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Purpose: The German Retina.net ROP registry and its Europe‐wide successor, the EU‐ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries. Methods: Exemplary datasets from the two databases over a 1‐year period each (German Retina.net ROP Registry, 2011, 22 infants; EU‐ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments. Results: The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU‐ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti‐VEGF therapy in 2021 (86.1%). Within the anti‐VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021. Conclusion: Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti‐VEGF, and within the anti‐VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021. [ABSTRACT FROM AUTHOR]

Purpose: Reports of gene therapy-associated retinal atrophies and inflammation have highlighted the importance of preclinical safety assessments of adeno-associated virus (AAV) vector systems. We evaluated in nonhuman primates (NHPs) the ocular safety and toxicology of a novel AAV gene therapy targeting retinitis pigmentosa caused by mutations in PDE6A, which has since been used in a phase I/II clinical trial (NCT04611503)., Methods: A total of 34 healthy cynomolgus animals (Macaca fascicularis) were treated with subretinal injections of rAAV.hPDE6A and followed over 13 weeks. Three dose levels (low: 1 × 1011, intermediate: 5 × 1011, and high: 1 × 1012 vector genomes [vg]) were compared to sham-injected controls. Safety and toxicity were determined using ophthalmic examinations, electroretinography, ocular histology, and retinal imaging., Results: At the low and intermediate doses, inflammation was mild, electroretinography response was unimpeded, and histology results were in line with surgically induced changes. In contrast, three high-dose animals displayed atrophic changes of the retina and abnormalities in electroretinography, which were considered test article related and adverse., Conclusions: A single subretinal injection of up to 5 × 1011 vg was well tolerated, and a 10-fold lower dose of 5 × 1010 vg was chosen as the starting dose for the ongoing phase I/II clinical trial. Atrophic retinal changes and abnormalities in electroretinography emerged as dose-limiting findings in the high-dose cohort., Translational Relevance: This study demonstrates that treatment candidate rAAV.PDE6A was well tolerated in NHPs. Occurrence of retinal atrophy as a dose-limiting finding highlights the importance of further study into the mechanisms of atrophy induction after retinal gene therapy.

Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: N. Ferrand, S. Thaler, D. Süsskind und J.M. Rohrbach geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patient/-innen zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern/Vertreterinnen eine schriftliche Einwilligung vor. Eine Einwilligung in die Erstellung und Veröffentlichung eines Fallberichts gemäß Art. 7 Datenschutzgrundverordnung (DSGVO) liegt vor.

Purpose: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry., Design: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP., Subjects: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany., Methods: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters., Main Outcome Measures: Changes over time in demographic parameters and treatment patterns for ROP in Germany., Results: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare., Conclusions: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors., Methods: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed., Results: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated., Conclusion: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest., (© 2024. The Author(s).)

Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered a special form of primary diffuse large cell lymphoma (DLBCL) of the CNS (central nervous system) (PCNSL) and arises primary or secondary to PCNSL. According to the cell of origin (COO) classification of DLBCL, PVRL largely belongs to the activated B‑cell (ABC) type of DLBCL. Based on a recently established genetic-biological classification of DLBCL, PCNSL and thus also PVRL belong to a group of DLBCL of the MYD88/CD79B-mutated (MCD) or cluster 5 subtype, which often shows extranodal manifestations and MYD88 and CD79A mutations as well as CDKN2A deletions.PVRL diagnostics is often complicated as it represents a classic masquerade syndrome. Due to the usually limited material with often large numbers of reactive lymphocytes and/or degenerative changes in the cells, the results of diagnostic tests are difficult to interpret. Classic diagnostic tests include cytology on vitreous aspirates, immunocytochemistry, and clonality analysis.New insights into the spectrum of genetic alterations of vitreoretinal lymphomas (VRL) confirm the close relationship to PCNSL and could significantly improve pathological diagnosis. Next-generation sequencing panel-based diagnostics allow VRL diagnosis confirmation with little DNA in almost 100% of patients in cases with insufficient cytological evidence or lack of clonality detection. PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: To evaluate the standard of care, in particular the use of topical or subconjunctival interferon- α 2b, in treating ocular surface squamous neoplasia or melanocytic tumours in tertiary eye centres in Germany., Methods: A survey containing 14 questions was sent to 43 tertiary eye centres in Germany. The questions addressed the surgical and medical management of ocular surface squamous neoplasia and melanocytic tumours (primary acquired melanosis and malignant melanoma), as well as the clinical experiences and difficulties in prescribing off-label interferon- α 2b eye drops and subconjunctival injections., Results: Twenty-four tertiary eye centres responded to the survey. Eighty-three percent of centres had used interferon- α 2b in their clinical practice and 25% prescribed it as the first-line cytostatic agent following surgical excision of ocular surface squamous neoplasia, while 10% would do so for melanocytic tumours. Correspondingly, the majority of respondents selected mitomycin C as their first-line agent. Side effects were uncommon with topical interferon- α 2b eye drops but were more frequently reported after subconjunctival interferon- α 2b injections. In total, eight centres had experience with interferon- α 2b injections. The most significant obstacles perceived by ophthalmologists when prescribing interferon- α 2b were its high cost and the reimbursement thereof., Conclusion: Off-label mitomycin C was the preferred adjuvant therapy for epithelial and melanocytic tumours, with interferon- α 2b being the standard second-line option. Interferon- α 2b has predominantly been used to treat ocular surface squamous neoplasia and, to a lesser extent, melanocytic tumours at German tertiary eye centres. Following its market withdrawal, supply shortages of interferon- α 2b are likely to have a profound impact on patient care and their quality of life., Competing Interests: The authors declare that they have no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Thieme. All rights reserved.)

Metastatic uveal melanoma (UM) is a rare form of melanoma differing from cutaneous melanoma by etiology, prognosis, driver mutations, pattern of metastases and poor response rate to immune checkpoint inhibitors (ICI). Recently, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, tebentafusp, has been approved for the treatment of HLA-A*02:01 metastatic or unresectable UM. While the treatment regime is complex with weekly administrations and close monitoring, the response rate is limited. Only a few data exist on combined ICI in UM after previous progression on tebentafusp. In this case report, we present a patient with metastatic UM who first suffered extensive progression under treatment with tebentafusp but in the following had an excellent response to combined ICI. We discuss possible interactions that could explain responsiveness to ICI after pretreatment with tebentafusp in advanced UM., Competing Interests: AF served as consultant to Immunocore, Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT. AF and CS report institutional research grants from BMS Stiftung Immunonkologie. IB received speaker fees from Novartis, Bayer, Pfizer, Takeda and AstraZeneca and honoraria for advisory board participation from BMS and Novartis. The remaining 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 Reiter, Schroeder, Broche, Sinnberg, Bonzheim, Süsskind, Flatz and Forschner.)

Vitreoretinal lymphoma (VRL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) considered a variant of primary central nervous system lymphoma (PCNSL). The diagnosis of VRL requires examination of vitreous fluid, but cytologic differentiation from uveitis remains difficult. Because of its rarity and the difficulty in obtaining diagnostic material, little is known about the genetic profile of VRL. The purpose of our study was to investigate the mutational profile of a large series of primary and secondary VRL. Targeted next-generation sequencing using a custom panel containing the most frequent mutations in PCNSL was performed on 34 vitrectomy samples from 31 patients with VRL and negative controls with uveitis. In a subset of cases, genome-wide copy number alterations (CNAs) were assessed using the OncoScan platform. Mutations in MYD88 (74%), PIM1 (71%), CD79B (55%), IGLL5 (52%), TBL1XR1 (48%), ETV6 (45%), and 9p21/CDKN2A deletions (75%) were the most common alterations, with similar frequencies in primary (n = 16), synchronous (n = 3), or secondary (n = 12) VRL. This mutational spectrum is similar to MYD88mut/CD79Bmut (MCD or cluster 5) DLBCL with activation of Toll-like and B-cell receptor pathways and CDKN2A loss, confirming their close relationship. OncoScan analysis demonstrated a high number of CNAs (mean 18.6 per case). Negative controls lacked mutations or CNAs. Using cell-free DNA of vitreous fluid supernatant, mutations present in cellular DNA were reliably detected in all cases examined. Mutational analysis is a highly sensitive and specific tool for the diagnosis of VRL and can also be applied successfully to cell-free DNA derived from the vitreous., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Eye-preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce., Methods: The efficacy and side effects of two different eye-preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non-interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event-free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated., Results: The EFES after VEC (2-year EFES 72.3%) was higher than after CyVEC (2-year EFES 50.4%) (p logrank  < .001). The OES did not differ significantly between the two treatment groups (p logrank  = .77; 2-year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES (p logrank  < .0001; 2-year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES (p logrank  < .0001; 2-year OES ICRB A/B/C 93.1% vs. ICRB D/E 61.5%). The multivariate analysis showed that age at diagnosis older than 12 months and ICRB A/B/C were associated with better EFES. No second malignancies or ototoxicities were reported after a follow-up of median 3.1 years after diagnosis of retinoblastoma (range 0.1-6.9 years)., Conclusions: Despite omitting cyclophosphamide, the EFES was higher after VEC chemotherapy that contains higher doses of carboplatin compared to CyVEC. The major risk factor for enucleation was advanced ICRB tumor grouping. Randomized clinical trials on efficacy and side effects of eye-preserving chemotherapy are required to tailor treatment protocols for retinoblastoma patients., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A group of 36 UM patients with and 137 patients without metastases were included in the study. Their plasma OPN levels were measured by ELISA; serum BAFF and GDF-15 levels were determined with a Luminex MAGPIX system. Receiver operating characteristic (ROC) analysis was performed to calculate the cutoff values of the three markers for identifying the patients with metastases. The ability to identify patients with metastases was compared between the single markers and the combination as a three-marker panel. By using the Student's t -test, we also investigated the kinetic changes of the levels of BAFF, GDF-15 and OPN across six periods (i.e., 0-6 months, 6-12 months, 12-18 months, 18-24 months, >24 months and post-metastasis) before the imaging diagnosis of metastases. By maximizing the Youden's index, the serum GDF-15 level of 1209 pg/mL and the plasma OPN level of 92 ng/mL were identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. The three-marker panel offered a better performance in distinguishing patients with metastases, with an area under the curve of 0.802, than any single biomarker. Increasing trends of the levels of three biomarkers were observed in the two-year period before the imaging diagnosis of metastases. The combined panel of BAFF, GDF-15 and OPN might be a utilizable implementation for the detection of UM metastases. In the bioinformatics study with two external datasets, the high expression of gene BAFF and GDF-15 in primary UM tissues was identified to be associated with poor overall survival rates. As the current work is a single-center retrospective study, more well-designed prospective investigations employing larger cohorts are urgently needed to validate our findings.

Purpose: While B-cell activating factor (BAFF) was identified to promote the invasion in other malignancies, its role in the progression of uveal melanoma (UM) still remains unexplored. Here, we analysed the serum level of BAFF in UM patients with regard to its significance as biomarker for the metastases., Methods: In this retrospective study, serum BAFF levels in 173 UM patients (36 with metastases and 137 without), and 23 healthy controls were measured with a multiplexed sandwich ELISA system and then correlated with clinicopathological characteristics such as primary tumor size, tumor location, histological cell type, sex, cancer stage, cytogenetic alterations of chromosome 3, and the metastatic burden. Immunohistochemical staining of 50 UM tissue specimens was also performed to evaluate the expression of BAFF and its receptors BAFF-R and TACI., Results: The metastatic patients were identified to have significantly higher serum BAFF levels (mean ± SD, 1520.8 ± 1182.1 pg/ml) than those without metastases (950.4 ± 494.6 pg/ml) and controls (810.3 ± 140.5 pg/ml). While no distinctions were detected with regard to tumor location, histological cell type, gender, and monosomy 3, the patients in cancer stages II, III, and IV displayed higher serum BAFF levels than those in stage I. The serum BAFF level was significantly correlated with the metastatic burden. The serum BAFF level of 1120 pg/ml was identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. In the kinetic study, we noticed that 20.8% of the analysed patients already demonstrated elevated serum BAFF concentrations before the clinical diagnosis of metastases. Positive BAFF staining was detected in the cytoplasm of single tumor cells (in 13 specimens), macrophages (in 12 specimens), and tumor-infiltrating lymphocytes (TILs) (in 13 specimens). The expressions of BAFF-R and TACI were also observed in 17 and 36 of the 50 tested UM specimens, respectively., Conclusions: Our study first suggests that BAFF might be a promising serum marker for the detection of UM metastases.

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.

Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht.