Calcium Electroporation versus Electrochemotherapy with Bleomycin in an In Vivo CAM-Based Uveal Melanoma Xenograft Model.

Despite recent advancements in the diagnosis and treatment of uveal melanoma (UM), its metastatic rate remains high and is accompanied by a highly dismal prognosis, constituting an unmet need for the development of novel adjuvant therapeutic strategies. We established an in vivo chick chorioallantoic membrane (CAM)-based UM xenograft model from UPMD2 and UPMM3 cell lines to examine its feasibility for the improvement of selection of drug candidates. The efficacy of calcium electroporation (CaEP) with 5 or 10 mM calcium chloride (Ca) and electrochemotherapy (ECT) with 1 or 2.5 µg/mL bleomycin in comparison to monotherapy with the tested drug or electroporation (EP) alone was investigated on the generated UM tumors. CaEP and ECT showed a similar reduction of proliferation and melanocytic expansion with a dose-dependent effect for bleomycin, whereas CaEP induced a significant increase of the apoptosis and a reduction of vascularization with varying sensitivity for the two xenograft types. Our in vivo results suggest that CaEP and ECT may facilitate the adequate local tumor control and contribute to the preservation of the bulbus, potentially opening new horizons in the adjuvant treatment of advanced UM.

Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures.

Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As ß-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of ß1-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three ß-adrenoceptors with a dominance of ß2-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of ≥20 µM. Mechanistically, nebivolol induced ATP depletion and caspase-3/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the ß2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both ß1- and ß2-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis.

Choroidal Manifestation of Smoldering Myeloma: Case Report.

This case illustrates clinical, histopathological, immunohistochemical, and molecular pathological diagnostic testing of smoldering myeloma with atypical ophthalmic manifestations. In our case, the choroidal lesion presented as a solitary manifestation of a systemic disease. Choroidal lesions of monoclonal plasma cells are extremely rare and should be included in the differential diagnosis of amelanotic choroidal lesions, even if the histopathological examination of the primary lesion is not informative. Clinical course, immunohistochemistry, and molecular pathology are essential components of the diagnostic pathway.

Outcome Measures of New Technologies in Uveal Melanoma: Review from the European Vision Institute Special Interest Focus Group Meeting.

Uveal Melanoma (UM) is the most common primary intra-ocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma", addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's wellbeing. This review highlights the meeting's presentations in the context of the published literature.

[Echography]. / Echografie.

Echography (also ultrasound) is a clinical, non-invasive imaging module that is used for the measurement of the axial length of the eye and for the investigation of pathologic entities of the chamber angle, the iris and the ciliary body. Furthermore, its role in the management of vitreoretinal pathologies and the differentiation of intraocular tumors is indisputable. Echography remains the first-choice imaging tool in case of insufficient visualization of the posterior segment due to opacity or obstruction of the optical media of the eye. In addition, it can contribute to a more precise diagnostic characterization of lesions in all eye segments. Patients with corneal opacities, abnormalities of the iris, the chamber angle and the ciliary body, as well as patients with dense cataract, vitreous hemorrhage or inflammatory opacities can be properly diagnosed via ultrasound and be treated accordingly.

Brachytherapy for Peripheral Retinal Capillary Haemangioblastoma in von Hippel-Lindau Disease. / Brachytherapie peripherer retinaler kapillärer Hämangioblastome beim Von-Hippel-Lindau-Syndrom.

AIM: To report our experience with 106ruthenium-brachytherapy of peripheral capillary haemangioblastomas in patients with von Hippel-Lindau disease. DESIGN: Retrospective case series. METHODS: A total of 53 haemangioblastomas, treated with 106ruthenium-brachytherapy, were included in our study. The applied radiation dose, visual outcome, angioma activity, need for vitreoretinal surgery and incidence of secondary complications such as macular oedema, secondary glaucoma, vitreous haemorrhage, and epiretinal gliosis were assessed. RESULTS: All treated eyes could be preserved. In 11 patients (20.8%), single brachytherapy did not achieve complete inactivation of the tumour. 31% developed macular oedema postoperatively. Tractional retinal detachment developed in 23.8%, and epiretinal gliosis was observed in 2.4% of patients. Vitreoretinal surgery was necessary in 50% of all treated eyes. At the end of the follow-up, 40.5% of all treated eyes achieved visual acuity (VA) of 0.6 or better, and one third reached a VA of less than 0.1. Mean irradiation dose to the tumour apex was 144 Gy. Higher apex doses correlated with better tumour control of irradiated haemanigoblastomas and lower complication rates. CONCLUSIONS: Brachytherapy of peripheral retinal capillary haemangioblastomas is an effective treatment modality. Higher irradiation doses seem to lead to more successful treatment.

[Traumatic Macular Hole]. / Traumatisches Makulaforamen.

The traumatic macular hole (TMH) is a rare complication of a blunt or an open injury of the globe and can lead to permanent loss of vision. The pathomechanism of TMH differs from that of the idiopathic macular hole (IMH). A sudden compression and expansion of the globe leads to vitreous traction, which can result in a TMH. The final visual acuity depends on the severity of the disruption of the photoreceptors and the retinal pigment epithelial cells. The posttraumatic approach is discussed controversially. A spontaneous closure and, therefore, a conservative approach should be considered in young patients with minor defects and good visual acuity without detachment of the posterior vitreous body. In these cases, it is advisable to wait for months. In the absence of adhesion at the edges of the hole and concomitant pathologies of the pigment epithelium, the spontaneous closure is improbable. In this case, a pars plana vitrectomy with removal of the vitreous and epiretinal membranes can lead to anatomical reconstruction and improvement of the visual acuity. The success of an operative intervention is complex and is associated with the experience of the surgeon as well as the characteristics of the trauma.

Traumatic globe rupture after deep anterior lamellar keratoplasty-A novel management technique.

A traumatic wound dehiscence can occur many years after surgery in 2-6% of all keratoplasties. Intraocular tissue prolapse can lead to severe visual loss. Deep anterior lamellar keratoplasty (DALK) leads to higher wound stability because of the intact Descemet membrane. We report a case of a novel management of wound dehiscence following DALK. A 59-year-old patient underwent uncomplicated DALK for advanced keratoconus. Eighteen months later he experienced a traumatic wound dehiscence (globe rupture) after a fall. Visual acuity decreased to light perception on the affected eye, the iris and prolapsed vitreous were incarcerated, and no retinal details were recognizable. The corneal graft was dehiscent over eight clock hours, the Descemet membrane was ruptured, and the stroma dissolved over 30% of its surface in a bell shape. Primary wound closure was performed with nylon 10-0 single interrupted corneal sutures. One day after emergency treatment, a 23-gauge pars-plana-vitrectomy for vitreous hemorrhage was conducted and a retinal tear was treated with laser photocoagulation. The Descemet membrane was repositioned using a 23 g vitrectomy probe under air and the globe was filled with SF6 gas. Postoperatively, visual acuity increased to 6/15 and the cornea cleared up. Corneal graft and Descemet membrane repositioning after trauma can avoid a further keratoplasty and the risk of immunological rejection of donor endothelial cells. Clin. Anat. 31:56-59, 2018. © 2017 Wiley Periodicals, Inc.

Tenonplasty for closing defects during sclerocorneal surgery-A brief review of its anatomy and clinical applications.

To provide insight into the clinical anatomy of Tenon's capsule and to describe a technique to manage sclerocorneal defects using autologous Tenon's tissue. A thin layer of Tenon's capsule harvested from the patient's own eye is used to seal the defect and act as a scaffold. The Tenon's flap is spread over the defect and held in place by Vicryl sutures. A bandage contact lens is then placed on the eye. Tenon's capsule is composed of thick fibrous tissue with smooth muscle fibers and a thin posterior capsule of orbital fat. It is rich in fibroblasts, which can accelerate wound healing and eventually lead to robust scarring without risk of immunogenicity and without cost. Tenonplasty uses easily-available autologous Tenon's tissue in patients with sclerocorneal defects to preserve globe morphology. The technique is a feasible alternative not limited by the availability of graft tissue. Clin. Anat. 31:72-76, 2018. © 2017 Wiley Periodicals, Inc.

Methods of fixation of intraocular lenses according to the anatomical structures in trauma eyes.

Ocular trauma can lead to severe visual impairment and morbidity, depending on the anatomical structures affected. The main causes of ocular trauma include foreign bodies, impact by an object, falls, and chemicals. Most ocular traumas occur in children or young male adults. A meticulous slit lamp examination is crucial for assessing all anatomical structures. Trauma to the crystalline lens can result in dislocation, an intralenticular foreign body, cataract, fragmentation, and capsular breach. An intraocular lens (IOL) can endure subluxation or luxation under the conjunctiva, into the anterior chamber or the vitreous, or can be extruded. The surgical approach depends on the condition and morphology of the lens and the anatomical structures surrounding it. If there is capsular bag support, a secondary IOL can be placed in the sulcus using remnants of the damaged capsule. If there is no capsular bag support, a secondary IOL can be fixated to the anterior chamber angle, to the iris, or to the sclera. A detailed history of injury cannot always be obtained in trauma settings. Proper education, supervision, and certified safety eye protectors could prevent up to 90% of ocular injuries. Lens trauma can be treated with various surgical procedures and fixation techniques, which nevertheless require advanced surgical skills owing to the fine anatomical structure of the anterior segment. A careful surgical strategy should be established for a globe reconstruction after trauma with secondary lens implantation. Clin. Anat. 31:6-15, 2018. © 2017 Wiley Periodicals, Inc.

Clinical anatomy of the anterior chamber angle in congenital aniridia and consequences for trabeculotomy/cyclophotocoagulation.

Intraocular pressure lowering surgery in congenital aniridia glaucoma (CAG) can be complicated by dysgenesis of the limbal region, anterior chamber angle, iris, and lens. The anterior segments of 23 eyes (17 patients) with congenital aniridia were investigated under general anesthesia using ultrasound biomicroscopy (UBM). The structures of the anterior segment were examined: distance of ciliary body processes from the anterior chamber angle and positioning of Schlemm's canal. A surgical plan was created on the basis of these data. Schlemm's canal was detected in 21 of the 23 examined eyes. The mean distance from the anterior chamber angle was 1.3 ± 0.4 mm (range: 0.5-to 2.1 mm). The mean distance between the anterior chamber angle and the ciliary body was 561 ± 301 µm (range: 270-1,300 µm). The mean prominence of the ciliary body towards the lens was 799 ± 352 µm (range: 210-1,660 µm). This resulted in a precise UBM-based trabeculotomy. In addition, the ciliary body was detected and coagulated ab externo with a diode laser probe (810 nm) using diaphanoscopy and UBM. An initial UBM examination of the anterior segment is essential in eyes with CAG scheduled for trabeculotomy or cyclophotocoagulation. Clin. Anat. 31:64-67, 2018. © 2017 Wiley Periodicals, Inc.

[Dacryoendoscopic Surgery-Factors Influencing Postoperative Results]. / Dakryoendoskopische Tränenwegschirurgie ­ Einflussfaktoren auf das postoperative Ergebnis.

BACKGROUND: Dacryoendoscopy (DE) is an established method in lacrimal surgery. Long-term follow-up-analyses of this surgery are of great interest. Here, factors influencing postoperative success rates should be considered to elect suitable patients. METHODS: In this retrospective study, patients having had dacryoendoscopic surgery were included. Using a questionnaire, a prospective follow-up analysis was made. Pre- and intraoperative factors were correlated with treatment success, which was defined as improved epiphora, absence of a second lacrimal surgery and no signs of chronic dacryocystitis (secretion, pain at the lacrimal sac). Additionally, we asked for patient's satisfaction with the postoperative result (categorized in "very good", "good", "poor", and "bad"). RESULTS: Overall, 215 DE of 182 patients (130 women, 52 men) were studied. Mean patient age was 58 ± 17 years (range: 18 to 91 years). Follow-up was 31 to 77 months (median: 55 months). Treatment success after this time was 59.1%, in which neither patient's age nor sex showed significant influences. In comparison to complete stenosis, incomplete obstruction could be treated successfully twice as often (p = 0.02). Patients suffering from ectatic lacrimal sacs had a risk of 1.9 for failing therapy (p = 0.01). A trend concerning worse cure rates could be observed in patients with postsaccal localization of stenosis (p = 0.2) and an age of older than 49 years (p = 0.1). Surgical results evaluated by the patients were "very good" in 32.1% and "good" in 30.2%. CONCLUSION: Dacryoendoscopy with its minimally invasive approach is suitable as a first-step procedure in lacrimal surgery. The absence of a scar and the quick recovery are vitally important for the patients. Medically important is that the topographic anatomy is preserved by using dacryoendoscopy, so other surgical techniques can be performed later without limitations, if necessary. Patients with incomplete obstructions and a localization of stenosis, being pre- to intrasaccal, profit from this treatment method in particular.

Anatomic landmarks in lacrimal surgery from an ophthalmologist's point of view: Clinical findings of external dacryocystorhinostomy and dacryoendoscopy.

Epiphora is a common clinical symptom of nasolacrimal duct obstruction. However, it is present in several pathologies and can lead to decreased quality of life for patients. A careful clinical examination including a detailed patient's history and diagnostic tests such as the fluorescein dye disappearance test and diagnostic syringing of the lacrimal duct are essential. Depending on the time of presentation (congenital, primary, or secondary acquired), grade (subtotal or total) and location of the stenosis, different surgical approaches can be considered. These are subdivided into minimally invasive (transcanalicular) and anastomosing (dacryocystorhinostomy) procedures. Furthermore, the anatomical landmarks and the site of surgical intervention differentiate the surgical techniques into endoscopic or transcutaneous. Modern intubation techniques offer a large spectrum of therapeutic possibilities enabling patient care to be customized and individualized. Knowledge of the topographical anatomy is crucial for achieving greater success and a lower complication rate. Clin. Anat. 30:1034-1042, 2017. © 2017 Wiley Periodicals, Inc.

The Chick Chorioallantoic Membrane as a Xenograft Model for the Quantitative Analysis of Uveal Melanoma Metastasis in Multiple Organs.

Uveal melanoma (UM) is the most common intraocular tumor in adults, and nearly 50% of patients develop metastatic disease with a high mortality rate. Therefore, the development of relevant preclinical in vivo models that accurately recapitulate the metastatic cascade is crucial. We exploited the chick embryo chorioallantoic membrane (CAM) xenograft model to quantify both experimental and spontaneous metastasis by qPCR analysis. Our study found that the transplanted UM cells spread predominantly and early in the liver, reflecting the primary site of metastasis in patients. Visible signs of pigmented metastasis were observed in the eyes, liver, and distal CAM. Lung metastases occurred rarely and brain metastases progressed more slowly. However, UM cell types of different origins and genetic profiles caused an individual spectrum of organ metastases. Metastasis to multiple organs, including the liver, was often associated with risk factors such as high proliferation rate, hyperpigmentation, and epithelioid cell type. The severity of liver metastasis was related to the hepatic metastatic origin and chromosome 8 abnormalities rather than monosomy 3 and BAP1 deficiency. The presented CAM xenograft model may prove useful to study the metastatic potential of patients or to test individualized therapeutic options for metastasis in different organs.

Leadership in ophthalmology training : Opportunities and risks of medical specialist education.

Medical specialist training requires constant improvement and adaptation of the contents to the current situation. Nowadays, young physicians have the opportunity to select among the most renowned institutions and can choose the one most qualified for their training. Hospitals on the other hand still have the desire to recruit highly qualified physicians for their resident programs, which requires a good, well-rounded and reliable offer by the department under good leadership. Thus, among other issues a modern and multilingual homepage is already an important instrument for successfully addressing applicants and winning them over for the department. In addition to a well-planned and structured training plan (e.g., the "Homburg Curriculum") and a so-called "resident guide", many other additional offers are nowadays part of a successful training, such as structured internal and external specialist training courses, well thought out research concepts available to all interested parties, wet labs for practical exercises on pig's eyes and as the latest most innovative addition, a virtual reality simulator. Due to a structured curriculum with regular continuous education during the daily early morning meetings and an exchange program with another university eye hospital, not only the residents can benefit but ultimately also the department itself. In addition, future specialists are involved in the respective organization (so-called "service teams") from the very beginning. This conveys a great deal of knowledge and expertise but also organizational skills and thus improves the quality of training. In any case, standardized residency training with a view beyond the horizon, which is transparently organized and reliably carried out, improves the quality of training in order to become a certified ophthalmologist and increases the satisfaction of the residents. A department which is committed and can offer a wide range of services will benefit from motivated and satisfied employees in a good interpersonal climate, which in the end benefits not only the team but also the patients.

Electroporation with Calcium or Bleomycin: First Application in an In Vivo Uveal Melanoma Patient-Derived Xenograft Model.

Uveal melanoma (UM) represents a rare tumor of the uveal tract and is associated with a poor prognosis due to the high risk of metastasis. Despite advances in the treatment of UM, the mortality rate remains high, dictating an urgent need for novel therapeutic strategies. The current study introduces the first in vivo analysis of the therapeutic potential of calcium electroporation (CaEP) compared with electrochemotherapy (ECT) with bleomycin in a patient-derived xenograft (PDX) model based on the chorioallantoic membrane (CAM) assay. The experiments were conducted as monotherapy with either 5 or 10 mM calcium chloride or 1 or 2.5 µg/mL bleomycin in combination with EP or EP alone. CaEP and ECT induced a similar reduction in proliferative activity, neovascularization, and melanocytic expansion. A dose-dependent effect of CaEP triggered a significant induction of necrosis, whereas ECT application of 1 µg/mL bleomycin resulted in a significantly increased apoptotic response compared with untreated tumor grafts. Our results outline the prospective use of CaEP and ECT with bleomycin as an adjuvant treatment of UM, facilitating adequate local tumor control and potentially an improvement in metastatic and overall survival rates.

Wolfram-silicone implants as effective radiation shielding for ocular brachytherapy: dosimetric features and in vivo animal study on biocompatibility.

OBJECTIVE: To evaluate wolfram as a photon and beta absorber in the management of uveal melanoma with radiotherapy, examining its potential ocular adverse effects and physiologic tolerance using an in vivo rabbit ocular model. METHODS: A method of manufacturing implants from mixtures of wolfram and silicone was developed. Their shielding effect on the radiation of sources used in ocular brachytherapy was investigated by dosimetric measurement in an eye phantom as well as numerical simulations. Different wolfram implantation techniques, such as extraocular fixation of a wolfram-silicone implant (n = 1), vitrectomy with silicone oil and intravitreal injection of a wolfram-silicone oil suspension (n = 2), and concurrent attachment of a wolfram implant onto the sclera (n = 2), were tested to investigate the long-term effects of wolfram. A vitrectomy with silicone oil without wolfram implantation was carried out in 2 rabbits (n = 2), constituting the control group. The eyes were enucleated after 3 months for histologic analysis. RESULTS: Wolfram-silicone mixtures have been dosimetrically proven to be very effective radiation absorbers for use in ocular brachytherapy. Severe complications, such as endophthalmitis, secondary glaucoma, cornea decompensation, and vessel occlusion, were not documented in the tested rabbit eyes after the application of wolfram. Histologic examination of the bulbi after enucleation showed epiretinal gliosis without further pathologic findings in all eyes after vitrectomy. CONCLUSIONS: The results of this study show that wolfram and wolfram-silicone implants constitute a promising candidate as potential radiation shielding substrates.

Surgical Outcome After Treatment of Radiation-Induced Scleral Necrosis in Patients With Uveal Melanoma.

PURPOSE: Surgical repair might be required in patients with uveal melanoma (UM) that develop advanced forms of radiation-induced scleral necrosis (RISN). In this monocentric long-term observational study, we aimed at analyzing the treatment outcome after RISN surgery. METHODS: All consecutive cases with UM who underwent surgical intervention for RISN between 1999 and 2020 were included. Achievement of the tectonic stability and evaluation of incidence and the risk factors for a repetitive patch surgery (RPS) were the main endpoints. RESULTS: The final analysis included 57 patients (mean age: 58.7 years; 63.2% female patients), where 55 individuals underwent a patch grafting, and 2 cases were treated with conjunctival reconstructive surgery. The mean follow-up time after grafting was 38.5 months (0.03-221.1 months). Tectonic stability was achieved in 56 (98.3%) patients. Scleral graft (38/55, 69.1%) was the most frequent patching material, followed by Tutopatch (7/55, 12.7%), corneal graft (7/55, 12.7%), dura graft (2/55, 3.6%), and fascia lata (FL) graft (1/55, 1.8%). Eleven patients (20%) underwent RPS after the mean time of 12.9 months (0.3-50.3 months). In the final multivariate Cox regression analysis, the use of Tutopatch (5/7; 71.4%, adjusted hazard ratio = 4.66, P = 0.044) and RISN progression after patch grafting (9/11; 81.8%, adjusted hazard ratio = 9.67, P = 0.008) were independent risk factors for RPS. CONCLUSIONS: RISN surgery maintains long-term tectonic stability in most of the cases underwent surgical repair for RISN after brachytherapy for UM. Depending on graft material and, particularly, further RISN progression, an RPS might be necessary in certain cases.

Prognostic factors for surgical treatment of radiation-induced scleral necrosis after brachytherapy for uveal melanoma.

PURPOSE: Radiation-induced scleral necrosis (RISN) is a less frequent complication of brachytherapy for uveal melanoma, and may require surgical treatment in selected cases. We aimed to identify the prognostic factors for RISN treatment. METHODS: All patients with brachytherapy for uveal melanoma treated at our institution between 01/1999 and 12/2016 who developed RISN were followed until 02/2021. Various parameters were evaluated through univariable and multivariable Cox regression analysis. The surgical intervention due to RISN was the principal outcome event of this study. RESULTS: Of 115 patients in the final cohort, 51 individuals (44%) underwent RISN treatment (conjunctival revision [n = 2], patching [n = 46] or enucleation [n = 3]) at median 1.80 months after RISN occurrence. Significant RISN characteristics were summarized into a novel RISN severity scale - Grade I: largest diameter ≤ 5 mm and no progression; Grade II: largest diameter > 5 mm or any progression during the follow-up; Grade III: presence of uveal prolapse; and Grade IV: leakage through open eyewall perforation. In the multivariable analysis, the RISN severity scale (aHR = 2.37 per grade increase, p = 0.01) and the time between brachytherapy and RISN occurrence (<15 months, aHR = 6.33, p < 0.0001) were independently associated with the study endpoint. The RISN severity scale showed high diagnostic accuracy for prediction of RISN treatment (AUC = 0.869). CONCLUSIONS: In our series, about the half of RISN cases underwent surgical treatment. The presented novel severity scale for RISN might become a helpful tool for clinical management of individuals with RISN. We recommend external validation of the diagnostic accuracy of the presented scale.