, Toxoplasma gondii, and herpes simplex virus 1 as tested by a Clinical Laboratory Improvement Amendments-certified laboratory were correctly identified with MDS. Rubella virus was identified in one case of chronic bilateral idiopathic uveitis. The subject's strain was most closely related to a German rubella virus strain isolated in 1992, one year before he developed a fever and rash while living in Germany. The pattern and the number of viral identified mutations present in the patient's strain were consistent with long-term viral replication in the eye., Conclusions: MDS can identify fungi, parasites, and DNA and RNA viruses in minute volumes of intraocular fluid samples. The identification of chronic intraocular rubella virus infection highlights the eye's role as a long-term pathogen reservoir, which has implications for virus eradication and emerging global epidemics.

Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with a high rate of distant tumor spread and consequent mortality. Unlike retinoblastoma, for which treatment advances over the last few decades have resulted in a dramatic improvement in survival, outcomes for patients with uveal melanoma remain unchanged. Despite improvement in local control of this tumor, roughly 50% of patients develop metastatic disease within 15 years. Delays in diagnosis and marked vascularity of this tumor may underlie that situation. Tumor size, location, histopathologic appearance, cytogenetic abnormalities, and molecular profiling are used in prognostication. The revised 7th edition of the American Joint Committee on Cancer (AJCC) manual has presented new information that may improve that process as well. Herein, we review current knowledge on uveal melanoma., (Copyright © 2016 Elsevier Inc. All rights reserved.)