Genetic Basis and Molecular Mechanisms of Uveal Melanoma Metastasis: A Focus on Prognosis.

Uveal melanoma (UM) is the most frequently found primary intraocular tumor, although it accounts for only 5% of all melanomas. Despite novel systemic therapies, patient survival has remained poor. Indeed, almost half of UM patients develop metastases from micro-metastases which were undetectable at diagnosis. Genetic analysis is crucial for metastatic risk prediction, as well as for patient management and follow-up. Several prognostic parameters have been explored, including tumor location, basal dimension and thickness, histopathologic cell type, vascular mimicry patterns, and infiltrating lymphocytes. Herein, the Authors review the available literature concerning cytogenetic prognostic markers and biochemical pathways correlated to UM metastasis development.

Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor's daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.

Evaluation of the Choroid in Eyes With Retinitis Pigmentosa and Cystoid Macular Edema.

Purpose: To study the anatomical choroidal features associated with the presence of cystoid macular edema (CME) in eyes with retinitis pigmentosa (RP). Methods: A total of 159 eyes (from 159 patients) with a diagnosis of RP were enrolled in this retrospective cross-sectional case-control study and divided into two groups based on the presence (67 eyes) or absence (92 eyes) of CME. Retinal and choroidal features were evaluated on spectral domain optical coherence tomography including central macular thickness (CMT) and subfoveal choroidal thickness (CT). Total choroidal area (TCA), choroidal luminal area (LA), and choroidal stromal area (SA) were measured and the choroidal vascularity index (CVI) was calculated in all study eyes. Results: Average age was 49.2 ± 14.9 and 47.1 ± 15.5 years (P = 0.40) and logMAR Snellen visual acuity (VA) was 0.4 ± 0.6 (median 0.3, 20/40) and 0.2 ± 0.4 (median 0.1, 20/25) in the RP groups with and without CME, respectively (P = 0.05). Mean CMT was 334.1 ± 93.5 and 252.6 ± 47.6 µm in the RP groups with and without CME, respectively (P < 0.001). The subfoveal CT was significantly increased in the RP group with versus without CME (294.2 ± 110.9 µm vs. 198.1 ± 75.5 µm, respectively, P < 0.001). In patients with CME, the CVI was lower (P < 0.001) and the TCA, LA, and SA were all significantly higher (P < 0.001). Conclusions: In patients with CME associated with RP, the choroid exhibited significantly greater subfoveal thickening and decreased CVI. The choroid may be an important factor to consider in the etiology of CME in patients with RP.

New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma.

Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches.

Wide field retinal imaging and the detection of drug associated retinal toxicity.

BACKGROUND: To describe the peripheral retinal findings associated with systemic medication toxicity and to outline the importance of ultra-widefield imaging in the detection, analysis and monitoring of these abnormalities. MAIN TEXT: This review highlights the retinal manifestations associated with the more common drug toxicities, with emphasis on the peripheral features and the indications for wide field imaging. The presenting findings, underlying pathophysiology, and retinal alterations in hydroxychloroquine, thioridazine, didanosine, tamoxifen, MEK-inhibitor, and immune checkpoint inhibitor associated drug toxicity will be described and the importance of wide field imaging in the evaluation of these abnormalities will be emphasized. CONCLUSIONS: Wide field retinal imaging can improve the detection of peripheral retinal abnormalities associated with drug toxicity and may be an important tool in the diagnosis and management of these disorders.

High prevalence of serum IgG antibodies reacting to specific mimotopes of BK polyomavirus, a human oncogenic polyomavirus, in patients affected by uveal melanoma.

The uveal melanoma (UM) is the most common human intraocular tumor. The BK polyomavirus (BKPyV) is a small DNA tumor virus whose footprints have been detected in different human cancers. BKPyV has oncogenic potential. Indeed, BKPyV, when inoculated into experimental animals, induces tumors of different histotypes, whereas in vitro, it transforms mammalian cells, including human cells from distinct tissues. In this investigation, the association between UM and BKPyV was studied employing indirect enzyme-linked immunosorbent assays (ELISAs) using synthetic peptides that mimic BKPyV viral capsid 1 (VP1) antigens. Indirect ELISAs were used to detect serum IgG antibodies against this polyomavirus with oncogenic potential in samples from patients with UM and controls, represented by healthy subjects (HS). It was found that serum samples from patients with UM had a higher prevalence of BKPyV antibodies, 85% (51/60), compared with that detected in HS1, 62% (54/87), and HS2, 57% (68/120). The different prevalence of BKPyV antibodies detected in UM versus the two control groups, HS1 and HS2, is statistically significant (p < 0.005). Our immunologic data suggest a significantly higher prevalence of antibodies against BKPyV VP1 epitopes in serum samples from patients with UM compared with HS. These results indicate an association between UM and BKPyV, suggesting that this small DNA tumor virus may be a cofactor in the UM onset or progression.

Specific Detection of Serum Antibodies against BKPyV, A Small DNA Tumour Virus, in Patients Affected by Choroidal Nevi.

Ocular or choroidal nevus (CN) is a rare benign neoplastic lesion of the eye. The cause of CN onset/progression, which arises from the transformation of ocular melanocytes, is not known. A fraction of CN patients may develop uveal melanoma. The objective of this study was to investigate the association between CN and BK polyomavirus (BKPyV), a small DNA tumor virus. Serum IgG antibodies which react with BKPyV antigens were analyzed. An indirect E.L.I.S.A. using synthetic peptides that mimic BKPyV antigens was employed. Serum antibodies against BKPyV were also investigated by haemagglutination inhibition (HAI) assay. Sera were from CN patients and healthy subject (HS) were the control. A statistically significant higher prevalence of antibodies against BKPyV capsid protein antigens in serum samples from CN patients was detected, compared to HS, using two independent techniques, indirect E.L.I.S.A. and HAI (87.3% CN vs. 62.1% HS and 91.5% CN vs. 64.4% HS, respectively; p < 0.005). Our data suggest an association exists between CN and BKPyV indicating that this small DNA tumor virus could be responsible in the onset of this benign neoplastic lesion affecting eye melanocytes. This investigation reports the association between choroidal nevi and BKPyV infection for the first time. These data are innovative in this field and may represent a starting point for further investigation into the putative role of BKPyV in CN onset/progression.

Clinical assessment of retinal changes by spectral-domain OCT.

PURPOSE: To evaluate optical coherence tomography changes in patients with retinal thinning at the posterior pole. METHODS: In this cross-sectional and retrospective study, 648 files were reviewed, and 67 patients were selected. Optical coherence tomography images that showed an area with a retinal thickness reduction at the macular region by using the Asymmetry Analysis Map in Heidelberg Spectralis were selected. The presence of hemisphere asymmetry in the same eye and asymmetry between the paired eyes were calculated and used for the analysis. Retinal thickness was measured in 3 different retinal areas (squares): (1) the area (square) involved by the pathology (IA), (2) the specular area (square) in the opposite hemifield (SA), and (3) the corresponding IA in the contralateral eye (CIA) (area used to recruit the patients). Retinal layer morphology was analyzed observing the Spectralis screen. RESULTS: The thickness of the IA was 235.54 ± 39.95 µm (mean ± standard deviation), while it was 269.84 ± 36.16 µm and 293.81 ± 37.52 µm for SA and CIA, respectively. CONCLUSIONS: Different retinal layers could be involved in reduction of the retinal thickness: a reduction of the inner layers was related to disease in which ciliary or retinal arterial vessel flow was involved, while a reduction of the outer retinal layer was related to pathologies related to choroidal flow diseases.