[Epigenetic markers of choroidal melanoma]. / Epigeneticheskie markery melanomy khorioidei.

MicroRNAs (miRNAs) are short non-coding RNAs (18-25 nucleotides in length) that are important participants in the regulation of gene expression. In 2003, their active role in oncogenesis was demonstrated. In 2008, the first report on the isolation of miRNAs from uveal melanoma (UM) tissue was published. Four years later (2012), the presence of miRNAs in the plasma of patients with this category was shown. To date, changes in the expression level of 100 miRNAs in the plasma of cancer patients (with cancer of various localizations) out of the 2654 miRNAs described in mirbase.org have been proven. In the plasma of patients with UM, changes in the expression of only 13 miRNAs have been confirmed. As a rule, studies were conducted in patients at the stage of hematogenous metastasis of UM. PURPOSE: This study analyzed the expression pattern of miRNA-223 and miRNA-126 in patients with localized choroidal melanoma (CM) taking into account biometric parameters in the absence of metastases. MATERIAL AND METHODS: Blood plasma of 84 patients with M0N0 CM aged 35-86 years (mean age 63.4±1.2 years) was investigated. The basis for the diagnosis of CM was the results of ophthalmological examination, optical coherence tomography, and ultrasound scanning. In all cases, the absence of metastases was proven (using computed tomography or magnetic resonance imaging). Control - plasma of 28 volunteers (mean age 62.9±1.42 years, age range 45-78 years), who did not have tumoral, autoimmune, or chronic inflammatory processes. The expression levels of miRNAs circulating in blood plasma were determined by real-time polymerase chain reaction. RESULTS: An increase in the expression levels of miRNA-223 and miRNA-126 in the plasma of all 84 patients with CM was confirmed compared to the control group. Features of the miRNA expression pattern that emerged with changes in the tumor's quantitative parameters were identified. CONCLUSION: Evaluation of the levels of miRNA-223 and miRNA-126 in the blood plasma of patients with CM can be used in clinical practice to clarify the diagnosis of CM, as well as to predict the development of hematogenous metastases.

[Transformation of choroidal nevus into melanoma]. / Transformatsiya nevusa khorioidei v melanomu.

The risk of choroidal melanoma developing from choroidal nevus (CN) varies in range of 0.78-7%. Absence of a common terminology and distinct diagnostic criteria characterizing small melanoma de novo and unusual CN often complicates treatment choice and patient prognosis. PURPOSE: To study the clinical features and the role of visualization methods in the diagnosis of CN transformation into melanoma. MATERIAL AND METHODS: The study analyzes the clinical picture and visualization results of 11 patients with initial diagnosis of «choroidal nevus¼ (n=3) and «suspicious choroidal nevus¼ (n=8). RESULTS AND DISCUSSION: Examination and continued observation revealed 7 patients to have melanoma that had developed from CN (2 of them confirmed with histological studies). The time before CN transformed into melanoma varied between 4 and 13 years, with median 5 [4; 12] years. Two patients were diagnosed with primary melanoma (melanoma de novo), two other patients - with suspicious CN. In progressive CN transforming into melanoma, visual impairments occurred between 6 months and 13 years in 6 out of 7 patients. Initial prominence of suspicious CN at the first visit was 1.9±0.68 mm (0.9 mm to 2.67 mm). The characteristic features of suspicious CN transforming into initial melanoma are: 1) asymmetric shape of the edges of expanded choroidal complex; 2) presence of areas of damaged choriocapillaris layer, direct and indirect signs of loss of integrity of the Bruch's membrane; 3) areas of accumulation of moderately hyperreflective subretinal exudate; 4) presence of intraretinal hyperreflective inclusions. The signs distinguishing primary choroidal melanoma from melanoma that had developed from CN are: 1) absence of areas with tomography pattern characteristic of nevi; 2) more pronounced asymmetry of the shape of edges, compared to melanoma developed from CN; 3) presence of cysts in larger tumors, compared to melanoma developed from CN. CONCLUSION: All patients with CN should be regularly followed up by an ophthalmologist.

[Influence of CYP3A4, CYP3A5, and NR3C1 genes polymorphism on the effectiveness of glucocorticoid therapy in patients with endocrine ophthalmopathy]. / Vliyanie polimorfizma genov CYP3A4, CYP3A5 i NR3C1 na effektivnost' glyukokortikoidnoi terapii u bol'nykh endokrinnoi oftal'mopatiei.

For more than 60 years, glucocorticoid therapy has been practically the only method for treating patients with endocrine ophthalmopathy - non-specific autoimmune inflammation of the soft tissues of the orbit. Steroid-resistant forms of this disease are known to exist. The reasons for the formation of glucocorticoid resistance are not fully understood yet. PURPOSE: To study the possibilities of pharmacogenetic testing for the polymorphism of the glucocorticoid receptor gene NR3C1 and cytochrome P450 in predicting the effectiveness of glucocorticoid therapy in patients with edematous exophthalmos - one of the clinical forms of endocrine ophthalmopathy. MATERIAL AND METHODS: The results of glucocorticoid therapy were analyzed in 75 patients with different clinical forms of endocrine ophthalmopathy aged 27 to 84 years. All patients underwent standard ophthalmological examination, external examination of the eye with assessment of the state of periorbital tissues, determination of the shape and size of the palpebral fissure (vertical size), position of the eye in orbit, Hertel exophthalmometry, ultrasound scanning and computed tomography of the orbits. Genetic analysis of the polymorphism of the studied genes was carried out using real-time polymerase chain reaction (real-time PCR). RESULTS: The study did not find patterns in the distribution of homo- and heterozygous genotypes of A6986G polymorphic markers of the CYP3A5 gene, 6 C>T intron of the CYP3A4 gene and rs6190 of the NR3C1 gene in patients with endocrine ophthalmopathy and their effect on the glucocorticoid response (p>0.05). CONCLUSION: Results of pharmacogenetic testing of the gene for the glucocorticoid receptor NR3C1 and cytochrome P450 do not provide a reliable confirmation of the influence of the polymorphism of the studied genes on the effectiveness of glucocorticoid therapy in patients with endocrine ophthalmopathy.

[Protocol of intravitreal drug delivery. Consensus of the Expert Counsil of Retina and Optic Nerve Diseases of the All-Russian Public Organasation «Association of Ophthalmologists¼]. / Protokol vypolneniya intravitreal'nogo vvedeniya lekarstvennykh preparatov. Konsensus Ekspertnogo soveta po zabolevaniyam setchatki i zritel'nogo nerva Obshcherossiiskoi obshchestvennoi organizatsii «Assotsiatsiya vrachei-oftal'mologov¼.

Intravitreal drug administration is a procedure that has become widespread in modern ophthalmology. However, there is no global consensus on certain aspects of this manipulation, and practitioners feel the need for guidelines. In the Russian Federation, until now, such a document was not available. The expert council on diseases of the retina and optic nerve of All-Russian public organization «Association of Ophthalmologists¼, with participation of invited specialists, has studied and analyzed the existing foreign guidelines for performing intravitreal injections, as well as the regulatory framework in Russia. As a result, this Protocol was developed and approved for use in the healthcare system of the Russian Federation. The document regulates the requirements for specialists and organizations, the conditions for performing the procedure and the necessary material resources and presents an algorithm for performing intravitreal drug administration, a patient examination check-list for various conditions of the procedure, as well as parameters for evaluating and monitoring the quality of the procedure.

[Clinical features of malignant orbital lymphoma]. / Osobennosti klinicheskoi kartiny zlokachestvennoi limfomy orbity.

INTRODUCTION: The occurrence of malignant lymphoma (ML) among patients with malignant orbital tumors ranges between 10 and 37.3% making early diagnosis clarification crucial for timely treatment. PURPOSE: To study clinical features of ML with consideration of its morphological type and localization in the orbit. MATERIAL AND METHODS: Clinical picture of primary malignant orbital lymphoma of 34 patients (36 orbits) was examined retrospectively with consideration of the tumor's morphotype. Median observation time was 6 years. Patients aged between 34 and 84 years, female to male ratio was 1.27:1. RESULTS: The final diagnoses were: small cell MALT-type ML (23 patients), large cell B-lymphoma (5 patients), diffuse malignant lymphoma (5 patients), T-cell lymphoma (1 female patient). Systemic changes developed in 29.41% of cases after 6.7 years on average. 23.53% of patients has died. Clinical signs of MALT-type ML were described with consideration of tumor's localization in the orbit, and clinical features of B-cell, large cell, diffuse and T-cell lymphoma were shown. Signs helping differentiate ML from false tumor, composite tear gland tumor and malignant orbital tumor were established. CONCLUSION: Despite the higher prevalence of malignant MALT-type lymphoma, primary malignant orbital lymphoma is characterized by unfavorable vital prognosis: in a third of all cases, signs of systemic lesion develop in 6.7 years on average. Clinical picture of MALT-type ML is defined by tumor's localization in the orbit. Recurrence of MALT-type ML after combined treatment (surgical, radiotherapy, polychemotherapy) happens in every fourth case among patients with tumor primarily localized in the orbital cellular tissues or in the tear gland. Describing clinical features of primary malignant orbital lymphoma allows faster diagnosis clarification reducing the number of orbital diseases that require differential diagnositcs.

[Choroidal melanoma and retinal changes]. / Melanoma khorioidei i izmeneniia setchatki.

Literary sources suggest the existence of a new phenotype - retinoinvasive choroidal melanoma (CM). However, the factual evidence of its spreading over the inner retinal surface cannot be dismissed. PURPOSE: To study the capabilities of optical coherence tomography (OCT) in terms of finding the ways CM spreads into the retina based on pathomorphological examination of the eyes enucleated due to CM. MATERIAL AND METHODS: OCT tomograms of 64 eyes with CM (mean tumor elevation - 2.89±0.19 mm, diameter - 9.58±0.43 mm) were studied. Pathomorphological study was conducted on 18 eyes with CM elevated by up to 7 mm and without previous treatment. RESULTS: OCT revealed signs of melanoma invading into the retina in 49 eyes. Among those signs were: presence of retina/CM aggregation (21 eyes), tearing of Bruch's membrane and retinal pigment epithelium, disturbed differentiation of outer retinal layers (15 eyes). Combination of two types of invasion was found in 11 eyes. Pathomorphological study showed low mitotic activity of CM and the presence of a small number of fine-local necroses and hemorrhages. Invasion of CM into the retina was determined in 13 eyes. Retinal invasion began with local destruction of Bruch's membrane (BM) and was often limited by the photoreceptor level, disturbing architectonics of the retina and nuclear layers. Large CMs were accompanied by rough destruction of the Bruch's membrane, tumor cells - in the edematous retina with cystoid dystrophy, in its inner layers, invading into the vitreous body. Infiltration of the retina to inner nuclear layer was accompanied by its transudative detachment and cystoid dystrophy. CONCLUSION: Invasion of CM into the retina affecting all of its layers imposes use of OCT to examine the integrity of the retina, even with a tumor of small thickness. Tumoral infiltration of the retina and localization of tumor near the optic disc are two contraindications for local endovitreal resection. Brachytherapy requires consideration of tumor characteristics and thickness of the retina for calculation of apical radiation dose.

[Local treatment of choroidal melanoma: possibilities and limitations]. / Lokal'noe lechenie melanom khorioidei: vozmozhnosti i ogranicheniia.

Local treatment of choroidal melanoma (CM) attracts the attention of many ophthalmology specialists, especially in recent years as the capabilities to target irradiation at small objects and possibilities of surgical interventions on the eyeball have expanded. The article discusses the medical indications for local treatment of CM. Review of literature of the last 16 years and author's own observations on CM patients who underwent almost all kinds of conventional methods of local treatment allowed thorough analysis of indications and counter-indications for their usage. Among the authors who favor local destruction and removal of large CM, the main indication is the possibility to preserve vision and anatomical structures of the eye. This led to unreasonably wide spread of local destruction (removal) of large CM, primarily the endovitreal resection method. However, such metastasis risk factors as CM size and its localization are being overlooked. Literature analysis and author's own observations helped validate the unsafety of the local treatment of large CM. The article features long-term results of contact and distant radiation therapy, and presents CM metrics for best therapeutic effect.

[Late complications of choroidal melanoma brachytherapy and possibility of their prevention]. / Pozdnie oslozhneniia brakhiterapii melanom khorioidei i vozmozhnosti ikh profilaktiki.

Complications and the frequency of their occurrence as the criteria of eye preservation after brachytherapy (BT) are presented in literature with inconsistencies due to the assessment being done after varied follow-up periods (1 month to 5-10 years). The evaluation of complications occurring after applying radioiodine can be found in literature. The complications after BT beta particle emitting ophthalmic applicators are seldom discussed in articles. PURPOSE: to examine the frequency of complications, the characteristics of their development after choroidal melanoma (CM) brachytherapy with ruthenium ophthalmic applicators (OA) during long-term follow-up and determine the possibility of their prevention. MATERIAL AND METHODS: Characteristics of postradiation period after BT were studied in 200 patients with CM (200 eyes). Among them, 127 patients were treated by authors of this study, 73 were provided treatment by other specialized medical facilities in Moscow. The study involved 84 male and 116 female patients aged 56.14±12.8 in average. The follow-up periods spanned 2 to 39 years (mean length 9.84±6.16 years). BT was done only with ruthenium OA (beta radiation) manufactured in Russian. RESULTS: Follow-up period after BT for 83% of patients was 5 years. Complications occurred in 68.5% of patients. Complications were found in 74.63% of patients with CM localized pre-equatorially and in 65.4% of patients with CM localized in the posterior part of the eye. Complications associated with radiation-induced injuries in crystalline lens, retina and choroidal blood vessels were more frequent. CONCLUSION: The frequency of complications depends on the size of CM and its localization. Complications were the least frequent in patients with CM thickness of 5 mm or less.

[Diagnostic potential of optical coherence tomography for small choroidal melanomas]. / Opticheskaya kogerentnaya tomografiya v diagnostike nachal'nykh melanom khorioidei.

AIM: To investigate the sequence of OCT manifestations in choroidal melanoma (CM) with account to its growth. MATERIAL AND METHODS: A total of 28 CM patients were examined. Of them, 18 patients with early CM, 10 - with medium-sized CM. The mean patient age at diagnosis was 60.54±5.31 years. Tumor location was macular (15 eyes) or perimacular (13 eyes), its prominence varied from 0.98 to 4.9 mm and basal diameter - from 5.08 to 18.9 mm. Additionally to OCT, tumor autofluorescence was studied in all cases. RESULTS: The sequence of OCT manifestations in CM has been investigated with account to its growth. Our findings include an early change in choroidal profile with often uneven configuration and a plateau in the most prominent part of the lesion. Along with changes in the retinal pigment epithelium (RPE), one could see signs of an initially local small neuroepithelial detachment (NED) with alterations in the photoreceptor layer. We have identified three types of photoreceptor damage. Destruction of all retinal layers (its morphofunctional disorder) indicates the transition of an early CM to a medium one. As to autofluorescence RESULTS: there were lipofuscin deposits in RPE cells detected in OCT scans that showed an evident hyperautofluorescence. The central part the tumor was notable for its hypoautofluorescence. The periphery of the lesion was hyperautofluorescent due to NED. CONCLUSION: Qualitative changes in the retina overlying choroidal melanoma develop early in the course of the disease, practically in the moment of the first shift of choroidal profile. Destruction begins with the RPE and neuroepithelium (detachment and structural changes). As the tumor grows, retinal architectonics gets irreversibly distorted: the tissue becomes thicker due to edema, cysts, and intraretinal deposits. This process is, of course, accompanied by changes in metric parameters of all retinal layers and the choroid within the area of interest.

[Precise diagnosis of choroidal hemangioma]. / Gemangioma khorioidei i vozmozhnosti ee utochnennoi diagnostiki.

AIM: to determine potential benefits of optical coherence tomography (OCT) for precise diagnosis of choroidal hemangioma (CH). MATERIAL AND METHODS: A total of 27 patients (22 women, 5 men) with unilateral CH were examined. The age at diagnosis ranged from 30 to 76 years and averaged 53.7±5.29 years. Tumor thickness varied from 0.9 to 5.3 mm (2.17±0.41 mm; median of 1.9 mm), basal diameter - from 2.64 to 13.86 mm (median of 7.7 mm). RESULTS: Having analyzed OCT findings in CH patients, we came to the conclusion that retinal architectonics does not get distorted (like in cystic dystrophy, for example) before the tumor prominence reaches 1.8 mm. As to retinal edema, it is associated with even greater tumor thicknesses. It should be also noted that any of the CH-related morphofunctional changes in the retina take a really long time to progress. At autofluorescence assessment, choroidal hemangioma had the appearance of a large hypoautofluorescent spot. Areas of fibrosis as well as hyperplasia or atrophy of the retinal pigment epithelium (RPE) also exhibited hypoautofluorescence. Sites of hyperautofluorescence corresponded to lipofuscin deposits. In two cases, there were wide zones of moderate hyperautofluorescence around the tumor due to recent subretinal effusion and photoreceptor damage. Hypoautofluorescent spots within these hyperautofluorescent areas corresponded to RPE atrophy by OCT. CONCLUSION: Ophthalmoscopic presentation of choroidal hemangioma may be not comprehensive enough; therefore modern diagnostic methods, such as widely accepted fluorescence angiography and also spectral OCT (especially, in the «deeper penetration mode¼ for examination of the choroid) and autofluorescence assessment in the MultiColor mode may be used to ensure a more precise diagnosis.

[Size-based classification of choroidal melanoma and its role in treatment decision-making].

AIM: To specify indications for brachytherapy (BT) in large choroidal melanoma (CM) so that tumor size and vital prognosis were considered. MATERIAL AND METHODS: We retrospectively analyzed data from 161 CM patients who were treated with BT and followed-up at either the Ophthalmological Clinical Hospital or some other Moscow medical facility and also registered by the City Cancer Registry. RESULTS: Patient age at the time of starting the treatment lied within the range of 17 to 84 years and averaged 56.89±1.93 years. During the follow-up period (12-275 months, 95.65±8.4 months on average) hematogenous metastases were found in 23 (14.29%) patients. Liver involvement was diagnosed in 8 patients within the average of 23.13 months after treatment. Their average survival time was 11 months. A total of 142 patients were followed up for more than 36 months (104.87 months on average). Of them, 15 patients were diagnosed with metastatic CM within 37-167 months after BT (80.27 months on average). Despite metastatic disease they generally survived 2.8 time longer than the aforementioned patients (30.8 months). The cases were then divided into 3 groups according to J. Shields classification of CM. Small melanoma patients did not develop metastases within 99.96±12.47 months of follow-up. In medium melanomas, as many as 13.35% of cases were metastatic (with the average survival time of 20.66 months); in large melanomas - 19.51% (with the average survival time of 13.5 months). CONCLUSION: Treatment modality and follow-up periods being the same (7-8 years after BT), larger choroidal melanomas has been shown to be associated with higher risk of hematogenous metastases. For local treatment to be successive, the maximal diameter of the tumor should not exceed 10 mm. Every fifth patient of those with CM larger than 15 mm is likely to develop hematogenous metastases. The results obtained indicate the necessity of decreasing the size thresholds for choroidal melanomas, small and medium in the first place.

[Choroidal nevi: clinical features].

UNLABELLED: The prevalence of choroidal nevi (CN) ranges from 1% to 10%. It may be hard to differentiate a small melanoma from an atypical ("malignatized") CN, which occupies an intermediate position between typical nevi and actual melanomas and can be referred to as "progressive" or "suspicious". The risk of malignant transformation of a CN ranges from 0.78% to 7%, thus necessitating the need for a detailed description of its clinical features. OBJECTIVE: To study clinical features of choroidal nevi in conjunction with their growth patterns. MATERIAL AND METHODS: A total of 80 patients (84 eyes) with choroidal nevi were studied, including 23 men and 57 women aged 65.33±3.26 years on average. The follow-up period was 12-48 months. In 26 cases (30.95%) age-related macular degeneration (AMD) was also present. RESULTS: Choroidal nevus is generally more common in women (71.25%). The right eye was involved in 36 cases, the left--in 48. Bilateral CN was diagnosed in 5% of cases. The follow-up period was 12-48 months. The nevi were mostly located in the juxtapapillary (11.9%) and macular (29.76%) regions. In 10 eyes they spread to the parafovea and foveola. The shape was typically round (73.8%), in the rest of cases--oval (26.2%). The size at presentation varied from 1 mm to 9 mm (2.93 mm on average). Diagnostic features of a stationary nevus (does not require a follow-up) have been identified. Nevus enlargement and changes in the overlying retina are indicative of progression. CONCLUSION: On the basis of clinical presentation all choroidal nevi can be classified as either stationary or progressing. If progression is suspected, a close follow-up is required. Progressive destruction of the overlying retina and early signs of visual impairment are risk factors for melanoma development.

[Peculiarities of tear production in patients with dacryoadenitis].

The influence of chronic adenitis and its surgical treatment on tear production and osmolarity was studied. A long-term follow-up (2-65 months) after lacrimal gland extirpation showed a trend for recovery of both basal and reflex lacrimation. Comparison of complaints and functional and pathohistological results allowed to consider retention cysts as a risk factor for dry eye syndrome in the postoperative period.

[Ophthalmic oncology: achievements over the last two decades].

The article describes current trends in scientific research, especially those that concern treatment of the most common cancers. The latter include malignant eyelid and conjunctiva tumors, retinoblastoma and choroidal melanoma. Relevant publications in Russian and foreign journals demonstrate a progressive advance in treatment approaches: from radical methods associated with surrounding tissue damage to local tumor destruction. Comparative analysis of the methods and their effectiveness suggest that Russian ophthalmic oncology meets state-of-the-art international criteria.

[Rationale for distinguishing the lipogenic form of thyroid orbitopathy].

Pathogenesis of lipogenic form of thyroid orbitopathy (TO) is presented. 172 patients with TO are presented, among them 47 males (93 orbits) and 125 females (250 orbits). Features of clinical manifestations of lipogenic form of TO are described. The results of CT of extraocular muscles (EOM) and orbital fat volume are studied in these patients and the density of EOM is assessed.

[Radio-induced maculopathy].

Macula was examined using fundus photo and OCT in 115 patients with choroidal melanoma located distant from macula before and after brachytherapy. Macular changes were revealed in 24,35% of irradiated eyes. Nevertheless primary radiation-induced maculopathy after ruthenium plaque radiotherapy occurred in 9,59% only. In the rest of cases (10,43%) macular changes were present before brachytherapy. The causes of their development were choroidal melanoma (tumor-associated maculopathy) and AMD.

[Method of implant insertion in anophthalmic socket].

The method of extraocular muscles fixation is presented, it consist in direct fixation to alloplant according to their physiological attachment to ensure stump movement after enucleation. A total of 54 patients aged 26-82 years were treated. Primary enucleation was performed in 46 patients and 8 patients were previously treated with brachytherapy. Surgery was performed under general anesthesia using microsurgical technique. After alloplant was fixed to the anterior surface of tenon's capsule a running suture was put horizontally and conjunctival suture had vertical orientation. A pressure dressing was applied for 2-3 days. Generally there were no technical difficulties, but in patients after brachytherapy separation of muscles and tenon's capsule was complicated because of scarring in the site of previous radiation.

[Choroidal melanoma and maculopathy].

Distant macular changes were revealed in 21 of 28 patients with intraocular melanoma. In 13 eyes maculopathy was very distant from choroidal melanoma (CM), in 4 cases the tumor was located preequatorially and in 9 patients in the posterior fundus beyond the macular zone. In 8 patients bilateral AMD was found along with CM. Revealed changes are considered to be tumor-associated sign of progressing CM. Association of AMD and CM should be considered as a combination of two distinct conditions, when CM disturbs hematoretinal barrier and thus leads to AMD progression.

[Optimization of indications for transpupillary thermotherapy for choroidal melanomas].

The paper analyzes recent literature and the authors' experience in treating choroidal melanoma with transpupillary thermotherapy. Analysis of the results of treatment in 30 patients shows the efficiency of the technique only the tumor is less than 2 mm thick. When the latter is larger, transpupillary thermotherapy may be used only in combination with brachytherapy. Risk factors worsening the efficiency of thermotherapy are defined. These include tumors that are more than 2 mm thick or slightly pigmented, and the presence of a subretinal exudate. The frequency and severity of complications were estimated after transpupillary thermotherapy. The occurrence of complications and their pattern depend on the baseline sizes of choroidal melanoma, the number of performed sessions, and previous treatment (local tumor resolution). Comparison of the data available in the literature and the authors' experience made it possible to define clear indications for transpupillary thermotherapy in order to treat choroidal melanomas and to identify factors promoting the prevention of possible complications.