Uveal melanoma: Recent advances in immunotherapy.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, which is still characterized by poor prognosis. No standard therapeutic approaches for its prevention or treatment have been established. The application of immunotherapy agents, such as immune checkpoint inhibitors that are effective in cutaneous melanoma, has shown limited effects in the treatment of ocular disease. This is due to UM's distinct genetics, natural history, and complex interaction with the immune system. Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations, UMs are usually triggered by a mutation in GNAQ or GNA11. As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

Diabetic macular edema: Safe and effective treatment with intravitreal triamcinolone acetonide (Taioftal).

PURPOSE: To suggest the safety and efficacy of preservative-free triamcinolone acetonide intravitreal injectable suspension (Taioftal) for the treatment of diabetic macular edema. METHODS: A prospective clinical study involved 49 patients (49 eyes), that were treated with Taioftal and followed-up for six months. Complete ophthalmic examination, including spectral domain optical coherence tomography, was performed at baseline, and at month 1, 3, 6 after the intravitreal injection. Accurate collection and analysis of best-corrected visual acuity (BCVA), central foveal thickness (CFT), intraocular pressure (IOP), and adverse events (AEs) were carried out in order to evaluate visual function and macular morphology before and after treatment. RESULTS: Median BCVA value chosen as comparing statistics was significantly improved at every follow-up time points (gain of 6 letters at month 1, 12 at month 3 -improvement up to 24% at month 3 with stabilization until month 6) compared to baseline, as certified by Kruskal-Wallis rank sum test (P<0.05). Median CFT significantly waned at each follow-up times (decrease of about 65 µm at month 1, 155 at month 3 -reduction up to 28% at month 3 keeping good outcome until month 6) compared to baseline (P<0.05). IOP elevation, with no severe increases, was the most common among spotted AEs (median of 23 mmHg at month 1, 20 at month 3). CONCLUSION: Intravitreal injection of preservative-free triamcinolone (Taioftal) is an effective, safe and inexpensive drug used to improve visual acuity and reduce central foveal thickness in eyes affected by diabetic macular edema during an average time of 6 months. Temporary, never severe, elevation of IOP is totally manageable with topical medications. No serious vision-threatening complications are related to the use of intravitreal triamcinolone injections.

Qualitative Alterations on Corneal Endothelial Cell Morphometry and Hexagonality After Cataract Surgery.

AIM: To deeply analyze quantitative and qualitative changes of corneal endothelium after longitudinal phacoemulsification. METHODS: In this prospective interventional case series study, 50 eyes with age-related cataract have been evaluated preoperatively, intraoperatively and postoperatively. The measured parameters were surgically induced endothelial cell loss (ECL), average endothelial cell area (AVG) and hexagonality (HEX). RESULTS: The relationship among the measured parameters and the energy dissipated during the two phases of phacoemulsification, sculpting and quadrant removal, has been analyzed with regard to the 5-score harm scale, a new method suggested to categorize cataracts. Two phases of phacoemulsification are linearly related (r = 1.5, P < 0.001, r2 = 79%). Plus, a quadratic model described the correlation between the percentages of ECL and AVG (P < 0.0001), while there was no specific model for the correlation between ECL and HEX. CONCLUSION: The 5-score harm scale allows to predict the mean changes in percentages of ECL, AVG and HEX of endothelial cells after longitudinal phacoemulsification. Also, this study confirms that the main damage on corneal endothelium is due to the energy delivered in the second phase of phacoemulsification.

Application of Artificial Intelligence in Targeting Retinal Diseases.

Retinal diseases affect an increasing number of patients worldwide because of the aging population. Request for diagnostic imaging in ophthalmology is ramping up, while the number of specialists keeps shrinking. Cutting-edge technology embedding artificial intelligence (AI) algorithms are thus advocated to help ophthalmologists perform their clinical tasks as well as to provide a source for the advancement of novel biomarkers. In particular, optical coherence tomography (OCT) evaluation of the retina can be augmented by algorithms based on machine learning and deep learning to early detect, qualitatively localize and quantitatively measure epi/intra/subretinal abnormalities or pathological features of macular or neural diseases. In this paper, we discuss the use of AI to facilitate efficacy and accuracy of retinal imaging in those diseases increasingly treated by intravitreal vascular endothelial growth factor (VEGF) inhibitors (i.e. anti-VEGF drugs), also including integration and interpretation features in the process. We review recent advances by AI in diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity that envision a potentially key role of highly automated systems in screening, early diagnosis, grading and individualized therapy. We discuss benefits and critical aspects of automating the evaluation of disease activity, recurrences, the timing of retreatment and therapeutically potential novel targets in ophthalmology. The impact of massive employment of AI to optimize clinical assistance and encourage tailored therapies for distinct patterns of retinal diseases is also discussed.

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the efficacy of photodynamic therapy in patients with neovascular age-related macular degeneration.

The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12-0.32] and 0.09 [95% CI, 0.04-0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15-0.39] and 0.03 [95% CI, 0.01-0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy.

Diabetic retinopathy and endothelin system: microangiopathy versus endothelial dysfunction.

In the face of the global epidemic of diabetes, it is critical that we update our knowledge about the pathogenesis of diabetes and the related micro alterations on the vascular network in the body. This may ultimately lead to early diagnosis and novel treatment options for delaying the progression of diabetic complications. Research has recently revealed the pivotal role of endothelin in the pathogenesis of diabetic complications, particularly in the regulation of the capillary flow, which is affected in the course of retinopathy. Although there are several reviews on various approaches to the treatment of diabetes, including normalization of glucose and fat metabolism, no reviews in literature have focused on the endothelin system as a therapeutic target or early indicator of diabetic microangiopathy. In this review, we summarize some of the experimental and clinical evidence suggesting that current therapeutic approaches to diabetes may include the modulation of the blood concentration of compounds of the endothelin system. In addition, we will briefly discuss the beneficial effects produced by the inhibition of the production of high levels of endothelin in vasculopathy, with focus on diabetic retinopathy. The cutting-edge technology currently widely used in opththalmology, such as the OCT angiography, allows us to detect very early retinal morphological changes alongside alterations in choroidal and retinal vascular network. Combination of such changes with highly sensitive measurements of alterations in serum concentrations of endothelin may lead to more efficient early detection and treatment of diabetes and related macro/microvascular complications.

Torsional phacoemulsification: A pilot study to revise the "harm scale" evaluating the endothelial damage and the visual acuity after cataract surgery.

PURPOSE: To study the effect of torsional phacoemulsification energy on corneal endothelium evaluating the relationship between changes of endothelial cells and postoperative visual acuity. METHODS: This prospective clinical observational cohort study included 50 patients with cataract who underwent torsional phacoemulsification. Sequential quantitative and qualitative morphometric endothelial cell analyses of the cornea were performed four weeks preoperatively and six weeks postoperatively using noncontact specular microscopy. RESULTS: This work confirmed the strong relationship, described by a linear model (one-way ANOVA, R2 = 77.9%, P < 0.0001), between the percentage of endothelial cell loss (ECL%) and the 5-score harm scale. According to the Tukey post-hoc pairwise comparison test, distinct values of ECL% are grouped in 3 subsets. The value of ECL = 10% has been identified as cut-off to discriminate patients with excellent postoperative best-corrected visual acuity (BCVA > 85 letters) from those with just a good/satisfied visual outcome (BCVA ≤ 85 letters). Within the 5-score harm scale, there was a significant correlation among phaco energy intraoperatively delivered and the average endothelial cell loss. CONCLUSIONS: This study confirms the validity of the 5-score harm scale first proposed by Sorrentino and colleagues in 2016. This time, the method categorizes cataracts taking into account nucleus hardness and phaco cumulative dissipated energy. Predicting the harm on corneal endothelium, we can discriminate patients with excellent BCVA and with just good/satisfied BCVA. With torsional phacoemulsification with respect to longitudinal, the percentage of patients who can reach excellent BCVA is remarkably increased.

The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy.

Diabetic retinopathy (DR) is a remarkable microvascular complication of diabetes and it has been considered the leading cause of legal blindness in working-age adults in the world. Several overlapping and interrelated molecular pathways are involved in the development of this disease. DR is staged into different levels of severity, from the nonproliferative to the advanced proliferative form. Over the years the progression of DR evolves through a series of changes involving distinct types of specialized cells: neural, vascular and glial. Prior to the clinically observable vascular complications, hyperglycemia and inflammation affect retinal glial cells which undergo a wide range of structural and functional alterations. In this review, we provide an overview of the status of macroglia and microglia in the course of DR, trying to briefly take into account the complex biochemical mechanisms that affect the intimate relationship among neuroretina, vessels and glial cells.

A Pilot Study to Propose a "Harm Scale", a New Method to Predict Risk of Harm to the Corneal Endothelium Caused by Longitudinal Phacoemulsification, and the Subsequent Effect of Endothelial Damage on Post Operative Visual Acuity.

PURPOSE: To study the effect of longitudinal phacoemulsification energy on corneal endothelium and to evaluate the relationship between changes of endothelial cells and postoperative visual acuity. METHODS: This prospective clinical observational cohort study included 50 patients with cataract who underwent longitudinal phacoemulsification. Sequential quantitative and qualitative morphometric endothelial cell analyses of the cornea were performed 4 weeks preoperatively and 6 weeks postoperatively using noncontact specular microscopy. RESULTS: There was a relationship between ECL percentage (ECL%) and the 5-score harm scale, well-described by a linear model (one-way ANOVA, R2 = 73.3%). Analyzing the distribution of ECL% Mean with Tukey post-hoc pairwise comparison test (P < 0.001), the value of ECL = 20% has been regarded as cut-off to discriminate patients who obtained an excellent postoperative best-corrected visual acuity (BCVA > 85 letters) from those who just had a good visual outcome (BCVA ≤ 85 letters). There was a significant correlation among the 5-score harm scale, phaco energy intraoperatively delivered, and average cell area postoperatively. CONCLUSIONS: The 5-score harm scale, a new method that enables to pigeonhole cataracts taking into account nucleus hardness and phaco times, allows to predict the harm on corneal endothelium after longitudinal phacoemulsification. Assessment of ECL% permits to discriminate between patients with excellent BCVA and with just good BCVA, postoperatively.

The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa.

Retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction, which may bring about severe central vision impairment. Haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina-choroidal and in retroocular vascular system. Moreover, several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye. This might account for vasoconstriction and ischemia, typical in vascular dysregulation syndrome, which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa.