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Background: Dose-response relationships for optic neuropathy and optic nerve atrophy after brachytherapy for posterior uveal melanoma were poorly defined from previous studies. Here, the outcome differences were analyzed in dependence on dosimetric factors, the applicator type, and tumor dependent variables., Purpose: Primary objective was to evaluate the association of applied dose and on-set of optic nerve atrophy after brachytherapy for posterior uveal melanoma in order to allow risk estimation for new patients., Materials and Methods: This retrospective study was performed at a single high volume centre for ocular oncology. Patients receiving brachytherapy with Ruthenium-106 applicators for posterior uveal melanoma with a maximum distance between optic nerve and the nearest tumor margin of 4 optical disc diameters and follow-up with fundus photographs were included. The dose distribution at the optic nerve was reconstructed from the fundus photographs at latest follow-up and the dose-distribution of the applicator using a dedicated software. A first mask with important structural elements such as optic nerve, macula, tumor and vessels was first superimposed on the fundus photograph and adapted to the real contours. In a second step, an applicator contour mask was adapted to the radiation scar in order to calculate the dose distribution in all structures. Dose-response relations were obtained by weighted logistic regression., Results: The maximum dose at the optic disc (OD max ) in this group of 109 patients ranged from 5.8 Gy - 242.2 Gy, median 48.7 Gy. Optic nerve atrophy was observed in 29patients. Median time to radiation induced optic nerve atrophy was 18months. Using weighted logistic regression, the dependence of optic nerve atrophy on OD max was significant (p = 0.0001, chi 2 -test). There was a considerable interobserver variability in OD max values (p < 0.02, signed rank test). An additional factor influencing the dose-response was the applicator type (p = 0.0315, chi 2 -test). The OD max for a probability of optic nerve atrophy of 50 % (ED50) were 77.6 Gy ± 7.0 Gy for patients treated with notched COB applicators and 53.2 Gy ± 8.2 Gy for patients with other applicators. Including the applicator type, the area under ROC curve reached a value of 0.857 (95 %-CI: 0.793-0.921) for the logistic model with OD max . The ED50 for optic nerve neuropathy, classified as grade ≥ 1 toxicity, was estimated to be 46.9 Gy ± 4.1 Gy for the maximum dose at the optic disc., Conclusions: Significant dose-response curves were found for optic nerve atrophy at low dose rate brachytherapy. A standard position of COB applicators was identified that allows estimation of the dose-response relation from the scleral dose of the applicator for risk estimation without fundus photographs. This larger data set enhances the knowledge of dose-response relationships for irradiation near the optic nerve., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite advances in precision oncology, clinical decision-making still relies on limited variables and expert knowledge. To address this limitation, we combined multimodal real-world data and explainable artificial intelligence (xAI) to introduce AI-derived (AID) markers for clinical decision support. We used xAI to decode the outcome of 15,726 patients across 38 solid cancer entities based on 350 markers, including clinical records, image-derived body compositions, and mutational tumor profiles. xAI determined the prognostic contribution of each clinical marker at the patient level and identified 114 key markers that accounted for 90% of the neural network's decision process. Moreover, xAI enabled us to uncover 1,373 prognostic interactions between markers. Our approach was validated in an independent cohort of 3,288 patients with lung cancer from a US nationwide electronic health record-derived database. These results show the potential of xAI to transform the assessment of clinical variables and enable personalized, data-driven cancer care., Competing Interests: Competing interests: V.G. receives honoraria from Bristol Myers Squibb, Pfizer, Ipsen, Eisai, Merck Sharp & Dohme (MSD) Oncology, Merck HealthCare, EUSAPharm, Apogepha and Ono Pharmaceutical; has an advisory role at BMS, Pfizer, MSD Oncology, Merck HealthCare, Ipsen, Eisai, Debiopharm, PCI Biotech, Cureteq and Oncorena; and received travel funding from Pfizer, Ipsen and Merck HealthCare. B.H. has an advisory role at ABX, AAA/Novartis, Astellas, AstraZeneca, Bayer, BMS, Janssen R&D, Lightpoint Medical and Pfizer; receives research funding from Astellas, BMS, AAA/Novartis, German Research Foundation, Janssen R&D and Pfizer; and receives travel funding from Astellas, AstraZeneca, Bayer and Janssen. D.S. receives personal fees for advisory boards of BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, Sanofi and Regeneron; personal fees as an invited speaker from BMS, Merck Serono, MSD, Novartis, Roche and Sanofi; personal fees (financial interest) for steering committee membership from BMS and MSD; personal support (no financial interest) for steering committee membership from Novartis; institutional support as a coordinating principal investigator (no financial interest) from BMS, MSD, Novartis and Pierre Fabre; institutional support as a local principal investigator (no financial interest) from Philogen and Sanofi; institutional research grant support (financial interest) from BMS and MSD; and is an EORTC-MG Member of the Board of Directors (no financial interest). J.T.S. receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech and Servier; his institution receives research funding from Abalos Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio and Roche/Genentech; and he holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work. M.T. receives speaker fees and personal support from AstraZeneca, Daiichi Sankyo, Novartis, Bayer, Asklepios and Edwards LifeSciences. M.W. receives honoraria and has an advisory role: Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. M.S. is a consultant (compensated) for Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi and Takeda; receives honoraria for CME presentations from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, Novartis, Roche and Sanofi; and receives research funding (institutional) from AstraZeneca and Bristol-Myers Squibb. K.-R.M., F.K. and G.M. hold patents related to this work (9558550; 20180018553) and are co-founders of the computational pathology start-up Aignostics, Berlin. The remaining authors declare no competing interests related to this study., (© 2025. The Author(s).)

Retinoblastoma (RB) is an intraocular tumor arising from retinal cone progenitor cells affecting young children. In the last couple of years, RB treatment evolved towards eye preserving therapies. Therefore, investigating intratumoral differences and the RB tumor microenvironment (TME), regulating tumorigenesis and metastasis, is crucial. How RB cells and their TME are involved in tumor development needs to be elucidated using in vitro models including RB derived stromal cells. In the study presented, we established primary RB derived tumor and stromal cell cultures and compared them by RNAseq analysis to identify their gene expression signatures. RB tumor cells cultivated in serum containing medium were more differentiated compared to RB tumor cells grown in serum-free medium displaying a stem cell like phenotype. In addition, we identified differentially expressed genes for RB tumor and stromal derived cells. Furthermore, we immortalized cells of a RB1 mutated, MYCN amplified and trefoil factor family peptid 1 (TFF1) positive RB tumor and RB derived non-tumor stromal tissue. We characterized both immortalized cell lines using a human oncology proteome array, immunofluorescence staining of different markers and in vitro cell growth analyses. Tumor formation of the immortalized RB tumor cell line was investigated in a chicken chorioallantoic membrane (CAM) model. Our studies revealed that the RB stromal derived cell line comprises tumor associated macrophages (TAMs), glia and cancer associated fibroblasts (CAFs), we were able to successfully separate via magnetic cell separation (MACS). For co-cultivation studies, we established a 3D spheroid model with RB tumor and RB derived stromal cells. In summary, we established an in vitro model system to investigate the interaction of RB tumor cells with their TME. Our findings contribute to a better understanding of the relationship between RB tumor malignancy and its TME and will facilitate the development of effective treatment options for eye preserving therapies., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Medical Faculty of the University of Duisburg-Essen (approval # 06-30214; date of approval: 5 December 2006; approval # 14-5836-BO; date of approval: 11 March 2020)., (© 2024. The Author(s).)

Purpose: Patients with incurable corneal diseases experience visual impairment (VI) despite having a healthy retina and optic pathway. Low-vision aids (LVAs) can optimize the use of remaining vision through magnification and contrast enhancement, but do not harness the full visual capacity because they rely on the optic media. Therefore, we investigated a novel laser eyewear (LEW) technology that bypasses the anterior segment of the eye. Images captured by an integrated camera are projected directly onto the retina using a low-energy laser. The patient is able to view a full-color video, realized as augmented reality. We aimed to evaluate the efficacy of the LEW to enhance the vision of individuals with corneal diseases., Design: Prospective, randomized, crossover clinical trial., Participants: We examined the retinal projection glasses in 21 patients (25-69 years) with VI (0.7 logarithm of the minimum angle of resolution [logMAR] or worse) resulting from corneal diseases. Patients with comorbidities that impact vision, such as retinal disorders, were excluded., Methods: Standardized measurements of visual acuity (VA) for near vision (NV) and distance vision (DV) were conducted using ETDRS charts with the respective best correction (BC) and then with LEW. In addition reading speed, vision-related quality of life (QoL) and capacity to carry out daily tasks were assessed at an initial visit and at 2 subsequent visits after a home phase with and without the device. Six weeks after last use of the LEW, an ophthalmologic examination including spectral-domain-OCT or full-field-electroretinography was conducted and compared with baseline findings to evaluate the safety of the device. Four patients participated and completed a subsequent 12-month follow-up phase., Main Outcome Measures: Improvement of VA using the LEW. Secondary objectives included safety, reading speed, QoL, and usability in daily activities., Results: The mean VA in patients with VI was improved by 0.43 logMAR in DV using the LEW compared with BC (P < 0.0001). Using the ×2 magnification mode of the LEW resulted in an average improvement of 0.66 logMAR compared with BC (P < 0.0001). In NV, an increase of 0.47 logMAR was achieved compared with BC (P < 0.0001). Although only 4 of 21 participants were able to read with BC, 17 of 21 participants were able to read with the LEW. Quality of life significantly improved in the 17 participants who completed all visits., Conclusions: We demonstrated that the retinal projection glasses resulted in enhanced VA for all participants by directly projecting images onto the intact retina. In future, the LEW could represent a new option as an LVA for patients with corneal diseases. No pathological alterations were observed in the safety assessments., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate the midterm results of tumour resection with or without adjunctive therapy for ocular surface squamous neoplasia of the fornix, including conjunctival reconstruction with buccal mucosa and amniotic membrane., Methods: A retrospective case-series analysis including slit-lamp examination, photographic documentation, and biopsy results (repeated when clinical findings changed). Analysis centred on eye function, complications, additional procedures, and recurrence rate. Surgical technique included tumour resection and subsequent reconstruction of lost conjunctiva with buccal mucosa and amniotic membrane., Results: We included 83 affected eyes from 76 patients (mean age, 63.10 ± 14.45 years; 34 females) seen over a mean follow-up period of 26.56 ± 21.17 months. We achieved bulbus oculi salvage in 82 eyes (98.79%) and typically preserved visual acuity (mean 0.2 ± 0.5 logMAR and 0.3 ± 0.5 logMAR at presentation and last follow-up, respectively). Moreover, only 23 patients (27.71%) required corrective surgery for clinically relevant complications. The main complications included symblepharon (9.64%; n = 8), cicatricial ectropion (9.64%; n = 8), pannus (9.64%; n = 8), and corneal decompensation (8.43%; n = 7). Local tumour recurrence was seen in 23 patients (27.71%)., Conclusions: These midterm results confirm the efficacy of conjunctival reconstruction with amniotic membrane and buccal mucosa after resection of ocular surface squamous neoplasia from the fornix with palpebral and bulbar conjunctiva involvement. We not only achieved good tumour control and organ salvage with high levels of organ preservation but we also achieved good functional outcomes and acceptable recurrence rates. All clinically significant complications could be corrected in separate procedures., (Copyright © 2022 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Irradiation with electrons is the primary treatment regime for localized conjunctival low-grade lymphomas. However, radiation-induced cataracts are a major cause of treatment-related morbidity. This study investigates whether lens-sparing electron irradiation produces sufficient disease control rates while preventing cataract formation. All consecutive patients with strictly conjunctival, low-grade Ann Arbor stage IE lymphoma treated with superficial electron irradiation between 1999 and 2021 at our department were reviewed. A total of 56 patients with 65 treated eyes were enrolled with a median follow-up of 65 months. The median dose was 30.96 Gy. A lens-spearing technique featuring a hanging rod blocking the central beam axis was used in 89.2% of all cases. Cumulative incidences of 5- and 10-year infield recurrences were 4.3% and 14.6%, incidences of 5- and 10-year outfield progression were 10.4% and 13.4%. We used patients with involvement of retroorbital structures treated with whole-orbit photon irradiation without lens protection-of which we reported in a previous study-as a control group. The cumulative cataract incidence for patients treated with electrons and lens protection was significantly lower ( p = 0.005) when compared to patients irradiated without lens protection. Thus, electrons are an effective treatment option for conjunctival low-grade lymphomas. The presented lens-sparing technique effectively prevents cataract formation.

Retinoblastoma (RB) is the most common form of eye cancer experienced in childhood. Its aggressive malignancy is associated with excellent survival rates in high-income countries; however, the prognosis in third-world countries is less favorable. Early diagnosis can maximize the patient's visual outcomes and their survival rate. Therapy should be conducted in highly specialized treatment centers. Intravenous chemotherapy (IVC) in bilaterally affected children currently forms the majority of therapy. Local destructive procedures and local chemotherapies such as intra-arterial chemotherapy (IAC) or intravitreal chemotherapy can be taken into consideration depending on the extent and size of the tumor. Nonetheless, children and parents remain under constant stress, revisiting doctors for medical treatment and fearing vision loss and even enucleation of the eye. Adequate molecular patient stratification to improve targeted therapy is still lacking. This retrospective study analyzed formalin-fixed paraffin-embedded specimens from a cohort of 21 RB samples. A total of 11 of those samples showed undifferentiated retinoblastoma (URB) histopathological risk features, and the other 10 showed differentiated retinoblastoma (DRB) histopathological grading. RNA from all samples was isolated and analyzed via digital gene expression patterns. Conductors of cell survival and DNA repair were dominant in the DRB samples. In contrast, the agents responsible for cell-cycle progression and apoptosis were overexpressed in URB samples. Our work reveals the importance of molecular mechanisms within the immune system subjected to histologic subtypes of RB, providing more detailed background on their genetic behavior. This is of great interest for therapeutic strategies, such as targeted immune- and gene-based therapies, for retinoblastoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Al-Ghazzawi, Wessolly, Dalbah, Ketteler, Kiefer, Bechrakis, Leyla, Ting, Biewald and Mairinger.)

Purpose: Ocular surface squamous neoplasia (OSSN) has a high recurrence rate if only treated with surgical excision, especially in cases with positive excision margins. To reduce recurrence, we used brachytherapy after surgical excision for limbal and bulbar lesions in addition to chemotherapy/immunotherapy, cryotherapy, or external beam radiotherapy as adjunctive or primary therapies., Methods: Nine eyes with isolated OSSN lesions were included in the study. Adjunctive brachytherapy with Ruthenium 106 -plaques was administered. The follow-up included regular biomicroscopic slit-lamp examination and photo-documentation. Additionally, a staging check for metastasis was performed in cases with squamous cell carcinoma (SCC)., Results: The average age of patients at the time of presentation was 66 ± 12 years. Follow-up time was 52.8 ± 44.6 months. The maximal tumour base varied between 3 and 28 mm. SCC was confirmed by histology in all cases. No recurrences were recorded during the follow-up, and organ salvage and eye function preservation were achieved. Radiotherapy-induced complications included secondary glaucoma (n = 1) and scleral melting (n = 1). Other complications, such as radiogenic retinopathy, were not observed., Conclusion: Brachytherapy with Ruthenium 106 -plaques offers an additional option for adjunct treatment of limbal and bulbar OSSN presenting with only a focal spread. Organ salvage can be achieved with a low complication rate and recurrence-free survival. This technique offers globe salvage in patients with tumours involving intraocular infiltration., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Severity of Graves' orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO., Methods: We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio's for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models., Results: We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave's disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO., Discussion: Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oeverhaus, Winkler, Stähr, Daser, Bechrakis, Stöhr, Chen and Eckstein.)

Our purpose was to assess response after ablation of thyroid remnants (ATR) with radioactive iodine therapy in patients with unstable Graves' orbitopathy (GO) after subtotal thyroidectomy. Methods: Thirty patients with mild ( n = 4, 13%), moderate-to-severe ( n = 25, 83%), or very severe GO ( n = 1, 3%) were analyzed in this retrospective study. The primary endpoint was the improvement of GO-related symptoms as assessed by clinical activity scores, NOSPECS, and soft-tissue inflammation scores at 3 and 12 mo after ATR. Ablation success was defined by a decrease in 99m Tc uptake on thyroid scintigraphy, remnant volume, and thyrotropin receptor antibody levels at 3 mo after ATR. Results: Twelve months after ATR, clinical activity scores, NOSPECS, and soft-tissue inflammation scores showed a significant decrease from 3.4 to 1.3 ( P < 0.0001), 5.9 to 4.9 ( P = 0.007), and 4.7 to 2.1 ( P = 0.0001), respectively. The GO was inactive in 27 of the 30 (90%) patients after 3 mo and in 29 (97%) after 12 mo. No new activation of GO occurred. Remnant volume (1.4 vs. 0.4 cm 3 , P = <0.0001), mean thyrotropin receptor antibody level titer (19.02 vs. 13.37 IU/L, P < 0.0001), and 99m Tc uptake (0.5% vs. 0.1%; n = 12; P = 0.04) decreased significantly until 3 mo after ATR. Discussion: Radioactive iodine therapy after thyroidectomy can successfully ablate residual thyroid remnants, leading to an improvement in GO, a reduction in inflammatory activity, and stabilization of thyroid function. Thus, scintigraphy should be considered for patients with unstable GO after thyroidectomy to rule out thyroid remnants., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

We systematically analyzed the kinetics of tumor regression, the impact of residual lesions on disease control and the applicability of the Lugano classification in follow-up MRI of orbital non-Hodgkin lymphomas that were irradiated with photons. We retrospectively analyzed a total of 154 pre- and post-irradiation MRI datasets of 36 patients with low-grade, Ann-Arbor stage I, orbital non-Hodgkin lymphomas. Patients with restricted conjunctival involvement were excluded. Lymphoma lesions were delineated and volumetrically analyzed on T1-weighted sequences. Tumor residues were present in 91.2% of all cases during the first six months after treatment. Volumetric partial response rates (> 50% volume reduction) were 75%, 69.2%, and 50% at 12-24 months, 36-48 months and > 48 months after the end of treatment. The corresponding complete response (CR) rates according to the Lugano classification were 20%, 23.1% and 50%. During a median clinical follow-up of 37 months no significant differences in progression free survival (PFS) rates were observed between the CR and non-CR group (p = 0.915). A residual tumor volume below 20% of the pretreatment volume should be expected at long-term follow-up beyond one year after radiotherapy., (© 2023. The Author(s).)

We assessed the long-term outcomes and treatment-related adverse effects of patients with Stage I, "orbital-type" lymphomas that were uniformly treated with photons. All consecutive patients diagnosed with low-grade, Ann Arbor Stage IEA orbital lymphoma treated between 1999 and 2020 at our department were retrospectively reviewed. We excluded patients with exclusive conjunctival involvement, typically treated with en face electrons. In order to quantify radiotherapy related side effects we applied the CTCAE criteria, analyzed changes in visual acuity, quantified dry eye symptoms by use of the Ocular Surface Disease Index (OSDI) score and applied the EORTC QLQ-C30 questionnaire for quality of life (QoL) assessment. In total 66 eyes of 62 patients were irradiated with a median dose of 30.6 Gy. The median follow-up was 43.5 months. The predominant histological subtype were MALT lymphomas. No local failure occurred in this cohort. Of nine outfield relapses, six solely occurred in the contralateral eye. The 5- and 10- years distant progression free survival rates (PFS) were 81.4% and 63.5%. The 5- and 10-years overall survival rates were 85.1% and 71.9% without any tumor related death. Of the acute toxicities none was higher than CTCAE grade 1. The predominant late toxicities were dry eyes (21.2%) of CTCAE Grade <2 and radiation induced cataracts (19.7%). During long-term follow up the average visual acuity did not deteriorate. The global QoL was worst before treatment and improved significantly after 24 months (p = 0.007). External beam radiotherapy of "orbital-type" lymphomas with photons is an effective and gentle treatment option with excellent local control rates. From the high control rates the trend to use slightly lower total doses of 24-27 Gy with conventional fractionation is supported. As non-coplanar radiotherapy techniques improved and total doses can slightly be reduced, the current status of radiotherapy as first line therapy is provided., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are currently treated with non-specific immunosuppressive agents based on non-randomized, uncontrolled studies. Therefore, relapses and prolongated courses are common and remain challenging. For a more specific therapy, a better understanding of the underlying pathophysiology is crucial. Therefore, we aimed to analyze signaling pathways to expand the knowledge on the pathophysiology and possibly identify specific targets in the future, as occurred recently in Graves' orbitopathy with the IGF-1 receptor. Furthermore, we analyzed potential mechanisms for the described potential progression to orbital MALT (mucosa-associated lymphoid tissue) lymphoma. The investigation cohort for this screening study comprised of 12 patients with either typical NSOI (n = 6), IgG4-ROD or MALT lymphoma (n = 3 each). Mean age was 56.4 ± 17 years. MALT samples, in contrast with IgG4-ROD and NSOI, showed overall upregulation for extracellular matrix receptor interaction (ECM) and adipocytokine signaling. Investigating signaling compounds for MALT samples, differentially expressed genes were re-identified as targets with relevant expression. Even though pathway analysis showed differentially altered products when comparing IgG4-ROD with MALT, main conductors of differentiation in B- and T-cell signaling were commonly altered when observing the microenvironment of examined tissues. Our data reveal the characteristic differences and similarities in genetic-expression-based pathway profiles between MALT lymphoma, IgG4-ROD and NSOI, which may be useful for elucidating the associated pathogenic mechanisms and developing specific treatments for these orbital diseases.

The main objective of this prospective observational study was the characterization of the feasibility and early outcome of image-guided (IG) volumetric modulated arc (VMAT) radiosurgery (SRS) followed by resection for patients with large intraocular melanoma. Our study included consecutive patients with unfavorable-risk melanoma, enrolled in an ophthalmic oncology center. IG-VMAT-SRS was applied by high-resolution 4D image guidance and monitoring. Current stereotactic technique parameters were evaluated for comparison. Side effects and eye function, based on a 5-point CTC assessment score, were quantified. In patients with tumors located more than 0.7-1 mm apart from the optic nerve, partial to complete volume-sparing of the optic nerve head could be achieved. In 95.5% of this subgroup, the vitality of the optic nerve and vision could be preserved by the multimodality-treatment approach (mean follow-up: 18 months (7.5-36 months)). The advanced technology of stereotactic radiotherapy demonstrated the achievability of steep dose gradients around the high-dose volume, with 4D-IG-VMAT dose application. These results enforce IG-VMAT-SRS followed by resection as one of the major therapeutic options for patients with large intraocular melanoma. The combination of 4D-IG high-precision SRS and resection provides an effective treatment for large intraocular melanoma, with few side effects, and enables an eye bulb and even vision preserving modus operandi.

Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene expression analysis to differentiate orbital autoimmune diseases and elucidate genetic overlaps. First, we established a database of NSOI, relapsing NSOI, IgG4-ROD and MALT lymphoma patients of our orbital center (2000−2019). In a consensus process, three typical patients of the above mentioned three groups (mean age 56.4 ± 17 years) at similar locations were selected. Afterwards, RNA was isolated using the RNeasy FFPE kit (Qiagen) from archived paraffin-embedded tissues. The RNA of these 12 patients were then subjected to gene expression analysis (NanoString nCounter®), including a total of 1364 target genes. The most significantly upregulated and downregulated genes were used for a machine learning algorithm to distinguish entities. This was possible with a high probability (p < 0.0001). Interestingly, gene expression patterns showed a characteristic overlap of lymphoma with IgG4-ROD and NSOI. In contrast, IgG4-ROD shared only altered expression of one gene regarding NSOI. To validate our potential biomarker genes, we isolated the RNA of a further 48 patients (24 NSOI, 11 IgG4-ROD, 13 lymphoma patients). Then, gene expression pattern analysis of the 35 identified target genes was performed using a custom-designed CodeSet to assess the prediction accuracy of the multi-parameter scoring algorithms. They showed high accuracy and good performance (AUC ROC: IgG4-ROD 0.81, MALT 0.82, NSOI 0.67). To conclude, genetic expression analysis has the potential for faster and more secure differentiation between NSOI and IgG4-ROD. MALT-lymphoma and IgG4-ROD showed more genetic similarities, which points towards progression to lymphoma.

Purpose: To compare the efficacy and safety of PreserFlo™ MicroShunt (Santen, Osaka, Japan) combined with phacoemulsification to PreserFlo™ MicroShunt as a standalone procedure in eyes with moderate to advanced open-angle glaucoma., Methods: In an observatory, prospective, clinical study, 30 patients (30 eyes) with moderate to advanced angle glaucoma were allocated to either PreserFlo™ MicroShunt combined with phacoemulsification (15 eyes; Group A) or PreserFlo™ MicroShunt as a standalone procedure (15 eyes; Group B). The follow-up time of the study was 12 months., Results: Average intraocular pressure (IOP) at 12 months was 11.62 ± 1.6 mmHg in Group A and 13.8 ± 3.6 mmHg in Group B, which was significantly lower than baseline IOP (Group A: 23.47 ± 8.99 mmHg, P < 0.001; Group B: 23.4 ± 8.68 mmHg, P < 0.001). The absolute reduction of IOP within the 12 postoperative months was not significantly different between the two groups ( P = 0.056). The number of the topical medications that were administered 12 months after ocular surgery was 0 in Group A and 0.6 ± 0.8 in Group B, compared to 3.13 ± 1.02 in Group A ( P < 0.001) and 2.4 ± 1.45 in Group B ( P = 0.004) at baseline. Phacoemulsification combined with PreserFlo™ MicroShunt significantly reduced the number of antiglaucoma agents after 12 months compared to the standalone procedure ( P = 0.026). One eye in Group A was referred for bleb revision due to bleb fibrosis and a consequent acute postoperative rise in IOP. One eye in Group A required transscleral cyclophotocoagulation with MicroPulse ® laser. One bleb revision was also necessary in Group B at the 4 th postoperative week. Endothelial cell density did not significantly change over 12 months in either group (Group A: baseline, 2017.3 ± 346.8 cells/mm [2] ; 12 months, 1968.5 ± 385.6 cells/mm [2] ; P = 0.38; Group B: baseline, 2134.1 ± 382.6 cells/mm [2] ; 12 months, 2094.4 ± 373.3 cells/mm [2] , P = 0.42). The PreserFlo™ MicroShunt combined with phacoemulsification produced higher absolute success rates after 12 months in patients with moderate to advanced open-angle glaucoma than the PreserFlo™ MicroShunt as standalone procedure (Group A: 80% and Group B: 60%, P = 0.022)., Conclusions: In eyes with moderate to advanced open-angle glaucoma, PreserFlo™ MicroShunt with or without phacoemulsification is effective in reducing IOP and the number of the antiglaucoma agents with a very small incidence of complications and subsequent glaucoma surgeries. However, adding phacoemulsification to PreserFlo™ MicroShunt successfully reduces IOP without the need for ongoing topical medications as are needed after the standalone procedure., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Current Ophthalmology.)

Background: Graves' orbitopathy (GO) is an autoimmune-driven manifestation of Graves' disease (GD) where pathogenic autoantibodies to the thyrotropin receptor (TSHR) activate orbital fibroblasts/preadipocytes in the orbital tissue to induce inflammation and extracellular matrix deposition. Since there are significant limitations to study immunological and proinflammatory mediator expression in early and during disease progression in GO patients, we used our experimental mouse model to elucidate early pathogenic processes. Methods: We have developed a robust mouse model of GD/GO induced by electroporation immunization of plasmid encoding human TSHR A-subunit, comprising multiple injections over a course of 15 weeks to fully recapitulate the orbital pathology. In this study, we investigated kinetics of GO development in the model by serial analyses of immunological and cellular parameters during course of orbital inflammation. Results: Pathogenic anti-TSHR antibodies with thyroid-stimulating properties developed early after the second immunization step with concomitant induction of hyperthyroidism. Examination of orbital tissue showed an early wave of macrophage infiltration followed subsequently by CD3 + T cells into the orbital tissue. Examination of antigen-specific T cell activity using recombinant human A-subunit protein showed high CD8 + T cell proliferation during this early phase of disease onset, whereas effector CD4 + T cells and CD25 + FOXP3 + regulatory T cells (Tregs) were downregulated. The early phase of disease was also characterized by abundant presence of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Moreover, as the disease progressed, there was significant increase in browning of orbital fat tissue, which may be dependent on the proinflammatory milieu and/or the increased thyroid hormone levels during the established hyperthyroid status. Conclusions: This work revealed early infiltration of macrophages in the orbital region and induction of pathogenic anti-TSHR antibodies during disease onset in the model. This was followed subsequently by influx of CD8 + T cells specific for TSHR coupled with reduction in Tregs and substantial increase in brown adipose tissue. These new insights into the development of orbital inflammation in the model have implications for testing new therapeutic regimens by targeting macrophage function during early phases of orbital inflammation in the model.

Purpose: Currently, therapeutic management of patients with Graves' orbitopathy (GO) relies on clinical assessments and MRI. However, monitoring of inflammation remains difficult since external inflammatory signs do not necessarily represent the orbital disease activity. Therefore, we aimed to evaluate the diagnostic value of 18 F-FDG-PET/MRI to assess the inflammation of GO patients., Methods: Enrolled patients with new onset of GO underwent ophthalmological examinations to evaluate the activity (CAS) and severity of GO (NOSPECS), as well as an 18 F-FDG-PET/MRI (Siemens Biograph mMR) with dual time point imaging (immediately post-injection and 60 min p.i.). A subset of PET parameters including maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis (TLG) were obtained separately per eye and per extraocular eye muscle (EOM). EOM thickness was measured on the co-registered MRI., Results: Of 14 enrolled patients, three showed mild, seven moderate-to-severe, and four sight-threatening GO. Patients with severe GO showed statistically significant higher TLG than patients with mild GO (p = 0.02) and higher MTV than patients with mild (p = 0.03) and moderate (p = 0.04) GO. Correlation between NOSPECS on one hand and MTV and TLG on the other was significant (R 2  = 0.49-0.61)., Conclusion: TLG and MTV derived from FDG-PET appear to be good discriminators for severe vs. mild-to-moderate GO and show a significant correlation with NOSPECS. As expected, PET parameters of individual eye muscles were not correlated with associated eye motility, since fibrosis, and not inflammation, is mainly responsible for restricted motility. In conclusion, 18 F-FDG-PET/MRI can be used for assessment of GO inflammation., (© 2021. The Author(s).)

Background: Glaucoma can cause corneal decompensation and accelerate the failure of the graft. Previous antiglaucoma operations are one of the most important risk factors for endothelial failure., Methods: In this retrospective study, 40 eyes of 40 glaucoma patients with advanced corneal decompensation after glaucoma surgery were treated with keratoplasty and outcomes were assessed for 24 months., Results: 16, 9 and 15 eyes underwent Descemet Membrane Endothelial Keratoplasty (DMEK), Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) and penetrating keratoplasty (pKPL), respectively. Visual acuity improved at least 2 lines in 24 of 40 eyes after the three types of keratoplasty. All 40 eyes remained pain free for the follow-up period. The mean intraocular pressure (IOP) difference was not significantly different (p > 0.05) from the preoperative values 12 and 24 months after keratoplasty. The endothelial cell density of the donor cornea decreased from 2485.6 ± 165.18 to 1291.4 ± 467.1 and 1180.4 ± 397.2/mm 2 (p < 0.001) after 12 and 24 months, respectively. Nine eyes (22.5%) had therapy-resistant corneal decompensation in the context of a transplant failure and were treated with a re-keratoplasty (2 re-pKPLs, 3 re-DSAEKs and 3 re-DMEKs)., Conclusions: Eyes with previous glaucoma surgery show satisfying results after keratoplasty, mainly DMEK and pKPL., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The aim of the study was to investigate the use of serial measurements of TSH-receptor autoantibodies (TRAb) with the newest available assay technology to predict the course of Graves' Orbitopathy (GO) during the first 24 months from disease onset. Serial serum samples from patients with GO (103 mild/135 severe) were collected between 2007 and 2017 and retrospectively analyzed. The course of GO were classified into mild/severe 12 months after manifestation (severe: NOSPECS≥5; mild<5). TRAb were measured with automated binding immunoassays (IU/l): TRAb Elecsys (Cobas, Roche), TRAb bridge assay (IMMULITE, Siemens), and a cell-based bioassay (percent of specimen to reference ratio - SRR%) (Thyretain, Quidel). Variable cut off levels of measured TRAb were calculated at specificity of 90% from receiver operator curve (ROC) analysis for several timepoints during the course of GO. To select one: 5-8 months after first GO symptoms, which is the timepoint for usual referals for treatment mild course could be predicted at cut offs of 1.5 IU/l (Elecsys), 0.8 IU/l (Immulite) and 402% SRR (Thyretain) and the risc of severe course has to be anticipated if TRAb are above 11.6 IU/l (Elecsys), 6.5 IU/l (Thyretain), and 714% SRR (Thyretain). The Thyretain bioassay showed the highest diagnostic sensitivity (using the commercial cut off's) over the entire follow up period. TRAb measurements during the 24-month follow up of GO provide added value to the GO clinical activity and severity scores and should be used especially in the event of an unclear decision-taking situation with regard to therapy., Competing Interests: M.S., M.O., D.Z., L.M., A.S., N.B., D.F., U.B.P., J.P.B, S.P. and A.E. have nothing to disclose. S.L. consults for Quidel., (Thieme. All rights reserved.)

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.

The aim of this study was to investigate the potential of the new TSH-receptor antibody (TRAb) assays to predict remission or relapse of hyperthyroidism in patients with Graves' disease (GD) and Graves' orbitopathy (GO). TRAbs were measured retrospectively in sera from a cohort of GD patients with GO (n=117; remission n=38 and relapse n=79-Essen GO biobank) with automated binding immunoassays: TRAb Elecsys (Cobas Roche) and TRAb bridge assay (IMMULITE, Siemens), and the TSAb (thyroid stimulating Ab) cell-based bioassay (Thyretain, Quidel Corp.). To identify relapse risk/remission of hyperthyroidism patients were followed up at least 10 months after the end of antithyroid drug therapy (ATD) therapy. ROC plot analysis was performed to calculate cut-off levels of TRAb and TSAb for prediction of relapse and remission of hyperthyroidism. Cut-off serum levels are provided for timepoints around 3, 6, 10, and 15 months after the beginning of ATD. Repeated measurements of TRAb increase the rate of relapses predictions to 60% (Elecsys), 70% (IMMULITE), and 55% (Thyretain). Patients with remission have consistently TRAb levels below the cut off for relapse in repeated measurements. The cell-based bioassay was the most sensitive - and continued to be positive during follow up [at 15 months: 90% vs. 70% (IMMULITE) and 65% (Elecsys)]. Identification of relapsing hyperthyroidism is possible with automated immunoassays and cell-based bioassay especially with serial TRAb measurements during the course of ATD therapy. Patient who need eye surgery may profit from an early decision towards definitive treatment., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: This study aims to determine local diagnostic reference levels (LDRLs) of intra-arterial chemotherapy (IAC) procedures of pediatric patients with retinoblastoma (RB) to provide data for establishing diagnostic reference levels (DRLs) in pediatric interventional radiology (IR)., Methods: In a retrospective study design, LDRLs and achievable dose (AD) were assessed for children undergoing superselective IAC for RB treatment. All procedures were performed at the flat-panel angiography systems (I) ArtisQ biplane (Siemens Healthineers) and (II) Allura Xper (Philips Healthcare). Patients were differentiated according to age (A1: 1-3 months; A2: 4-12 months; A3: 13-72 months; A4: 73 months-10 years; A5: > 10 years), sex, conducted or not-conducted chemotherapy., Results: 248 neurointerventional procedures of 130 pediatric patients (median age 14.5 months, range 5-127 months) with RB (68 unilateral, 62 bilateral) could be included between January 2010 and March 2020. The following diagnostic reference values, AD, and mean values could be determined: (A2) DRL 3.9 Gy cm 2 , AD 2.9 Gy cm 2 , mean 3.5 Gy cm 2 ; (A3) DRL 7.0 Gy cm 2 , AD 4.3 Gy cm 2 , mean 6.0 Gy cm 2 ; (A4) DRL 14.5 Gy cm 2 , AD 10.7 Gy cm 2 , mean 10.8 Gy cm 2 ; (A5) AD 8.8 Gy cm 2 , mean 8.8 Gy cm 2 . Kruskal-Wallis-test confirmed a significant dose difference between the examined age groups (A2-A5) (p < 0.001). There was no statistical difference considering sex (p = 0.076) and conducted or not-conducted chemotherapy (p = 0.627). A successful procedure was achieved in 207/248 cases., Conclusion: We report on radiation exposure during superselective IAC of a pediatric cohort at the German Retinoblastoma Referral Centre. Although an IAC formally represents a therapeutic procedure, our results confirm that radiation exposure lies within the exposure of a diagnostic interventional procedure. DRLs for superselective IAC are substantially lower compared with DRLs of more complex endovascular interventions.

Purpose: We conducted this trial to investigate a new wearable laser-eyewear (LEW). Images of an integrated camera are projected to the retina by a RGB-Laser (<1µW) and MEMS-mirror system. This enables a full-color live video as augmented reality embedded in the field of vision of the wearer. Thin parallel laser beams are projected following the principle of Maxwellian view through the center of the ocular lens to ensure independency of refractive errors. We performed a study with healthy subjects to test this independency., Materials and Methods: LEW was tested in 20 healthy subjects (aged between 21 and 60 years) with hyperopia, myopia, astigmatism and/or presbyopia. Subjects underwent standardized visual acuity (VA) measurements (ETDRS) without any correction, with LEW and with best correction., Results: We found no significant correlation between refraction and VA while using LEW in linear regression (r=0.17). Still, younger participants performed better in terms of VA with the device compared to older participants despite no differences in BCVA (p<0.01). The achievable VA with LEW was in general reduced compared to uncorrected VA (0.50 vs 0.40 logMAR). Only myopic subjects reached a significantly higher VA using LEW (p<0.001). Presbyopic subjects showed enhanced near VA (0.25 logMAR) by reading at 15cm with LEW without any further necessary refractive correction. Nearly all patients (80%) showed stereopsis without need for additional adjustments., Conclusion: Our investigation could verify the independence of LEW of refractive errors. Therefore, the technology seems to be especially useful in patients with untreatable corneal conditions, e.g., after corneal burns, to achieve higher VA since the thin laser should penetrate even corneal opacities with less scattering., Competing Interests: M. Stöhr, D. Dekowksi, N. Bechrakis, J. Esser and M. Oeverhaus state that they have no conflicts of interest. A. Eckstein received funds as medical advisor for QD Laser Inc, reports grants from QD Laser outside the submitted work, and reports no other potential conflicts of interest for this work., (© 2020 Stöhr et al.)

Objective: Previous studies provided evidence that gadolinium can be found in the aqueous chamber (AC) of the eye several hours post injection (p.i.) of gadolinium-based contrast agents (GBCAs). This study aimed to investigate whether gadolinium can be detected promptly after injection of a macrocyclic GBCA on contrast-enhanced T1-weighted MRI in the AC of children., Methods: This retrospective study encompassed MRI of 200 healthy eyes of children suffering from retinoblastoma of the contralateral eye. MRI was performed with an orbital coil with the children in a state of general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between pre and post contrast-enhanced T1-weighted images (Dotarem®, Guerbet, 0.1 ml/kg body weight, mean (standard deviation) p.i. time = 12:24 (± 2:31) min)., Results: A highly significant signal intensity increase was found in the AC of healthy eyes 12 min after GBCA injection (median ∆SIR (interquartile range) = + 0.08 (0.05-0.12), p < 0.0001). In addition, gadolinium enhancement showed a strong negative correlation with children's age in multivariate analysis with adjustment for p.i. time (p < 0.0001)., Conclusions: GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between patient age and GBCA enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC., Key Points: • Leakage of gadolinium-based contrast agent into the aqueous chamber of infantile eyes was found promptly after intravenous injection (p < 0.0001). • Gadolinium enhancement of the anterior eye chamber was negatively correlated with the children's age (p < 0.0001).

Purpose: to explore whether the NK1 and Y2 receptors are involved in the pathogenesis of laser-induced CNV (choroidal neovascularization) in C57Bl/6N mice., Methods: CNV was induced by laser damage of Bruch's membrane and the CNV volume was determined by OCT and/or flatmount preparation. First, the development of the CNV volume over time was evaluated. Second, the CNV development in NK1- and Y2 KO mice was analyzed. Third, the effect on the development as well as the regression of CNV by intravitreal injections of the NK1 antagonist SR140333 and the Y2 antagonist BIIEO246 separately and each in combination with Eylea ® , was investigated. Furthermore, flatmount CNV volume measurements were correlated to volumes obtained by the in vivo OCT technique., Results: CNV volume peak was observed at day 4 after laser treatment. Compared to wild type mice, NK1 and Y2 KO mice showed significantly smaller CNV volumes. Eylea ® and the Y2 antagonist significantly reduced the volume of the developing CNV. In contrast to Eylea ® there was no effect of either antagonist on the regression of CNV, additionally no additive effect upon combined Eylea ® /antagonist treatment was observed. There was a strong positive correlation between CNV volumes obtained by OCT and flatmount., Conclusion: NK1 and Y2 receptors mediate the development of laser-induced CNVs in mice. They seem to play an important role at the developmental stage of CNVs, whereas VEGF via VEGF receptor may be an important mediator throughout the CNV existence. In vivo OCT correlates with flatmount CNV volume, representing a useful tool for in vivo evaluations of CNV over time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To validate a staging system for metastatic uveal melanoma that will facilitate planning, reporting, and interpreting the results of clinical trials., Design: Reliability and validity study., Methods: The performance index, the largest diameter of the largest metastasis and alkaline phosphatase level at the time of diagnosis of metastases, and overall survival of 249 patients from 7 ocular oncology centers who died of dissemination were analyzed. Predicted median survival time calculated according to the Helsinki University Hospital Working Formulation was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of ≥12, <12-6, and <6 months, respectively. The predictions were compared against observed survival., Results: The 3 variables used to assign stage were independent predictors of survival in the validation dataset. Of the 249 patients, 110 (44%), 109 (44%), and 30 (12%) were classified to Working Formulation stages IVa, IVb, and IVc, respectively. Corresponding median observed survival times were 18.6, 10.7, and 4.6 months and worsened by increasing stage (P < .001). Of 201 patients managed without surgical resection of metastases, 83 (41%), 89 (44%), and 29 (15%) were classified to stages IVa, IVb, and IVc, respectively, and their median observed survival times were 17.2, 10.0, and 4.6 months (P < .001). Survival of 47 patients who underwent resection did not differ by working formulation stage (P = .69)., Conclusions: This multicenter study confirms that the Working Formulation is a reliable and valid, repeatable system for dividing metastatic uveal melanoma into distinct prognostic subgroups, especially for stage-specific reporting of survival in prospective clinical trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of intravitreal injection of N-methyl-D-aspartate (NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) and the VIP-associated glial protein activity-dependent neuroprotective protein (ADNP) in the rat retina. These elements have well-documented neuroprotective properties and may thus be integrated in endogenous neuroprotective mechanisms in the retina which break down in NMDA excitotoxicity., Methods: A volume of 2 μl of 100 nmol NMDA was intravitreally injected into one eye of rats, the untreated eye served as a control. Time-dependent effects of NMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay and ELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluated by quantitative RT-PCR 20 days after NMDA injection. Topical flunarizine served to find out whether the effect of NMDA is counteracted., Results: Compared to PACAP-38, VIP levels significantly decreased on days 1, 7, 14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerable than PACAP-38-expressing cells. The expression of VIP and ADNP but not of PACAP-38 was found to be reduced, and application of topical flunarizine counteracted the decrease of VIP. BDNF levels significantly increased after days 1 and 3., Conclusion: The early upregulation of BDNF seems to act neuroprotectively and leads to a delay of ganglion cell loss. Although there is no direct evidence, the decrease of VIP and ADNP - the consequence of the presence of NMDA receptors on these peptide-expressing cells - might contribute to the breakdown of endogenous neuroprotective mechanisms given that the decrease of the VIP-related ADNP runs in parallel with the decrease of VIP. Activating and maintaining these mechanisms must be the primary aim in the therapy of diseases with retinal neuronal degeneration., (© 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.)

The aim of the study was to investigate the presence and distribution of PE-11, a peptide derived from chromogranin B, in the rat eye. For this purpose, newborn rats were injected with a single dosage of 50mg/kg capsaicin subcutaneously under the neck fold and after three months, particular eye tissues were dissected and the concentration of PE-11-like immunoreactivity was determined by radioimmunoassay. Furthermore, PE-11-like immunoreactivities were characterized in an extract of the rat eye by reversed phase HPLC. Then, the distribution pattern of PE-11 was investigated in the rat eye and rat trigeminal ganglion by immunofluorescence. As a result, PE-11 was present in each tissue of the rat eye and capsaicin pretreatment led to a 88.05% (±7.07) and a 64.26% (±14.17) decrease of the levels of PE-11 in the cornea and choroid/sclera, respectively, and to a complete loss in the iris/ciliary body complex. Approximately 70% of immunoreactivities detected by the PE-11 antiserum have been found to represent authentic PE-11. Sparse nerve fibers were visualized in the corneal and uveal stroma, surrounding blood vessels at the limbus, ciliary body and choroid and in association with the dilator and sphincter muscle. Furthermore, immunoreactivity was present in the corneal endothelium. In the retina and optic nerve, glia was labeled. In the rat trigeminal ganglion, PE-11-immunoreactivity was visualized in small and medium sized ganglion cells with a diameter of up to 30μm. In conclusion, there is unequivocal evidence that PE-11 is a constituent of capsaicin-sensitive sensory neurons innervating the rat eye and the distribution pattern is typically peptidergic in the peripheral innervation but in the retina completely atypical for neuropeptides and unique., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In a recent investigation using the NMDA-excitotoxicity model in the rat retina, we found that, whereas, following intravitreal injection of NMDA, a time-dependent decrease of the levels of a neuropeptide, namely vasoactive intestinal polypeptide (VIP), was fully counteracted by topical treatment with flunarizine eye drops, the levels of pituitary adenylate-cyclase activating peptide-38 (PACAP-38), another neuropeptide, remained unchanged. The aim of the present study was to find out if NMDA causes reduction in the levels of other neuropeptides such as secretoneurin (SN), neurokinin-A/B (NKA/NKB) and substance P (SP), and if so, whether flunarizine has the ability to counteract this effect or prevent such reduction. The reduction of the levels of SN and NKA/NKB 14 days after intravitreal injection of 2 μl of 100 nmol NMDA into one eye was more pronounced than after 7 days; topical flunarizine had a slight counteracting effect, but could not prevent the decrease in the levels of these peptides. Reduction in SP levels after 28 and 56 days was fully counteracted by flunarizine. By enabling a pronounced influx of Ca²+ ions into peptide-expressing cells, NMDA leads to cell death. Since each of these peptides exerts neuroprotective properties in the central nervous system, the drop in their levels caused by acute insult (e.g. NMDA excitotoxicity) or chronic insult (e.g. glaucoma) may cause a breakdown of endogenous neuroprotection in the retina given that these peptides feature neuroprotective properties in the retina as well., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The liver is the predominant site of metastases in the majority of patients with uveal melanoma, suggesting the evaluation of regional treatment approaches. Here we report our experience with transarterial chemoembolization (TACE) in uveal melanoma patients with pretreated liver metastases. Twenty-five patients were treated with fotemustine-based or cisplatin-based TACE after treatment failure of systemic therapy between 2003 and 2008 at our institution. Grade III toxicity consisted of gastric ulcer (n=1), fever (n=3), splenic infarction (n=1), and thrombocytopenia (n=1). No grade IV toxicity or catheter-associated complications were observed. Fourteen of 25 patients (56%) had stable disease for at least 2 months and four had partial remission. The median progression-free survival (PFS) was 3 months (95% confidence interval: 2-4 months) and the median overall survival (OS) was 6 months (95% confidence interval: 5-7 months), with 15% of patients alive at 1 year. Both PFS and OS were significantly longer, when pretreatment lactate dehydrogenase was below the two-fold upper limit of normal (n=11): PFS 5 versus 2 months (P<0.001) and OS 11 versus 5 months (P=0.012). All patients with lactate dehydrogenase less than 2xupper limit of normal had a clinically detectable benefit. TACE is well tolerated and effective in pretreated patients with liver metastases from uveal melanoma. TACE should further be evaluated as first-line therapy in prospective randomized clinical trials.

By means of highly sensitive radioimmunoassays, the levels of substance P (SP) and secretoneurin (SN) were detected in vitreous aspirates of patients with macular holes which served as controls, in patients with nonproliferative diabetic retinopathy (DR), active proliferative diabetic retinopathy (active PDR), inactive PDR, rhegmatogenous retinal detachment and proliferative vitreoretinopathy (PVR). Furthermore, SN-like immunoreactivities were characterized by reversed phase-HPLC. The concentration of SN was more than 20-fold higher in macular holes when compared with SP and reversed phase HPLC revealed evidence that the vitreous levels of SN represent authentic SN. SN was significantly decreased in patients with nonproliferative DR, active PDR and inactive PDR by more than 70% which seems to result from a reduced expression and/or secretion from the cilary epithelium and a reduced release from the retina both due to diabetes mellitus. By contrast SP was increased in rhegmatogenous retinal detachment most obviously due to an enhanced outflow of the peptide through retinal breaks. Despite their proangiogenic activities, SP and SN are unlikely to be involved in the pathogenesis of neovascularizations in DR because of their unchanged and reduced levels, respectively, but the low levels of both peptides may facilitate the regression of vasoproliferations following laser photocoagulation.

Purpose: The purpose of this work was to evaluate the characteristic appearance of untreated retinoblastoma on a large sample in comparison to the histological findings after therapeutical enucleation., Materials and Methods: In a prospective clinical trial 46 children with retinoblastoma in 63 affected untreated eyes were examined under general anesthesia on MRI using a 1.5-T system. The examinations were performed with a special surface coil applying an examination protocol including fast T2- and T1-weighted spin echo sequences and additional fast T1-WI after intravenous injection of Gd-DTPA in different planes. The imaging results were compared to the histopathological findings in 29 patients with 30 affected eyes., Results: Comparing MRI findings and histopathological results, optic nerve infiltration was detected with a sensitivity of 53.8% and a specificity of 82.3% on MRI, infiltration of the choroid with a sensitivity of 75.0% and a specificity of 100.0%, and the degree of tumor calcification with a sensitivity of 91.7% and a specificity of 88.9%. In this study the characteristic MR appearance of untreated retinoblastoma was evaluated., Conclusion: MRI was helpful in relevant aspects of pretherapeutical retinoblastoma staging, deficits remain regarding optic nerve infiltration.

Background: To determine the effectiveness and risk profile of combined ruthenium- (Ru)-106-brachytherapy and transpupillary thermotherapy (TTT) of the tumour apex for the treatment of large choroidal melanoma., Methods: A consecutive series of 31 large choroidal melanoma treated by Ru-106-brachytherapy and adjuvant TTT was studied. TTT was performed 1 day prior to plaque removal and up to 3 times (mean: 1.8) during follow-up. Evaluation comprised tumour regression, treatment-related adverse events, necessity of additional treatment and visual results., Results: Mean follow-up was 21.6+/-7.8 (10.8-38.3) months. Mean tumour thickness was 6.8+/-1.0 (5.0-8.9) mm prior to treatment. Mean residual tumour thickness at the end of follow-up was 2.5+/-1.0 mm. Relevant adverse treatment effects were exudative maculopathy or macula oedema (22.6%), vitreous haemorrhage (16.1%), optic neuropathy (16.1%) and retinal detachment (9.7%). One tumour recurrence occurred during follow-up, and was treated by enucleation., Conclusions: The combination of Ru-106-brachytherapy with TTT allows for the treatment of large posterior choroidal melanoma. The rate of treatment-related adverse events appears to be acceptable.

This trial was performed to define the maximum tolerated dose (MTD) of treosulfan administered in combination with a fixed dose of gemcitabine in uveal melanoma patients. Preclinical studies suggested synergistic activity against uveal melanoma. Gemcitabine (1 g/m2) and treosulfan (2.5-4 g/m2) were administered on days 1 and 8, and cycles were repeated on day 29 for a maximum of six cycles. For treosulfan, dose escalation cohorts of 2-4 patients were enrolled. An additional 25 patients were entered at treosulfan dose levels II (3 g/m2) and III (3.5 g/m2). Thirty three patients with uveal melanoma and six patients with other histologies were accrued. Side-effects were predominantly haematological. The MTD was 3.5 g/m2 of treosulfan together with 1 g/m2 of gemcitabine. In the uveal melanoma patients, one partial response (PR) and 15 stablisations of disease (SD) were recorded and whether this translates into a survival gain should be explored further.

Aim: To determine prognostic factors for recurrence of disease and tumour related mortality in patients with conjunctival melanoma., Methods: A retrospective analysis of clinical and histopathological data of 69 patients with histologically verified conjunctival melanoma., Results: As univariate analysis showed, significant risk factors for the development of recurrence were: irregular pigmentation (RR = 2.0, p = 0.0007), incomplete surgical excision (RR = 3.5, p = 0.008), tumour invasion deeper than in substantia propria (RR = 3.9, p = 0.008), and presence of epithelioid tumour cells (RR = 2.9, p = 0.05). For tumour related mortality a significantly increased risk was found for tumour location in palpebral conjunctiva, caruncle, plica, or fornices (RR = 5.9, p = 0.001), for tumour infiltration deeper than the substantia propria (RR = 5.5, p = 0.001), for incomplete surgical excision (RR = 4.4, p = 0.05), and for nodular or mixed (nodular and superficial) growth pattern of the tumours (RR = 1.2, p = 0.002). The use of an adjuvant therapy for the surgical excision of the melanomas had no statistically significant influence upon the development of recurrent disease nor upon the tumour related mortality., Conclusion: These data present similar clinical and histopathological risk factors for patients with conjunctival melanoma as reported previously. The present study also addresses the failure of retrospective studies on conjunctival melanoma to prove the efficacy of a supplementary therapy to surgical excision.

Background/aims: A checkpoint mechanism in late G1, whose regulation via loss of retinoblastoma protein (pRB) or p16, or overexpression of cyclin D1 or cyclin dependent kinase 4 (CDK4), has been proposed to constitute a common pathway to malignancy. The aims of this study were (a) to compare markers of cell cycle G1-S phase transition in an intraocular tumour with known pRB deficiency (retinoblastoma) and compare it with one with an apparently functional pRB (uveal melanoma); (b) to determine if one of these markers may have a role in the pathogenesis of uveal melanoma; and (c) to determine if there is a difference in cell cycle marker expression following treatment of uveal melanoma and retinoblastoma., Methods: 90 eyes were enucleated from 89 patients for retinoblastoma (n = 24) or for choroidal or ciliary body melanoma (n = 66). Conventional paraffin sections were assessed for cell type and degree of differentiation. Additional slides were investigated applying standard immunohistochemical methods with antibodies specific for cyclin D1 protein, pRB, p53, p21, p16, BCL-2, and MIB-1., Results: Cyclin D1 protein and pRB were negative in retinoblastoma using the applied antibodies. In contrast, cyclin D1 protein expression was observed in 65% of uveal melanomas; a positive correlation between cyclin D1 cell positivity and tumour cell type, location, growth fraction, as well as with pRB positivity was observed. p53, p21, and p16 could be demonstrated in both tumours. An inverse relation between p53 and p21 expression was demonstrated in most choroidal melanomas and in some retinoblastomas. Apart from a decrease in the growth fractions of the tumours as determined by MIB-1, a significant difference in the expression of G1-S phase transition markers in vital areas of uveal melanoma and retinoblastoma following treatment with radiotherapy and/or chemotherapy was not observed., Conclusion: Retinoblastomas and uveal melanomas, two tumours of differing pRB status, differ also in their immunohistochemical pattern for markers of the G1-S phase transition of the cell cycle. The results of the present study support the concept of (a) an autoregulatory loop between pRB and cyclin D1 in tumours with a functional pRB and the disruption of this loop in the presence of pRB mutation, as well as (b) a checkpoint mechanism in late G1, whose regulation via loss of p16 or pRB, or overexpression of cyclin D1 constitutes a common pathway to malignancy. Further, the results raise the possibility of cyclin D1 overexpression having a role in the pathogenesis of uveal melanoma.

Background: Eye retention rates after external beam therapy for advanced retinoblastoma are close to 90% with very few ocular side effects like radiation retinopathy or radiation induced optic neuropathy. Late complications, however, comprise a sixfold increase of secondary non-ocular cancers like soft tissue sarcomas demanding alternative treatment options in the management of advanced retinoblastoma., Purpose: A phase I study on primary chemotherapy using vincristine, cyclophosphamide, etoposide and carboplatin in advanced bilateral retinoblastoma was undertaken to evaluate the potential of a treatment regimen not including external beam therapy., Patients and Methods: 12 eyes with 17 tumors in 9 children were treated with primary chemotherapy as first treatment option with a mean follow-up of 16.7 months. Planned enucleation of a tumor containing eye was performed in 2 eyes. In one of these enucleated eyes no viable tumor cells were visible on histopathological examination while in the other eye marked tumor regression was detectable. Of the remaining 10 eyes clinical regression of the intraocular tumors was present in all eyes; on average the tumor size was reduced by 50% within 3-6 weeks. Most of the tumors showed a type I (cottage cheese) regression indistinguishable from regression patterns found after external beam radiotherapy. Ancillary treatments including laser photocoagulation, beta-ray brachytherapy, external beam radiotherapy and cryotherapy were performed in 15 out of the 17 tumors., Conclusion: Based on the results of this study and on the results published by others primary chemotherapy may result in the same eye retention rate as conventional external beam therapy avoiding the unacceptable high rate of secondary non-ocular cancers in the latter. A prospective study to be undertaken by the GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) and the RG (Retinologische Gesellschaft) is planned to further evaluate this new and promising approach.

Keratoconus is a progressive, noninflammatory, nonvascular axial corneal ectasia, with unclear etiology and pathogenesis. It has a prevalence of 50-230 per 100,000 and is a bilateral disorder in up to 90% of cases. The onset of keratoconus is usually at puberty and progresses over 10-20 years producing an irregular myopic astigmatism. The treatment depends on the severity of the irregular astigmatism. Advanced keratoconus, which cannot be treated with contact lenses, requires a surgical procedure--either penetrating keratoplasty, epikeratophakia, or thermokeratoplasty. The results of penetrating keratoplasty are good, with success rates of > 90% of the cases. Recurrence of keratoconus following penetrating keratoplasty has been previously reported, based on a clinical diagnosis, and confirmed by histopathological examination. We report the clinicopathologic features of two further cases of recurrent keratoconus.