Genetic and Epigenetic Features of Uveal Melanoma-An Overview and Clinical Implications.

Uveal melanoma (UM) is rare, but it is the most common primary intraocular malignancy among adults. This review represents the molecular, genetic, and immunobiological mechanisms involved in UM carcinogenesis and progression, as well as data about the association of chromosomal changes, genetic mutations, selective proteins, and biochemical biomarkers with the clinical implications of UM. Genetic analysis has the potential to identify patients with a high risk of UM metastasis, enabling management that is more effective and allowing for the follow-up of patients. Advancements in molecular characterization of UM offer opportunities to develop targeted therapeutic strategies by focusing on relevant signaling pathways. Changes in miRNA expression could be useful in the diagnosis and prognosis of UM, due to unique miRNA profiles in melanoma cells or tissue and its association with metastasis. Although liver function tests do not provide enough data on the prognosis of UM, due to the high frequency of liver metastasis, liver function tests (LFTs) might be useful indicators; however, the absence of rising LFT values cannot lead to the exclusion of liver metastases. Molecular analysis of tumor tissue will allow us to identify patients with the added benefit of new therapeutic agents and provide a better insight into melanoma pathogenesis and its biological behavior.

Expression of Androgen and Estrogen Receptors in the Human Lacrimal Gland.

Lacrimal gland dysfunction causes dry eye disease (DED) due to decreased tear production. Aqueous-deficient DED is more prevalent in women, suggesting that sexual dimorphism of the human lacrimal gland could be a potential cause. Sex steroid hormones are a key factor in the development of sexual dimorphism. This study aimed to quantify estrogen receptor (ER) and androgen receptor (AR) expression in the human lacrimal gland and compare it between sexes. RNA was isolated from 35 human lacrimal gland tissue samples collected from 19 cornea donors. AR, ERα, and ERß mRNA was identified in all samples, and their expression was quantified using qPCR. Immunohistochemical staining was performed on selected samples to evaluate protein expression of the receptors. ERα mRNA expression was significantly higher than the expression of AR and ERß. No difference in sex steroid hormone (SSH) receptor mRNA expression was observed between sexes, and no correlation was observed with age. If ERα protein expression is found to be concordant with mRNA expression, it should be investigated further as a potential target for hormone therapy of DED. Further research is needed to elucidate the role of sex steroid hormone receptors in sex-related differences of lacrimal gland structure and disease.

Liver metastasis in uveal melanoma - treatment options and clinical outcome.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults with a stable incidence rate between five and seven cases per million in Europe and the United States. Although UM and melanoma from other sites have the same origin, UM has different epidemiological, biological, pathological and clinical features including characteristic metastatic hepatotropism. Despite improvements in the treatment of primary tumours, approximately 50% of patients with UM will develop metastases. In 90% of cases the liver is the first site of metastasis, however the mechanisms underlying this hepatic tropism have not been elucidated. Metastatic disease is associated with a very poor prognosis with a median overall survival of 6 to 12 months. Currently, there is no standard systemic treatment available for metastatic UM and once liver metastases have developed, prognosis is relatively poor. In order to prolong survival, close follow-up in all patients with UM is recommended for early detection and treatment. The treatment of metastatic UM includes systemic chemotherapy, immunotherapy and molecular targeted therapy. Liver-directed therapies, such as resection, radioembolization, chemoembolization, immunoembolization, isolated and percutaneous liver perfusion as well as thermal ablation represent available treatment options. However, to date a consensus regarding the optimal method of treatment is still lacking and the importance of setting guidelines in the treatment and management of metastatic UM is becoming a priority. Improvement in knowledge and a better insight into tumour biology, immunology and metastatic mechanism may improve current treatment methods and lead to the development of new strategies paving the way for a personalized approach.

Psychiatric Disorders and Dry Eye Disease - A Transdisciplinary Approach.

Dry eye disease (DED) is a multifactorial disorder representing one of the most common ocular morbidities and a significant public health problem. It often results in eye discomfort, visual disturbances and potential damage to the corneal surface affecting quality of life (QOL). In recent years, the relationship between DED and psychiatric disorders has been gaining attention. A number of epidemiological studies have reported a possible association between dry eye and psychiatric disorders showing that the subjective symptoms of dry eye can be affected not only by changes of the tear film and ocular surface but also psychological factors such as anxiety, depression, schizophrenia, post-traumatic stress disorder (PTSP) and subjective happiness. Apart from psychiatric disorders, psychiatric medications are also considered as risk factors for DED due to their influence on the tear film status. The incidence of ocular side effects increases rapidly with the use of polypharmacy, a very common form of treatment used in psychiatry. There is often inconsistency between signs and symptoms of DED, where symptoms often are more related to non-ocular conditions including psychiatric disorders than to tear film parameters. Consequently, in many cases DED may be considered as a psychiatric as well as ophthalmological problem. Psychiatrists and ophthalmologists need to be aware of the potential influence of psychiatric disorders and medications on tear film stability. In treatment of psychiatric patients, an integrative and transdisciplinary approach will result in better functioning and higher QOL.

Transdisciplinary Approach in Type I Neurofibromatosis - Review of Psychiatric Disorders.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant a multisystem genetic disorder that primarily involves the skin and the nervous system. The incidence of the disease is 1:3000-4000 live-born children, equally in both sexes. The diagnosis of NF1 is determined individually with any two of the following clinical features: café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic glioma, distinctive bone lesions and first-degree family relative with NF1. NF1 is a disease most commonly diagnosed and treated by neuropediatricians. RESULTS: Cognitive and behavioral disorders affect between 50-80% of all children with NF1. Children with NF1 show impairments in attention, visual perception, language, executive function, academic skills, and behavior. This requires a multidisciplinary approach to the treatment s as seen in the case we present. Furthermore, NF1 is often associated with psychiatric disorders, which are more frequent in this disease than in general population, according to some studies even up to 33% patients. Psychiatric disorders are more frequent in NF1 than in the general population, particularly in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. CONCLUSIONS: We present a case of an eight-year-old boy with behavioural and learning disabilities referred for psychological and psychiatric evaluation as well as an overview of NF-related psychiatric illnesses described in the literature.

Inflammatory and angiogenic biomarkers in diabetic retinopathy.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus (DM) and a leading cause of blindness in working-age adults in developed countries. Numerous investigations have recognised inflammation and angiogenesis as important factors in the development of this complication of diabetes. Current methods of DR treatment are predominantly used at advanced stages of the disease and could be associated with serious side effects. Therefore, new diagnostic methods are needed in order to identify the initial stages of DR as well as monitoring the effects of applied therapy. Biochemical biomarkers are molecules found in blood or other biological fluid and tissue that indicate the existence of an abnormal condition or disease. They could be a valuable tool in detecting early stages of DR, identifying patients most susceptible to retinopathy progression and monitoring treatment outcomes. Biomarkers related to DR can be measured in the blood, retina, vitreous, aqueous humour and recently in tears. As the retina represents a small part of total body mass, a circulating biomarker for DR needs to be highly specific. Local biomarkers are more reliable as indicators of the retinal pathology; however, obtaining a sample of aqueous humour, vitreous or retina is an invasive procedure with potential serious complications. As a non-invasive novel method, tear analysis offers a promising direction in further research for DR biomarker detection. The aim of this paper is to review systemic and local inflammatory and angiogenic biomarkers relevant to this sight threatening diabetic complication.

Immunotherapy for Uveal Melanoma - Current Knowledge and Perspectives.

Uveal melanoma is the most prevalent primary intraocular tumour in adults with the incidence between five and six cases per million people in the United States and Europe. The prognosis of patients with uveal melanoma is unfavourable with a 5-year survival rate of 50-70% despite significant advances in local tumour treatment using radiotherapy or surgical resection. Approximately 50% of the patients develop metastases within 15 years from initial diagnosis, mostly in the liver. The median survival rate after the onset of metastases is 6 months. Potential treatment options for metastatic uveal melanoma are chemotherapy, targeted therapy, and immunotherapy but no method showed satisfactory results. Immunotherapy with checkpoint inhibition showed promising results in the treatment of cutaneous melanoma; however, it did not appear to be equally effective with uveal melanoma. This may be due to differences in mutational burden, expression of neoantigens between these two types of tumour, immunosuppressive tumour microenvironment, and low immunogenicity and immune privilege of uveal melanoma. Considering the disappointing results of treatment with anti-CTLA-4 and PD-1/PD-L1 blockade in patients with advanced uveal melanoma several new forms of therapies are being developed. This may include immunotherapy with IMCgp100, glembatumumab vedotin and the infusion of autologous TILs, targeted therapy with selective MEK inhibitors, epigenetic therapy, and nanotherapy. Better insight into the molecular and genetic profile of uveal melanoma will facilitate detection of new prognostic biomarkers and thus enable a better modification of the existing immunotherapy methods and development of new forms of treatment specifically designed for uveal melanoma patients.

Traumatic Optic Neuropathy - Case Report with Discussion on Diagnostic Procedures and Therapy.

Traumatic optic neuropathy (TON) is a serious vision threatening condition that can be caused by ocular or head trauma. Indirect damage to the optic nerve is the most common form of TON occurring in 0.5% to 5% of all closed head trauma cases. Although the degree of visual loss after indirect TON may vary, approximately 50% of all patients are left with 'light perception' or 'no light perception' vision, making TON a significant cause of permanent vision loss. We present a 47-year-old male patient with a history of right eye keratoconus following a motorcycle crash. Visual acuity was of 'counting fingers at 2 meters' on the right eye due to keratoconus and 'counting fingers at 1 meter' on the left eye as a consequence of trauma. The Octopus visual field showed diffuse re-duction in retinal sensitivity and the Ishihara color test indicated dysfunction of color perception on the left eye. Relative afferent pupillary defect was also present. Computed tomography revealed multifragmentary fracture of the frontal sinus and the roof of the left orbit without bone displacement. Based on the findings, conservative corticosteroid therapy without surgery was conducted. The patient responded well to treatment with complete ophthalmologic recovery.

Conjunctival Melanoma - Epidemiological Trends and Features.

Conjunctival melanoma is a rare but sight and life threatening malignancy. It accounts for 2%-5% of all ocular tumours and 5%-7% of all ocular melanomas with an incidence of 0.2-0.8 per million in the Caucasian population with rare cases reported in the non-Caucasians. In recent decades the incidence of uveal melanoma has been relatively stable whilst conjunctival and cutaneous melanoma have shown increasing incidence which may be connected to the result of environmental exposure to ultraviolet light. The dissimilarity in incidence between light and dark pigmented individuals observed in conjunctival melanomas compared to uveal and cutaneous melanomas may be related to differences in their histological structures and genetic profile. Recent molecular biological studies support the fact that each type of melanoma undergoes its own molecular changes and has characteristic biological behaviour. Further studies are required for each type of melanoma in order to ascertain their individual etiology and pathogenesis and based on this knowledge develop relevant preventative and treatment procedures.

Inflammation and pharmacological treatment in diabetic retinopathy.

Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus, is estimated to be the leading cause of new blindness in the working population of developed countries. Primary interventions such as intensive glycemic control, strict blood pressure regulation, and lipid-modifying therapy as well as local ocular treatment (laser photocoagulation and pars plana vitrectomy) can significantly reduce the risk of retinopathy occurrence and progression. Considering the limitations of current DR treatments development of new therapeutic strategies, it becomes necessary to focus on pharmacological treatment. Currently, there is increasing evidence that inflammatory processes have a considerable role in the pathogenesis of DR with multiple studies showing an association of various systemic as well as local (vitreous and aqueous fluid) inflammatory factors and the progression of DR. Since inflammation is identified as a relevant mechanism, significant effort has been directed to the development of new concepts for the prevention and treatment of DR acting on the inflammatory processes and the use of pharmacological agents with anti-inflammatory effect. Inhibiting the inflammatory pathway could be an appealing treatment option for DR in future practices, and as further prospective randomized clinical trials accumulate data, the role and guidelines of anti-inflammatory pharmacologic treatments will become clearer.

Maternal immune system adaptation to pregnancy--a potential influence on the course of diabetic retinopathy.

BACKGROUND: Progression of diabetic retinopathy occurs at least temporarily during pregnancy. Although the cause of this progression is not entirely understood, the immune phenomenon and chronic inflammation may play a significant role. During pregnancy in order to avoid fetus rejection, certain components of the immune system that are knowingly implicated in the pathogenesis of diabetic retinopathy are activated including generalized leukocyte activation and an increase in certain cytokine plasma levels. Activated leukocytes with up regulated adhesion molecules have an increased potential to bind to the endothelium cells of blood vessels. Leukocyte-endothelial interaction and the consequent leukostasis with capillary occlusion, ischemia and vascular leakage have a substantial role in the development of diabetic retinopathy. Furthermore, certain increased cytokines are known to cause blood-retinal-barrier breakdown whilst others promote angiogenic and fibrovascular proliferation and thereby can also be implicated in the pathogenesis of this diabetic complication. PRESENTATION OF THE HYPOTHESIS: We hypothesized that the activation of the immune system during gestation may have an influence on the course of retinopathy in pregnant diabetic women. TESTING THE HYPOTHESIS: We suggest two prospective follow up studies conducted on women with type 1 diabetes mellitus. The first study would include a group of non-pregnant women and a group of diabetic women undergoing normal pregnancy matched for age and duration of diabetes. In the second study pregnant women would be divided into two groups: one with normal pregnancy and the other with preeclampsia. The procedure and data collection in both studies will be identical: a complete ophthalmological examination, glycaemic control, blood pressure measurement and venous blood samples for the determination of plasma levels of cytokines (TNF-alpha, IL-1beta, IL-6, IL-8) and adhesion molecules (ICAM-1, VCAM-1). IMPLICATIONS OF THE HYPOTHESIS: Considering the present assumption, the gestational immune activation could be suggested as a potential risk factor for the development and progression of retinopathy in diabetic women. A better understanding of immunomodulatory effects of pregnancy on diabetic retinopathy pave the way for further investigations of the mechanism of its pathogenesis and could be essential for novel approaches to the treatment of this serious sight threatening complication of diabetes mellitus.

Retrospective analysis of reconstruction techniques after periocular basalioma excision.

The paper presents our approach to reconstruction after periocular basalioma (pBCC) excision, especially of large lower lid (LL) and medial canthal (MC) pBCC. Retrospective analysis of data of 123 patients with pBCC, confirmed on histologic examination (HE), operated in period from 1998 to 2006, was performed. Oncologic safety margins of 3 mm were marked after local anesthesia was administered. Reconstruction was done in time of surgery. In pBCC away from a lid margin, adjacent myocutaneous flaps were used. For lid margin involving (LM) pBCC, size of 10 mm and less in horizontal diameter (HD), full-thickness lid excision was performed, combined with lateral canthotomy and/or Tenzel or McGregor flap. When size of LM pBCC was more than 10 mm in HD and it was on a LL, ipsilateral upper lid (UL) tarsoconjunctival (TC) graft combined with single pedicle transposition myocutaneous flap were used. The same size of LM pBCC on a UL required ipsilateral full-thickness LL "switch" flap and/or contralateral LL Hübner graft. In MC pBCC combined approach was used. The follow-up was up to 5 years. The 19 patients (15.4%) had positive tumor margin on HE. Five of them refused further surgery, but only two had recurrence. The rest of 121 patients had no recurrence during follow-up. In 5/14 patients, who underwent additional surgery, no tumor cells were found on HE. The 10/123 patients (8.1%) had complications. The imperative of our approach to reconstruction after pBCC was good functional and cosmetic result, avoiding prolonged lid closure. Accordingly, in large LL LM pBCC we used ipsilateral UL TC graft combined with single pedicle transposition myocutaneous flap. In MC pBCC combined approach was mandatory.

Could diabetic retinopathy be an autoimmune disease?

Diabetic retinopathy is a common and progressive complication of diabetes mellitus. It is characterized by the loss of pericytes, hypertrophy of basement membrane, microaneurysms formation, increased vascular permeability, capillary occlusions, neovascularisation and fibrovascular proliferation. The pathogenesis of diabetic retinopathy is still insufficiently understood, although some reports have implicated the role of the immune system. We hypothesize that, according to some current data diabetic retinopathy could also be considered as an autoimmune disease. The finding of antipericyte and antiendothelial cell autoantibodies in the circulation of diabetic patients strongly suggests that some autoimmune activity has been involved in the early pathophysiology of diabetic retinopathy. There is even more evidence that implicates the presence of autoimmune mechanisms in the proliferative stage of this disease: elevated levels of tumor necrosis factor-alpha, interleukin-8 and soluble interleukin-2 receptor in the serum of diabetic patients, increased vitreous concentration of the interleukin-6 and interleukin-8 in patients with proliferative retinopathy. Furthermore, preretinal membranes in diabetic patients contain deposits of immunoglobulins, activated complement components, monocytes, T and B lymphocytes, fibroblastes and lymphokynes. In diabetic patients human leukocyte antigen DR and DQ expression on the retinal vascular endothelial cells as well as on pigment and nonpigment epithelial cells was found. These antigens are normally restricted to immunocompetent cells and play an important regulatory role in the immune response. Their aberrant expression has been found on nonlymphoid cells in various autoimmune diseases whilst abnormal expression of DR and DQ antigens at sites where they do not normally exist would result in autoimmunity by converting the target cell into a functional antigen-presenting cell. In conclusion, although the pathogenesis of diabetic retinopathy is not completely understood it is known that the immune system is certainly involved in its development. However, there is increasing evidence of the presence of some autoimmune processes in the early stages of diabetic retinopathy and particularly in its proliferative phases. Consequently, diabetic retinopathy could also be considered as an autoimmune disease.

Pseudoexfoliation syndrome and cataract surgery by phacoemulsification.

Pseudoexfoliation syndrome is a systemic age-related disease in which abnormal extracellular material is produced and accumulates in many ocular tissues. Its ocular manifestations involve all of the structures of the anterior segment as well as conjunctiva and orbital structures. The presence of pseudoexfoliation should alert the physicians to the increased risks associated during and after cataract surgery. Increasing awareness of this condition are important in the detection and preoperative determination of patients inclined to be at greater risk for complications during surgery. Data regarding the rate of complications during phacoemulsification suggest a lower complication rate than with exstracapsular extraction but still greater than in eyes without pseudoexfoliation. Despite the existence of a higher number of intraoperative and postoperative complications, experience with the phacoemulsification technique together with the improvement of the apparatus and instruments used enable similar results to obtained in eyes with pseudoexfoliation syndrome as in eyes without this pathology.