Preoperative Detection of Local Tumor Extent in Patients with Advanced Retinoblastoma: Predictive Value of MRI and Clinical Findings. / Präoperativer Nachweis der lokalen Tumorausdehnung bei Patienten mit fortgeschrittenem Retinoblastom: prädiktiver Wert MR-tomografischer und klinischer Befunde.

OBJECTIVE: Before planned enucleation, local tumor extension in advanced retinoblastoma is routinely assessed preoperatively using high-resolution magnetic resonance imaging (MRI). The aim of our study was to analyse the predictive value of MRI and clinical characteristics for predicting tumor extent, as confirmed by histopathology postoperatively. PATIENTS AND METHODS: All consecutive patients were included who underwent primary enucleation for advanced retinoblastoma after high-resolution MRI examination in our hospital between January 2011 and December 2021. The primary study endpoint was the evaluation of the predictability of histopathological risk factors on preoperative MRI examination. The sensitivity and specificity of the MRI examination with respect to clinically relevant optic nerve infiltration and choroidal infiltration were determined. RESULTS: The mean age of the 209 included patients was 1.6 years (range 1 month to 4.7 years). MRI indicated optic nerve infiltration in 46 (22%) patients, extensive choroidal infiltration in 78 (40.2%) patients, and scleral infiltration in one patient (2.6%). Histopathological examination demonstrated postlaminar optic infiltration in 25 (12%) patients and extensive choroidal infiltration in 17 (8.1%) cases. Scleral infiltration was evident in 8 (3.8%) patients. In the final multivariate analysis, MRI findings of tumor infiltration and a preoperative intraocular pressure ≥ 20 mmHg were independently associated with histopathological evidence of clinically relevant optic nerve (p = 0.033/p = 0.011) and choroidal infiltration (p = 0.005/p = 0.029). The diagnostic accuracy of the prediction models based on the multivariate analysis for the identification of the clinically relevant optic nerve (AUC = 0.755) and choroidal infiltration (AUC = 0.798) was greater than that of purely MRI-based prediction (respectively 0.659 and 0.742). The sensitivity and specificity of MRI examination for determining histopathological risk factors in our cohort were 64% and 65% for clinically relevant optic infiltration and 87% and 64% for clinically relevant choroidal infiltration. CONCLUSION: The local tumor extent of retinoblastoma with infiltration of the optic nerve and choroid can be well estimated based on radiological and clinical characteristics before treatment initiation. The combination of clinical and radiological risk factors supports the possibility of early treatment stratification in retinoblastoma patients.

Magnetic Resonance Imaging Can Reliably Differentiate Optic Nerve Inflammation from Tumor Invasion in Retinoblastoma with Orbital Cellulitis.

PURPOSE: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion. DESIGN: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case-control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls. PARTICIPANTS: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis. METHODS: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case-control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons. MAIN OUTCOME MEASURES: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed. RESULTS: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P < 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16-52) to 89% (95% CI, 72-98). CONCLUSIONS: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes.

Comparing efficacy and side effects of two systemic chemotherapy regimens for eye-preserving therapy in children with retinoblastoma.

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%) (plogrank  < .001). The OES did not differ significantly between the two treatment groups (plogrank  = .77; 2-year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES (plogrank  < .0001; 2-year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES (plogrank  < .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.

ADAM10 and ADAM17-Novel Players in Retinoblastoma Carcinogenesis.

A disintegrin and metalloproteinase (ADAM) family proteins, acting as sheddases, are important factors in a number of pathologies, including cancer, and have been suggested as promising therapeutic targets. The study presented focuses on the involvement of ADAM10 and ADAM17 in retinoblastoma (RB), the most common malignant intraocular childhood tumor. A significant correlation between ADAM17 expression levels and RB laterality and RB staging was observed. Levels of ADAM10 or ADAM17 regulating miRNAs miR-145, -152, and -365 were significantly downregulated in RB cell lines, and reduced miR levels with simultaneously upregulated ADAM10 and ADAM17 expression were found in RB patients. The involvement of both ADAMs analyzed in ectodomain shedding of the neuronal cell adhesion molecule L1 (L1CAM), shown to induce pro-tumorigenic effects in RB, was confirmed. Lentiviral ADAM10 and ADAM17 single or ADAM10/17 double knockdown (KD) induced caspase-dependent apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells. Moreover, differential phosphorylation of the serine/threonine kinase AKT was observed following ADAM17 KD in RB cells. Chicken chorioallantoic membrane (CAM) assays revealed that ADAM17 and ADAM10/17 depletion decreases the tumorigenic and migration potential of RB cells in vivo. Thus, ADAMs are potential novel targets for future therapeutic RB approaches.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

INTRODUCTION: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. METHOD: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. RESULTS: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. CONCLUSION: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

Estimation of radiation exposure of children undergoing superselective intra-arterial chemotherapy for retinoblastoma treatment: assessment of local diagnostic reference levels as a function of age, sex, and interventional success.

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 cm2, AD 2.9 Gy cm2, mean 3.5 Gy cm2; (A3) DRL 7.0 Gy cm2, AD 4.3 Gy cm2, mean 6.0 Gy cm2; (A4) DRL 14.5 Gy cm2, AD 10.7 Gy cm2, mean 10.8 Gy cm2; (A5) AD 8.8 Gy cm2, mean 8.8 Gy cm2. 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.

Scleral necrosis after brachytherapy for uveal melanoma: Analysis of risk factors.

BACKGROUND: Radiation-induced scleral necrosis (RISN) is a rare, but a serious complication of brachytherapy for uveal melanoma. We aimed at analysing the incidence, timing and risk factors associated with development of RISN in a large institutional series. METHODS: All consecutive cases with brachytherapy for uveal melanoma treated by the Departments of Ophthalmology and Radiotherapy at University Hospital Essen between 1999 and 2016 were eligible. Development of RISN during the post-treatment follow-up was recorded. A 1:2 propensity score matched case-control study was performed for the evaluation of the prognostic value of different tumour- and treatment-associated parameters. RESULTS: RISN was documented in 115 (2.9%) of 3960 patients with uveal melanoma included in the final analysis, and occurred at the mean 30.3 months (range: 1.26-226 months) after brachytherapy. In the whole cohort, younger age (p = 0.042), plaque type (p = 0.001) and ciliary body involvement (p < 0.0001) were independently associated with the RISN occurrence. In the case-control study, multivariable weighted proportional hazard analysis discovered the association of the following additional tumour- and treatment-associated characteristics with RISN: posterior tumour margin anterior to equatorial region (p = 0.0003), extraocular tumour extension (p = <0.0001), scleral contact dose (p = <0.0001), conjunctival dehiscence after therapy (p = 0.0001), disinsertion of the superior rectus muscle (p = 0.001) and the glaucoma medication (p = 0.014). CONCLUSIONS: Our study confirms RISN as a rare complication, which might occur even years later after the brachytherapy for uveal melanoma. Alongside with scleral dose five other tumour and therapy related factors predict the risk of RISN after brachytherapy for uveal melanoma were established.

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

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

Intraarterial Chemotherapy for Retinoblastoma - Initial Experiences of a German Reference Centre. / Intraarterielle Chemotherapie beim Retinoblastom ­ erste Erfahrungen eines deutschen Referenzzentrums.

BACKGROUND: Adequate management of retinoblastoma requires a multidisciplinary and individual approach to treatment. Intraarterial chemotherapy (IAC) is one of the most commonly used treatment modalities, and enables supraselective application of chemotherapy via the ophthalmic artery and is now established in almost all treatment centres. However, published treatment success rates are heterogeneous. There are some unanswered issues regarding sight-threatening ocular complications and the long-term occurrence of secondary malignancies and metastatic disease. The objective of the present study is to analyse the results of a German national reference centre. METHODS: Retrospective analysis of all children with an indication for at least one IAC from April 2010 to April 2020. IAC was used either as primary or recurrence therapy. Obligatory follow-up was at least 6 months. RESULTS: 137 eyes of 127 children with an indication for IAC could be included. 12 eyes with a follow-up of less than 6 months and 37 eyes in which IAC was technically not feasible were excluded. In summary, 88 eyes of 79 children were finally analysed. Mean follow-up was 38 months, ranging from 7 to 117 months. In total, 195 procedures were completed. In 30 eyes (34.1%) IAC was conducted as primary and in 58 (65.9%) as secondary therapy. There was an initial IAC treatment response in 75 eyes (85.2%) with a recurrence-free rate of 61.3%. Eye salvage rate was 68.1% with 28 enucleated eyes in total. Ocular complications were observed in 36 eyes (40.9%), with 19 eyes (21.6%) showing severe sight-threatening and 11 eyes (12.5%) presenting minor non-sight-threatening toxic reactions. During follow-up, 1 child developed a secondary malignancy, 1 child developed metastasis and 1 child died as a consequence of trilateral retinoblastoma. CONCLUSION: In summary, IAC is a potent modality for retinoblastoma treatment and has been very successful, even in advanced disease and heavily pretreated eyes. However, ocular complications should be taken in consideration, especially when the only seeing eye is treated. Long term incidences of secondary malignancies and metastatic diseases should be further investigated in prospective studies.

[Uveitis Masquerade Syndrome: Typical Symptoms and Presentations]. / Uveitis-Masquerade-Syndrome: Leitsymptome und Krankheitsbilder.

The uveitis masquerade syndrome (UMS) describes a series of malignant diseases that mimic inflammatory conditions without belonging to the group of immune-mediated uveitis entities. The correct diagnosis is often difficult to establish, despite a detailed ophthalmological and general medical history using all imaging modalities and interdisciplinary cooperation. In the case of recurrent inflammation, it is very important to consider an UMS, since any delay in proving the underlying diagnosis and initiating the appropriate therapy may be associated with the risk of systemic spread and consecutive deterioration of the prognosis. Often, after all conservative options have been exhausted, the only remaining option to confirm the correct diagnosis might be an intraocular biopsy. The present work focuses on the leading symptoms, differential diagnoses and clinical signs of UMS.