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.

[Tumors and Pseudotumors of the Retina and the Ciliary Epithelium]. / Tumoren und Pseudotumoren der Netzhaut und des Ziliarepithels.

The variety of retinal tumors ranges from harmless lesions to benign, locally destructive tumors and life-threatening diseases, and they are not always easy to distinguish from each other. The differential diagnosis includes real neoplasia, reactive inflammatory pathologies and vascular anomalies of the fundus as well. If possible, the diagnosis should be made clinically in order to avoid the danger of tumor cell spread via invasive diagnostic tools. Nevertheless, genetic analysis of the pathology is gaining more importance and adds to the precise characterization of the diagnosis. Depending on the tumor entity, therapy in a specialized center is necessary.

Feasibility of intra-arterial chemotherapy for retinoblastoma: experiences in a large single center cohort study.

PURPOSE: In the last 10 years, intra-arterial chemotherapy (IAC) has been increasingly used in the clinical management of retinoblastoma. It is reported to provide tumor control even in advanced stage disease that might have previously required enucleation. In our clinical experience, there are three conditions that may impair the use of IAC: (1) significant collaterals to meningeal arteries, (2) technical failure of ophthalmic artery catheterization, or (3) retina blood supply from collaterals different to the ophthalmic artery. In the current study, we assessed the rate of IACs that could not be carried out in our institution due to these three reasons. METHODS: All patients admitted for IAC in our hospital were retrospectively assessed by chart review. Non-application rate of IAC was assessed and classified according to the three abovementioned criteria. Complication rate of both finalized and interrupted interventions was recorded. RESULTS: Ninety-eight patients (median age 21.4 months, range 5.3 months-10.5 years) were identified. IAC was performed in 69 (70.4%) patients and interrupted in 12 (12.2%) cases because of meningeal collaterals, in 8 (8.2%) because of technical failure to cannulate the ophthalmic artery, and in 9 (9.2%) because of alternative blood supply of the retina. CONCLUSION: The rather defensive approach that is pursued in our center resulted in an overall non-application rate of IAC around 30%. The relatively high probability of conditions that impair the use of IAC needs to be addressed adequately in the patient conversation prior to the procedure. Our rate of 8% of abstention from IAC due to technical limitations might be reduced by the application of more rigorous therapeutic approaches such as balloon occlusion of the distal internal carotid artery. More research is finally needed to determine if IAC can be safely performed in the presence of meningeal collaterals and via branches of the external carotid artery.

TREFOIL FACTOR FAMILY 1 EXPRESSION CORRELATES WITH CLINICAL OUTCOME IN PATIENTS WITH RETINOBLASTOMA.

PURPOSE: Correlation of trefoil factor family 1 (TFF1) expression in retinoblastoma tumors with different clinical parameters to evaluate a potential involvement of TFF1 in tumor development and progression. METHODS: A representative cohort of 59 enucleated eyes from individual patients with retinoblastoma was analyzed for its TFF1 expression profile by immuno staining and real-time PCR. Trefoil factor family 1 expression was correlated with demographics, laterality, tumor-node-metastasis stage, International Classification of Retinoblastoma, tumor differentiation level, and treatment. RESULTS: According to our analysis, increased TFF1 expression significantly correlates with unilateral tumors diagnosed in older children and with poorly differentiated tumors and higher tumor-node-metastasis stages. CONCLUSION: This retrospective study reveals that unilateral tumors at a higher clinical tumor-node-metastasis stage and poorly differentiated tumor cells express significantly higher levels of TFF1 than those of differentiated tumors at lower tumor-node-metastasis stages. Besides, TFF1 expression correlates with the age of the patients at the time of tumor diagnosis. Our data indicate that TFF1 expression levels are potentially useful additional markers in the classification of tumor staging and prognosis of patients with retinoblastoma.

Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center.

BACKGROUND: Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined. PROCEDURE: This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment. RESULTS: The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population). CONCLUSIONS: Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

High-Resolution Magnetic Resonance Imaging Can Reliably Detect Orbital Tumor Recurrence after Enucleation in Children with Retinoblastoma.

PURPOSE: Orbital tumor recurrence is a rare but serious complication in children with retinoblastoma, leading to a high risk of metastasis and death. Therefore, we assume that these recurrences have to be detected and treated as early as possible. Preliminary studies used magnetic resonance imaging (MRI) to evaluate postsurgical findings in the orbit. In this study, we assessed the diagnostic accuracy of high-resolution MRI to detect orbital tumor recurrence in children with retinoblastoma in a large study cohort. DESIGN: Consecutive retrospective study (2007-2013) assessing MRI findings after enucleation. PARTICIPANTS: A total of 103 MRI examinations of 55 orbits (50 children, 27 male/23 female, mean age 16.3±12.4 months) with a median time of 8 months (range, 0-93) after enucleation for retinoblastoma. METHODS: High-resolution MRI using orbital surface coils was performed on 1.5 Tesla MRI systems to assess abnormal orbital findings. MAIN OUTCOME MEASURES: Five European experts in retinoblastoma imaging evaluated the MRI examinations regarding the presence of abnormal orbital gadolinium enhancement and judged them as "definitive tumor," "suspicious of tumor," "postsurgical condition/scar formation," or "without pathologic findings." The findings were correlated to histopathology (if available), MRI, and clinical follow-up. RESULTS: Abnormal orbital enhancement was a common finding after enucleation (100% in the first 3 months after enucleation, 64.3% >3 years after enucleation). All histopathologically confirmed tumor recurrences (3 of 55 orbits, 5.5%) were correctly judged as "definitive tumor" in MRI. Two orbits from 2 children rated as "suspicious of tumor" received intravenous chemotherapy without histopathologic confirmation; further follow-up (67 and 47 months) revealed no sign of tumor recurrence. In 90.2%, no tumor was suspected on MRI, which was clinically confirmed during follow-up (median follow-up after enucleation, 45 months; range, 8-126). CONCLUSIONS: High-resolution MRI with orbital surface coils may reliably distinguish between common postsurgical contrast enhancement and orbital tumor recurrence, and therefore may be a useful tool to evaluate orbital tumor recurrence after enucleation in children with retinoblastoma. We recommend high-resolution MRI as a potential screening tool for the orbit in children with retinoblastoma to exclude tumor recurrence, especially in high-risk patients within the critical first 2 years after enucleation.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Pediatric Survivors of Retinoblastoma Are at Risk for Altered Bone Metabolism After Chemotherapy Treatment Early in Life.

Survivors of childhood cancer frequently suffer from endocrine late effects, which are, at least partly, attributed to toxic effects of chemotherapy. Treatment of retinoblastoma typically involves chemotherapy at a very young age. The authors conducted a cross-sectional study to assess bone health in a pediatric cohort of 33 survivors of retinoblastoma (mean age: 4.4 years) who had undergone chemotherapy treatment at an especially young age (mean age: 0.76 years). Of these patients, 14 had unilateral and 19 bilateral retinoblastoma. Polychemotherapy consisted of treatment with cyclophosphamide, etoposide, vincristine, and carboplatin. Ten patients had undergone external beam radiotherapy. Clinical and biochemical parameters of growth, pubertal development, and bone health were obtained. A vitamin D deficiency was found in 51.7% of the patients, and 13.7% of patients displayed severe vitamin D deficiency. Secondary hyperparathyroidism and altered readings for bone formation or resorption markers were present in 15%. Nine percent reported bone pain or experienced fractures of the long bones after primary diagnosis. No difference between children with bilateral and unilateral disease or irradiated versus nonirradiated children was observed. The parameters of thyroid function, growth, and pubertal development were within age-appropriate norms in almost all children. In conclusion, altered parameters of bone health can be present in survivors of retinoblastoma at a young age and warrant regular follow-up in these children. The endocrine hypothalamic-pituitary axes, however, were not impaired at this early age in this group of survivors of retinoblastoma.

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

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

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

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