Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation.

The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p < 0.05). To test the effect of CCR7 blockade on graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end of the 8 week observation period, whereas 38% of the grafts survived in the control group (p < 0.05). Taken together, our study shows that blockade of CCR7 reduces the migration of mature corneal DCs to the draining lymph nodes and leads to improved graft survival in low-risk corneal transplantation.

Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals.

A major concept in autoimmunity is that disruption of Foxp3(+) regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3(+) Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3(+) Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3(+) Tregs, we report here that anti-CD4 treatment induces tolerance independent of Foxp3(+) Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4(+) T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti-CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome.

[Topical cyclosporine A 0.05% in the treatment of keratoconjunctivitis sicca]. / Ciclosporin A 0,05 % Augentropfen zur Therapie der Keratokonjunktivitis sicca.

BACKGROUND: The current understanding of the pathogenesis of dry eye disease has proceeded to recognition of inflammation as the key pathogenetic mechanism. The purpose of this study was to evaluate the effect of cyclosporine 0.05% eye drops on subjective symptoms and objective signs of patients with keratoconjunctivitis sicca. PATIENTS AND METHODS: In this clinical trial 62 patients with severe keratoconjunctivitis sicca (DEWS grade 3) were included. Over a time period of 3 months all patients received treatment with preservative-free hyaluronic acid artificial tears at one drop 5 times per day and in addition 31 patients received one drop of cyclosporine 0.05% twice daily. Screening parameters were LIPCOF, tear break-up time (BUT), fluorescein and rose bengal staining, the intraocular pressure (IOP) and the OSDI score. RESULTS: In the cyclosporine A group BUT, Jones test and OSDI score improved significantly after 3 months in contrast to the controls. Moreover the values of BUT and Jones test in the cyclosporine A group were significantly higher after 3 months compared to the healthy controls. Fluorescein and rose bengal staining improved only in the cyclosporine A group after 3 months. CONCLUSION: Anti-inflammatory therapy with cyclosporine A 0.05% eye drops as off label use significantly improves subjective symptoms and objective signs in patients with severe dry eye disease providing a good safety profile. These findings suggest a widespread use of cyclosporine A 0.05% eye drops in patients with moderate to severe keratoconjunctivitis sicca.

[Limbal stem cells and their niche: implications for bioengineered tissue constructs]. / Limbusstammzellen und ihre nische: bedeutung für biotechnologischen gewebeersatz.

Regeneration and repair of corneal epithelium rely on a reservoir of unipotent progenitor cells, which is situated within the basal epithelial layer at the corneoscleral limbus. If these cells are lost, corneal surface integrity is disturbed, which may lead to a painful loss of vision. Since the late 1990s cultivated grafts of limbal epithelium are being used therapeutically. Limbal epithelial cells are obtained from the fellow eye or from an allogeneic donor, propagated in culture on different types of carriers, and subsequently transplanted. This process entails removal of progenitor cells from their natural environment. However, surrounding cells and extracellular matrix are widely believed to provide important stimuli for stem cell maintenance and for correct differentiation. Therefore, new approaches aim at providing this so-called stem cell niche ex vivo and following transplantation. Niche factors can also drive transdifferentiation of alternative progenitor cell types towards a corneal phenotype. This permits the use of autologous cells in cases of bilateral limbal stem cell insufficiency. Several biosynthetic substrates have been devised for culture, transdifferentiation and transplantation of donor cells. This work intends to provide an overview of constructs that are currently available and to some extent clinically employed. In addition, a summary is given of novel concepts which aim at integrating putative niche factors into the stem cell carriers to replicate the stem cell niche.

Lens Epithelial Cell Proliferation in Response to Ionizing Radiation.

Lens epithelial cell proliferation and differentiation are naturally well regulated and controlled, a characteristic essential for lens structure, symmetry and function. The effect of ionizing radiation on lens epithelial cell proliferation has been demonstrated in previous studies at high acute doses, but the effect of dose and dose rate on proliferation has not yet been considered. In this work, mice received single acute doses of 0.5, 1 and 2 Gy of radiation, at dose rates of 0.063 and 0.3 Gy/min. Eye lenses were isolated postirradiation at 30 min up until 14 days and flat-mounted. Then, cell proliferation rates were determined using biomarker Ki67. As expected, radiation increased cell proliferation 2 and 24 h postirradiation transiently (undetectable 14 days postirradiation) and was dose dependent (changes were very significant at 2 Gy; P = 0.008). A dose-rate effect did not reach significance in this study (P = 0.054). However, dose rate and lens epithelial cell region showed significant interactions (P < 0.001). These observations further our mechanistic understanding of how the lens responds to radiation.

[Screening questionnaire for documentation of medical history and diagnostic findings in dry eye disease]. / Erhebungsbogen zur Anamnese und Diagnostik des trockenen Auges.

Keratoconjunctivitis sicca is one of the most common ocular diseases world-wide. These patients suffer from severe symptoms which lead to an extremely reduced quality of life. Dry eye syndrome constitutes a major diagnostic and therapeutic challenge to all ophthalmologists because there is often a discrepancy between objective ocular signs and subjective symptoms of the patients. Furthermore, there exist only few causal therapeutic options. The physician-patient relationship plays an outstanding role in this condition. For the treatment of moderate to severe dry eye syndrome, special dry eye clinics have proved to be extremely useful. For follow-up measurements as well as the realisation of evidence-based medicine and quality control, it is a fundamental necessity to document symptoms, signs and therapy of these patients in order to optimise therapeutic strategies. For this purpose, we have developed special forms and standardised questionnaires for the individual documentation of medical history and diagnostic findings. To objectively assess the patient's complaints we use the "ocular surface disease index" (OSDI score). Only the establishment of standardised diagnostic and therapeutic algorithms with the help of special forms and questionnaires can help in the long run to improve the treatment of these severely affected patients.

[Complications after posterior lamellar keratoplasty (DSAEK): prevention, detection and treatment]. / Komplikationen nach posteriorer lamellärer Keratoplastik (DSAEK): Vermeiden, Erkennen und Behandeln.

PURPOSE: The aim of this study was to outline typical complications after Descemet's stripping automated endothelial keratoplasty (DSAEK) and to discuss their prevention and management. METHODS: Our own clinical results and PUBMED literature search were evaluated. RESULTS: Postoperative flap dislocation, which can be effectively treated by re-bubbling the graft, is the most common and typical complication after DSAEK. CONCLUSIONS: Careful preoperative indication, surgery and postoperative care make DSAEK a safe and effective new therapeutic option for patients with endothelial corneal disease.

[Histopathology of retrocorneal membranes after keratoplasty]. / Histopathologische Untersuchung von retrokornealen Membranen bei irreversiblem Transplantatversagen.

BACKGROUND: This retrospective study examines the histopathological changes, especially the occurrence of retrocorneal membranes, in irreversible graft failure after penetrating keratoplasty. PATIENTS/MATERIALS AND METHODS: 371 corneas of 308 patients were examined. The examination was carried out using a light microscope. RESULTS: 45% of the corneas (167/371) showed a retrocorneal membrane with a thickness of 2-520 micrometers. Re-endothelialisation was detected in 75 cases. In 74% (124/167) cellular infiltration into the stroma could be observed. In 32% (119/371) the graft-host border was visible. CONCLUSIONS: Retrocorneal membranes are a frequent finding in irreversible graft failure after penetrating keratoplasty. Aetiologically the graft-host border as well as the formation of connective tissue seem to play a key role.

[Web-based electronic patient record as an instrument for quality assurance within an integrated care concept]. / Webbasierte elektronische Krankenakte im Rahmen eines integrierten Versorgungskonzepts als Instrument der Qualitätssicherung.

OBJECTIVE: A prerequisite for integrated care programmes is the implementation of a communication network meeting quality assurance standards. Against this background the main objective of the integrated care project between the University Eye Hospital Erlangen and the health insurance company AOK Bayern was to evaluate the potential and the acceptance of a web-based electronic patient record in the context of cataract and retinal surgery. METHODS: Standardised modules for capturing pre-, intra- and post-operative data on the basis of clinical pathway guidelines for cataract- and retinal surgery have been developed. There are 6 data sets recorded per patient (1 pre-operative, 1 operative, 4-6 post-operative). For data collection, a web-based communication system (Soarian Integrated Care) has been chosen which meets the high requirements in data security, as well as being easy to handle. This teleconsultation system and the embedded electronic patient record are independent of the software used by respective offices and hospitals. Data transmission and storage were carried out in real-time. RESULTS: At present, 101 private ophthalmologists are taking part in the IGV contract with the University Eye Hospital Erlangen. This corresponds to 52% of all private ophthalmologists in the region. During the period from January 1st 2006 to December 31st 2006, 1844 patients were entered. Complete documentation was achieved in 1390 (75%) of all surgical procedures. For evaluation of this data, a multidimensional report and analysis tool (Cognos) was used. The deviation from target refraction as one quality indicator was in the mean 0.09 diopter. CONCLUSIONS: The web-based patient record used in this project was highly accepted by the private ophthalmologists. However there are still general concerns against the exchange of medical data via the internet. Nevertheless, the web-based patient record is an essential tool for a functional integration between the ambulatory and stationary health-care units. In addition to the telemedicine functions of the system, we achieved the export of the data to a data warehouse system in order to provide a flexible and powerful tool for quality assurance analysis and reporting.

Surgery of the cornea: corneal, limbal stem cell and amniotic membrane transplantation.

PURPOSE: To demonstrate surgical treatment options for complications of severe forms of dry eye at the cornea, limbus and conjunctiva. METHODS: Corneal, limbal and conjunctival surgical treatment strategies are outlined. RESULTS: Amniotic membrane transplantation, different forms of corneal transplantation and limbal stem cell surgery all are treatment options for complications of dry eye disease. CONCLUSIONS: Nowadays a broad spectrum of surgical treatment options exists to treat corneal complications of severe forms of dry eye at the ocular surface. Currently available conservative therapy for patients with 'dry eye' is primarily focused on augmenting or stabilizing the tear film and reducing primary or secondary causative factors such as inflammation of the ocular surface. While most patients with 'mild' and 'moderate' forms of dry eye (accounting for more than 95% of all patients with dry eye) can be treated sufficiently with drug treatment as well as environmental measures, some patients with very severe forms of dry eye need surgical intervention. Corneal surgery in the context of dry eye has primarily the objective to correct surface pathologies of the cornea caused by severe dysfunctions of the precorneal tear film. This primarily means persistent epithelial defects of the ocular surface, corneal ulcerations and consecutive corneal scarring. Besides conservative approaches, the first can be treated by amniotic membrane transplantation. Lamellar or perforating corneal transplantations are used to treat stromal scarring or perforated ulcerations as a sequel of persistent epithelial defects and associated apoptotic degeneration of stromal keratocytes. Finally, limbal stem cell transplantation can correct limbal stem cell deficiency states associated with or caused by diseases leading to severe forms of dry eye (e.g. chemical burns leading to destruction of conjunctival mucus-producing cells). All three surgical approaches will be discussed below.

Increased homocysteine levels in tear fluid of patients with primary open-angle glaucoma.

AIMS: We assessed homocysteine (Hcy) levels in tear fluid and plasma of patients with primary open-angle glaucoma (POAG). We determined the association between Hcy levels, dry eye syndrome and B vitamin status. METHODS: This prospective case-control study included 36 patients with POAG and 36 controls. Hcy concentrations were measured by high-performance liquid chromatography. RESULTS: Patients with POAG had significantly higher mean Hcy levels both in tear fluid (205 +/- 84 nmol/l; p < 0.001, t test) and in plasma (13.43 +/- 3.53 micromol/l; p = 0.001, t test) than control subjects (130 +/- 53 nmol/l and 10.50 +/- 3.33 micromol/l, respectively). Hcy in tear fluid was significantly correlated with plasma Hcy in POAG patients (r = 0.459; p = 0.005, Pearson's correlation), but not in controls (r = 0.068; p = 0.695). POAG patients with dry eye disease had significantly higher Hcy levels both in tear fluid and plasma than POAG patients without dry eye disease. There was no association between Hcy levels and B vitamin status in subjects with POAG. CONCLUSIONS: The study suggests increased Hcy levels in tear fluid and plasma of patients with POAG. Elevated Hcy levels might be a risk factor for POAG and dry eye syndrome in subjects with glaucoma.

[Descemet's stripping with automated endothelial keratoplasty (DSAEK)]. / Posteriore lamelläre Keratoplastik (DSAEK).

BACKGROUND: Although penetrating keratoplasty remains the gold standard for surgically treating corneal endothelial pathologies, tremendous progress has been made in recent years to improve the technology of (posterior) lamellar keratoplasty. METHODS: Literature review from PubMed and own data. RESULTS: Posterior lamellar keratoplasty using a microkeratome (Descemet's stripping with automated endothelial keratoplasty, or DSAEK) is a reliable surgical technique for Fuchs' endothelial dystrophy and pseudophakic bullous keratopathy. Visual rehabilitation is faster with lamellar keratoplasty than penetrating keratoplasty. CONCLUSION: Posterior lamellar keratoplasty techniques such as DSAEK will become an important surgical treatment option for corneal endothelial pathologies.

[Topical application of EGF for the therapy of persisting corneal erosion under cetuximab treatment]. / Topische EGF-applikation bei therapierefraktärer erosio corneae unter Cetuximab-Behandlung.

BACKGROUND: Cetuximab (Erbitux), a monoclonal epidermal growth factor receptor (EGFR) antibody, has been used for the treatment of advanced colorectal carcinoma over the last two years. Inhibition of EGFR also influences corneal wound healing as EGF stimulates the proliferation of epithelial cells. METHOD: Extensive corneal erosion was seen in both eyes of a 62-year-old patient under treatment with cetuximab for a metastasized colorectal carcinoma. Progression was fast despite vigorous conservative treatment. The application of autologous serum could not be considered because of the antibody treatment. Human EGF was applied topically several times daily in order to utilize the proliferative effect on corneal epithelial cells and to antagonize the inhibition of EGF receptors. RESULTS: Improvement was seen shortly after the onset of therapy with EGF eye drops.. The epithelial defect was closed 7 days (left eye) and 19 days (right eye), respectively, after the onset of therapy. During this time treatment with cetuximab was continued. CONCLUSIONS: Cetuximab (Erbitux) can cause persisting epithelial defects. Patients with an impairment of corneal wound healing under cetuximab treatment can benefit from the topical application of human EGF. Consequently, surgical measures or complications such as infections can be avoided.

[Malignant melanoma of the lacrimal sac]. / Malignes Melanom des Tränensacks.

A 68-year-old woman presented with a 10-month history of right-sided epiphora, bloody tears, and medial canthal mass. Computed tomography revealed a soft tissue mass of the right lacrimal sac with widening of the bony nasolacrimal canal. External dacryocystorhinostomy with incisional biopsy confirmed the diagnosis of malignant melanoma. After staging, further therapy included orbital exenteration, lateral rhinotomy with en bloc resection of the lacrimal drainage apparatus, and adjuvant radioimmunotherapy. One year after surgery, no evidence of local recurrence or metastatic disease could be detected.

[Manufacture of autologous serum eye drops for out-patient therapy : cooperation between ophthalmic clinic and transfusion medicine department]. / Herstellung von Eigenserumaugentropfen zur ambulanten Therapie : Kooperation von Augenklinik und transfusionsmedizinischer Abteilung.

BACKGROUND: Autologous serum eye drops are an important therapy option in severe ocular surface disorders and the therapeutic effectiveness has been demonstrated in many clinical studies. The production and use of autologous serum eye drops is strictly controlled by legal regulations in Germany: Both the German Medicines Act (AMG) and the Blood Transfusion Act regulate production, distribution and application, unless it is carried out by one person under controlled conditions in a hospital setting. MATERIAL AND METHODS: In cooperation with the ophthalmic clinic and the department of transfusion medicine, a standard operating procedure (SOP) was developed and a license for production and delivery of autologous serum eye drops was obtained from the appropriate local authorities. The experiences of the first two years of practice were analyzed. RESULTS: By an interfaculty cooperation, the possibility of legal and feasible out-patient treatment with autologous eye drops has been established at the University Hospital Erlangen. From 07/2005 to 07/2007, there ware 240 prescriptions for autologous serum eye drops. Unexpectedly, a relatively high rate (3.3%) of patients with primarily unknown viral or bacterial infectious diseases were found, which were diagnosed during the screening. These patients had to be excluded from autologous serum eye drop therapy. CONCLUSION: The treatment with autologous serum eye drops in an out-patient setting is possible, when the infrastructure for manufacture and delivery is provided in accordance with existing regulations.

The cell-specific elastase I enhancer comprises two domains.

Two separate domains within the 134-base-pair rat elastase I enhancer and a third domain at the enhancer-promoter boundary are required for selective expression in pancreatic acinar cells. The domains were detected by a series of 10-base-pair substitution mutations across the elastase I gene regulatory region from positions -200 to -61. The effect of each mutant on the pancreas-specific expression of a linked chloramphenicol acetyltransferase gene was assayed by transfection into pancreatic 266-6 acinar cells and control NIH/3T3 cells. The two enhancer domains are nonredundant, because mutations in either eliminated (greater than 100-fold reduction) expression in 266-6 cells. DNase I protection studies of the elastase I enhancer-promoter region with partially purified nuclear extracts from pancreatic tissue and 266-6 cells revealed nine discrete protected regions (footprints) on both DNA strands. One of three footprints that lie within the two functional domains of the enhancer contained a sequence, conserved among several pancreas-specific genes, which when mutated decreased linked chloramphenicol acetyltransferase expression up to 170-fold in 266-6 cells. This footprint may represent a binding site for one or more pancreas-specific regulatory proteins.

Cooperation between elements of an organ-specific transcriptional enhancer in animals.

The elastase I gene enhancer that specifies high levels of pancreatic transcription comprises three functional elements (A, B, and C). When assayed individually in transgenic mice, homomultimers of A are acinar cell specific, those of B are islet specific, and those of C are inactive. To determine how the elements interact in the elastase I enhancer and to investigate further the role of the C element, we have examined the activity of the three possible combinations of synthetic double elements in transgenic animals. Combining the A and B elements reconstitutes the exocrine plus endocrine specificity of the intact enhancer with an increased activity in acinar cells compared with that in the A homomultimer. The B element therefore plays a dual role: in islet cells it is capable of activating transcription, whereas in acinar cells it is inactive alone but greatly augments the activity specified by the A element. The C element augments the activity of either the A or B element without affecting their pancreatic cell type specificity. The roles of each element were verified by examining the effects of mutational inactivation of each element within the context of the elastase I enhancer. These results demonstrated that when tested in animals, the individual enhancer elements can perform discrete, separable functions that combine additively for cell type specificity and cooperatively for the overall strength of a multielement stage- and site-specific transcriptional enhancer.

A single element of the elastase I enhancer is sufficient to direct transcription selectively to the pancreas and gut.

The elastase I (EI) gene is expressed at high levels in the exocrine pancreas and at lower levels in other regions of the gut. The transcriptional enhancer of the EI gene, from nucleotides -205 to -72, recapitulates the expression of the endogenous gene in transgenic mice; it directs not only pancreatic acinar cell expression of a human growth hormone (hGH) transgene but also expression to the stomach, duodenum, and colon. This pattern of selective expression limited to the gastroenteropancreatic organ system is specified by the A element, one of three functional elements in the EI enhancer. When multimerized, the A element directed expression of a hGH reporter gene selectively to the pancreas, stomach, and intestine in transgenic mice. Immunofluorescent localization of hGH indicated that the A element multimer transgenes were expressed in the acinar cells of the pancreas as well as in Brunner's gland cells of the duodenum. The A element binds a pancreatic acinar cell-specific factor, PTF1. Our results show that while the A element is responsible for directing tissue and cell type specificity, other elements of the enhancer must be involved in the regulation of the level of gene expression.

[Primary open angle glaucoma. Morphological bases for the understanding of the pathogenesis and effects of antiglaucomatic substances]. / Primäres Offenwinkelglaukom. Morphologische Grundlagen zum Verständnis der Pathogenese und der Wirkung antiglaukomatöser Substanzen.

The pathogenesis of glaucomatic illnesses is poorly understood. An increase in ocular pressure can be caused by an increase in the secretion of aqueous humour or a reduction in its outflow. In the elderly, outflow is reduced while at the same time less aqueous humour is produced. This balance is easily disturbed, so that age represents a risk factor for glaucoma in addition to increased ocular pressure. Therapeutic possibilities involve, on the one hand, reducing the secretion of aqueous humour, for example using, beta blockers, carbonic anhydrase inhibitors and clonidine. On the other hand, aqueous humour outflow can also be influenced by drugs. Conventional outflow is increased by the administration of miotics. The uveoscleral outflow can be increased by prostaglandin derivates. Drugs which only influence trabecular outflow are not yet available. Future therapeutic possibilities involve new aspects of the pathophysiology, e.c. the use of growth factors, free radical scavenging enzymes and choroidal blood flow.

[Differential diagnosis and treatment options for conjunctival tumors]. / Differenzialdiagnose und Therapieoptionen bei Tumoren der Konjunktiva.

The diagnostic classification of most conjunctival tumors is based on case history, inspection, and examination with the slit lamp microscope. Further imaging procedures are rarely indicated when malignant processes are not circumscribed. Clinical classification then also includes palpation and echographic examination of regional lymph nodes. Pigmented and nonpigmented melanocytic nevi are the most frequent conjunctival tumors. An important practical biomicroscopic cardinal symptom of the most frequent nevi is the presence of epithelial pseudocysts. Essential in practice is the histopathological confirmation of the clinical diagnosis, e.g., distinguishing between nonpigmented melanomas and sebaceous gland carcinomas with a pagetoid growth pattern or squamous cell carcinomas. Depending on the course and findings, the following therapeutic measures can be indicated: cryotherapy, chemotherapy, radiotherapy, modified enucleation, orbital exenteration, or a combination of different methods.