Multiple neoplasms in patients with uveal melanoma: a systematic review.

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.

EVALUATION OF VITRECTOMY AND REIMPLANTATION FOLLOWING LATE DISLOCATION OF THE INTRAOCULAR LENS-CAPSULAR BAG COMPLEX: A 3-Year Follow-up Study.

OBJECTIVES: To study the predisposition factors for dislocation of the intraocular lens (IOL)-capsular bag complex and analyze the results of subsequent reimplantation surgery. METHODS: The exclusion criteria were complicated cataract surgery and minor dislocations that appeared in the first year after cataract surgery. Thirty-six months of monitoring of the reimplantation surgery was required. The primary measurements of results were factors concerning dislocation, the interval between cataract surgery and dislocation, and postoperative complications. RESULTS: Thirty-six patients with dislocation of the capsular bag and lens were identified. Pseudoexfoliation was mentioned in 17 cases (47.2%) and was the main predisposition factor. The average interval between cataract surgery and dislocation was 11.5 years. The dislocated IOL was replaced by a posterior chamber implant in 38% of cases and an anterior chamber implant in 62%. The average best-corrected visual acuity improved significantly after the reposition surgery (P < 0.01). The average monitoring period after secondary reimplantation was 5.95 years (min. 3.03-max. 8.46). Three patients developed bullous keratopathy, all of them with an anterior chamber IOL implantation. CONCLUSION: According to our knowledge, this article is the one with the longest monitoring time to date. Pseudoexfoliation was the main risk factor for the dislocation of the IOL. Surgery significantly improved best-corrected visual acuity, and the reimplantation of the IOL in the posterior chamber was associated with less serious complications.

Foveal microvascular features following inverted flap technique for closure of large macular holes.

PURPOSE: To describe the anatomical and functional outcomes following use of the inverted flap technique (IFT) to close idiopathic macular holes (MH) of diameter greater than 400 µm. To compare the changes in the macular microvascularization following surgery in operated and healthy fellow eyes. METHODS: Retrospective study of 24 patients who underwent vitrectomy and IFT for large MH closure. The main variables were closure pattern, best corrected visual acuity (BCVA) and recovery of the external limiting membrane (ELM) and ellipsoid zone (EZ). Foveal avascular zones (FAZ) and vessel and perfusion densities, obtained by OCT angiography scans, were compared with those in healthy fellow eyes. RESULTS: Complete MH closure was achieved in 95.8% (23/24) of patients 6 months after surgery. There was a significant improvement in postoperative BCVA, from 1.0 to 0.4 logMAR (p < 0.001). The most frequent closure pattern was 1a (62.5%, 15/24), followed by 2c (12.5%, 3/24). The closure pattern was not correlated with height, minimum or maximum diameters or macular hole index (MHI) (p > 0.05). ELM and EZ recovery occurred in 87.5% and 83.3% of cases, respectively. FAZ were smaller in operated eyes than in the fellow eyes (p = 0.012). There were no differences in the vessel or perfusion densities between the operated and fellow eyes (p > 0.05). CONCLUSIONS: Use of the inverted flap technique for large MH closure provides a high rate of functional and anatomical recovery. We observed a reduction in the FAZ following surgery, with no differences in the macular microvascularization parameters, suggesting that the technique is safe.

Bilateral Uveal Melanoma: An Insight into Genetic Predisposition in Four New Unrelated Patients and Review of Published Cases.

Background: Primary bilateral uveal melanoma (BUM) is an exceptionally rare form of uveal melanoma (UM). This study aimed to explore the potential existence of a genetic predisposition towards the development of BUM. Methods: We employed an exome sequencing approach on germline DNA from four unrelated patients diagnosed with BUM, seeking pathogenic or likely pathogenic variants indicative of a genetic predisposition to UM. Results: None of the patients exhibited pathogenic variants in the BAP1 gene. However, loss-of-function (LoF) variants in the TERF2IP and BAX genes were identified in two of the BUM patients. For patients BUM1 and BUM2, no pathogenic/likely pathogenic variants of significant clinical relevance to BUM were found to warrant inclusion in this report. Conclusions: Our findings suggest the presence of yet-to-be-discovered genes that may contribute to UM predisposition, as evidenced by the absence of pathogenic variants in known UM predisposition genes among the four BUM patients studied. The TERF2IP and BAX genes emerge as noteworthy candidates for further investigation regarding their role in genetic predisposition to UM. Specifically, the potential role of UM as a candidate cancer within the spectrum of cancers linked to pathogenic variants in the TERF2IP gene and other genes associated with the shelterin complex warrants further examination. Additional functional studies are necessary to support or challenge this hypothesis.

Primary ILM peeling during retinal detachment repair: a systematic review and meta-analysis.

Epiretinal membrane (ERM) formation is a known postoperative complication following retinal detachment (RD) repair surgery. Prophylactic peeling of the internal limiting membrane (ILM) during surgery has been shown to reduce the risk of developing postoperative ERM formation. Some baseline characteristics and degrees of surgical complexity may act as risk factors for ERM development. In this review we aimed to investigate the benefit of ILM peeling in patients without significant proliferative vitreoretinopathy (PVR) who underwent pars plana vitrectomy for RD repair. A literature search using PubMed and various keywords retrieved relevant papers from which data were extracted and analyzed. Finally, the results of 12 observational studies (3420 eyes) were summarized. ILM peeling significantly reduced the risk of postoperative ERM formation (RR = 0.12, 95% CI 0.05-0.28). The groups did not differ in final visual acuity (SMD 0.14 logMAR (95% CI - 0.03-0.31)). The risk of RD recurrence (RR = 0.51, 95% CI 0.28-0.94) and the need for secondary ERM surgery (RR = 0.05, 95% CI 0.02-0.17) were also higher in the non-ILM peeling groups. In summary, although prophylactic ILM peeling appears to reduce the rate of postoperative ERM, this benefit does not translate into consistent visual recovery across studies and potential complications must be considered.

PARK7/DJ-1 inhibition decreases invasion and proliferation of uveal melanoma cells.

INTRODUCTION: PARK7/DJ-1 is an oncogene that is associated with tumorigenesis in many cancers. Recent studies have demonstrated the importance of DJ-1 in the origin and development of uveal melanoma (UM). We present an analysis of the role of the DJ-1 protein in UM cells, especially in its effect on proliferation and migration. METHODS: UM cells from a primary tumor, Mel 270, and its liver metastasis, OMM2.5, were transfected with lentiviral-delivered shRNA against PARK7/DJ-1. Evaluation of cell migration and proliferation was performed using the xCELLigence real-time cell analyzer (RTCA). The effect of DJ-1 inhibition on the PTEN-Akt signaling pathway was also studied by immunoblotting. RESULTS: The silencing of PARK7/DJ-1 oncoprotein expression produced a significant decrease of phosphorylated Akt (S473) in Mel270 and in metastatic OMM2.5 UM cells with no alteration on tumor suppressor PTEN expression. The diminution of PARK7/DJ-1 expression significantly inhibited real-time proliferation and invasion of Mel270 and OMM2.5 and the invasion potential of the metastatic cells. CONCLUSION: DJ-1 appears to play a key role on the PTEN/Akt pathway in UM. DJ-1 inhibition appears to have a negative effect on proliferation and invasion of UM cells. This suggests DJ-1 as a potential therapeutic target in UM.

GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma.

The GNAQ and GNA11 genes are mutated in almost 80-90% of uveal melanomas in a mutually exclusive pattern. These genes encode the alpha subunits of the heterotrimeric G proteins, Gq and G11; thus, mutations of these genes result in the activation of several important signaling pathways, including phospholipase C, and activation of the transcription factor YAP. It is well known that both of them act as driver genes in the oncogenic process and it has been assumed that they do not play a role in the prognosis of these tumours. However, it has been hypothesised that mutations in these genes could give rise to molecularly and clinically distinct types of uveal melanomas. It has also been questioned whether the type and location of mutation in the GNAQ and GNA11 genes may affect the progression of these tumours. All of these questions, except for their implications in carcinogenesis, remain controversial. Uveal melanoma has a distinctive genetic profile, and specific recurrent mutations, which make it a potential candidate for treatment with targeted therapy. Given that the most frequent mutations are those observed in the GNAQ and GNA11 genes, and that both genes are involved in oncogenesis, these molecules, as well as the downstream signalling pathways in which they are involved, have been proposed as promising potential therapeutic targets. Therefore, in this review, special attention is paid to the current data related to the possible prognostic implications of both genes from different perspectives, as well as the therapeutic options targeting them.

Applications of Non-Coding RNAs in Patients With Retinoblastoma.

Retinoblastoma (RB) is the most common primary intraocular malignancy in childhood. In the carcinogenic process of neoplasms such as RB, the role of non-coding RNAs (ncRNAs) has been widely demonstrated recently. In this review, we aim to provide a clinical overview of the current knowledge regarding ncRNAs in relation to RB. Although ncRNAs are now considered as potential diagnostic biomarkers, prognostic factors, and therapeutic targets, further studies will facilitate enhanced understanding of ncRNAs in RB physiopathology and define the roles ncRNAs can play in clinical practice.

Diagnosis and long-term monitoring of adenomas of the ciliary body epithelium by ultrasound biomicroscopy.

INTRODUCTION: The natural course of adenomas of the ciliary-body epithelium (ACE) is uncertain, due to their low incidence and their frequent initial surgical management.Their differential diagnosis with amelanotic melanoma or metastasis is challenging and diagnostic biopsies require sufficient tissue and highly specialized pathologists. Ultrasound biomicroscopy offers high resolution images and clear sonographic signs suggestive of ACE allowing a more precise differential diagnosis and therefore, a more conservative initial attitude. METHODS: Descriptive, retrospective, non-comparative study of consecutive cases of ACE observed between October 2003 and December 2019 in a reference unit in ocular oncology of a tertiary hospital. Patients were studied on a quarterly basis the first year and, subsequently, every 6 months with a complete ophthalmological exam and ultrasound biomicroscopy with the platform Aviso linear scanning 50 MHz probe (Quantel Medical, Clermont-Ferrand, France). RESULTS: Three ACE were analysed for a median of 3 years (interquartile range: 2.5-5.5 years). Clinical features include a whitish-to-brown spherical mass, with engorged superficial vessels. Ultrasound biomicroscopy shows an oval-spherical shape, medium-to-high echogenicity, low acoustic attenuation, regular internal structure, and respect for the neighboring structures. By their clinical-ultrasonographic characteristics, one was considered an adenoma of the pigmented ciliary-body epithelium (browner and hyperechogenic) and two were classified as adenomas of the non-pigmented ciliary epithelium (whitish appearance and medium-echogenicity). CONCLUSION: Ultrasound biomicroscopy allows a reasonable clinicalsonographic suspicion of ACE. An initial conservative management is proposed as a safer option for stable, mildly symptomatic patients, avoiding aggressive sight threatening treatments.

Current Situation and Challenges in Vitreous Substitutes.

Vitreo-retinal disorders constitute a significant portion of treatable ocular diseases. These pathologies often require vitreo-retinal surgery and, as a consequence, the use of vitreous substitutes. Nowadays, the vitreous substitutes that are used in clinical practice are mainly divided into gases (air, SF6 , C2 F6 , C3 F8 ) and liquids (perfluorocarbon liquids, silicone oils, and heavy silicone oils). There are specific advantages and drawbacks to each of these, which determine their clinical indications. However, developing the ideal biomaterial for vitreous substitution continues to be one of the most important challenges in ophthalmology, and a multidisciplinary approach is required. In this sense, recent research has focused on the development of biocompatible, biodegradable, and injectable hydrogels (natural, synthetic, and smart), which also act as medium and long-term internal tamponade agents. This comprehensive review aims to cover the main characteristics and indications for use of the extensive range of vitreous substitutes that are currently used in clinical practice, before going on to describe the hydrogels that have been developed recently and which have emerged as promising biomaterials for vitreous substitution.

Validation of an IGF1 Screening Method for Retinopathy of Pre-maturity.

Retinopathy of pre-maturity (ROP) is a retinal disease that causes arrest of vascularization of the retina and can result in retinal detachment and blindness. Current screening protocols may not be sufficiently accurate to identify all at-risk patients. The aim of this study is to validate a method for improved identification of newborns at risk of ROP. We conducted a prospective clinical trial of pre-term newborns <32 weeks of gestation and/or <1,500 g birth weight during a 6-year period in a tertiary care hospital. We applied our new method based on measurement of insulin-like growth factor 1 (IGF1) levels at 3 weeks of age and the presence of sepsis during the first 3 weeks of life. Our screening protocol allowed exclusion of 121 (79.1%) patients for whom American Academy of Pediatrics (AAP) guidelines recommended screening, had a negative predictive value of 100%, and correctly identified all patients with ROP. Following retrospective assessment of our data based on these findings, we propose further restriction of the current AAP indications for screening to <1,100 g and <28 weeks of gestation in order to improve diagnostic efficacy while ensuring optimal use of restriction of human and material resources.

Treatment of Metastatic Uveal Melanoma: Systematic Review.

INTRODUCTION: More than 50% of patients with uveal melanoma end up developing metastases. Currently, there is no standard first-line treatment that facilitates proper management of the metastatic disease. METHODS: A systematic review of the last 40 years in PubMed with an exhaustive and strict selection of studies was conducted, in which the unit of measurement was overall survival (OS) expressed in Kaplan-Meier curves or numerically. RESULTS: After the selection process, 110 articles were included. Regional therapies, such as intra-arterial liver chemotherapy (OS: 2, 9-22 months), isolated liver perfusion (OS: 9, 6-27, 4 months), or selective internal radiation therapy (OS: 18 months in monotherapy and 26 months in combination with other therapies) showed some superiority when compared to systemic therapies, such as chemotherapy (OS: 4, 6-17 months), immunotherapy (OS: 5-19, 1 month), immunosuppression (OS: 11 months), or targeted therapy (OS: 6-12 months), without being significant. CONCLUSIONS: The results of this review suggest that there are no important differences in OS when comparing the different current treatment modalities. Most of the differences found seem to be explained by the heterogenicity of the different studies and the presence of biases in their design, rather than actual extensions of patient survival.

The Role of Non-Coding RNAs in Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumor in adulthood. Approximately 50% of patients develop metastatic disease, which typically affects the liver and is usually fatal within one year. This type of cancer is heterogeneous in nature and is divided into two broad groups of tumors according to their susceptibility to develop metastasis. In the last decade, chromosomal abnormalities and the aberrant expression of several signaling pathways and oncogenes in uveal melanomas have been described. Recently, importance has been given to the association of the mentioned deregulation with the expression of non-coding RNAs (ncRNAs). Here, we review the different classes of ncRNAs-such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)-and their contribution to the development of UM. Special attention is given to miRNAs and their regulatory role in physiopathology and their potential as biomarkers. As important agents in gene regulation, ncRNAs have a huge potential for opening up therapeutic pathways, predicting response to treatment, and anticipating patient outcome for UM.

Blood Biomarkers of Uveal Melanoma: Current Perspectives.

The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.

Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis.

Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs.

Effects of internal limiting membrane peeling during vitrectomy for macula-off primary rhegmatogenous retinal detachment.

PURPOSE:: To determine the effectiveness of internal limiting membrane peeling during vitrectomy for macula-off primary rhegmatogenous retinal detachment in the prevention of postoperative epiretinal membrane formation and achievement of good visual outcomes and to identify preoperative and intraoperative risk factors for epiretinal membrane formation. METHODS:: We retrospectively analyzed data from 62 eyes of 62 consecutive patients with macula-off primary rhegmatogenous retinal detachment who underwent vitrectomy with (n = 30) or without (n = 32) internal limiting membrane peeling between January 2014 and March 2016 and were followed up for at least 12 months. The effects of internal limiting membrane peeling on visual outcomes and postoperative recovery of the macular structure were determined. We subsequently divided patients into an epiretinal membrane group and a non-epiretinal membrane group and assessed the effects of various preoperative and intraoperative factors on postoperative epiretinal membrane formation. RESULTS:: Postoperative epiretinal membrane developed in 10 patients in the no internal limiting membrane peeling group and three patients in the internal limiting membrane peeling group. Postoperative visual acuity significantly improved in both groups. Epiretinal membrane formation was found to be correlated with a higher number of retinal breaks. CONCLUSION:: Our results suggest that internal limiting membrane peeling during macula-off primary rhegmatogenous retinal detachment surgery can reduce the occurrence of postoperative epiretinal membrane, is safe, and results in favorable visual outcomes.

Intravitreal injections of anti-VEGF agents and antibiotic prophylaxis for endophthalmitis: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis to determine whether the use of local antibiotics is a beneficial prophylactic treatment for endophthalmitis in patients treated with anti-VEGF agents. We searched the MEDLINE and EMBASE databases, and the Cochrane Library over the period January 2007 to December 2016. The search terms used included "Endophthalmitis", "Antibiotic" and "Intravitreal injection". Studies in which the patients were treated exclusively with intravitreal injections of anti-VEGF were selected. Eight studies fit the inclusion criteria, which included a total of 276,774 injections; 109,178 (39.45%) were associated with the use of antibiotics and 114,821 (60.55%) were not associated with the use of antibiotics. Our meta-analysis indicated a significant risk for endophthalmitis that was 1.70 times greater with the use of antibiotics than that without antibiotics, with a confidence interval of 1.08 to 2.66 (p = 0.02). A meta-regression indicated that the location (operating rooms versus outpatient clinics) of injection did not have a significant effect on the incidence of endophthalmitis. The prophylactic use of antibiotics when administering anti-VEGF intravitreal injections may contribute to a greater incidence of endophthalmitis. This finding, in addition to reducing costs, would eliminate a treatment that has been shown to be unnecessary and even harmful to patients.

Ultrasonographic findings in circumscribed choroidal hemangioma after photodynamic therapy.

Circumscribed choroidal hemangioma (CCH) is a benign and relatively rare tumor located posteriorly to the equator. The most frequently associated clinical finding is an exudative retinal detachment (ERD). The aim of this work is to describe ultrasonographic findings in eyes diagnosed with CCH + ERD after photodynamic therapy (PDT). Five eyes of five patients diagnosed with CCH (2 men and 3 women; 3 right eyes and 2 left eyes; mean age 50.6 (range 42-63) years) were referred to the Unit of Ocular Oncology. All cases were selected for PDT since all of them showed a macula-off ERD and hence poor visual acuity. The PDT protocol consisted of verteporfin 6 mg/m2 body surface area and exposure to laser light dose at 689 nm at an intensity of 600 mW/cm2 (1 to 3 sessions depending on the persistence of ERD). Ultrasonographic examination was performed by use of the I3-ABD System (posterior segment 10 MHz B-scan and 8 MHz standardized diagnostic A-scan probes, Innovative Imaging Inc., Sacramento, CA, USA). Ultrasonographic findings recorded on the first examination were consistent with those previously described for CCH in the literature. Dimensions of the tumors were very similar in all cases. However, after PDT we detected significant reduction of the height of the tumor and increased reflectivity, without changes in internal structure. Moreover, we detected retinal reattachment in all cases and therefore a slight improvement in visual acuity. Significant changes in ultrasonographic findings can be found after PDT for CCH.