Tumor- and Radiation-Related Complications after Ruthenium-106 Brachytherapy in Small to Medium Uveal Melanomas (Part 1).

PURPOSE: The purpose of this study was to analyze tumor-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma, with respect to local tumor control, insufficient radiation response, enucleation, and metastasis rate. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated consecutively with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The occurrence of radiation-induced results was analyzed by estimating the risk by applying the Kaplan-Meier method, i.e., the "time to event" analysis. The Cox model test was used for the univariate and multivariate risk factor analyses. The median follow-up was 51 months after primary treatment. RESULTS: Tumor recurrence was found in 21 patients (3.5%) and repeated treatment due to insufficient effect after the initial ruthenium-106 brachytherapy was performed in 40 patients (6.6%). The 5-year cumulative risk of recurrence was 4.0% and that of insufficient effect was 7.3%. Thirteen patients (2.1%) underwent a secondary enucleation; 8 because of a local recurrence and 5 because of severe post-brachytherapy complications. The cumulative enucleation risk was 2.3% after 5 years and 2.9% after 10 years, corresponding to eye preservation of 97.7 and 97.1%, respectively. In forty-two patients (7.2%), metastatic disease was diagnosed during the follow-up. The metastatic rate as calculated by the Kaplan-Meier method was 9.0, and 13.1% at 5 and 10 years, respectively. CONCLUSION: Our study demonstrated that ruthenium-106 brachytherapy is an excellent treatment option for achieving local tumor control and eye preservation in well-selected patients. The metastatic rate is in agreement with that of previous studies analyzing small to medium size uveal melanomas.

Treatment-Related Complications and Functional Results after Ruthenium-106 Brachytherapy in Small to Medium Size Uveal Melanomas (Part 2).

PURPOSE: To analyze the treatment-related complications after ruthenium-106 brachytherapy in patients with uveal melanoma in terms of radiation-induced optic neuropathy, maculopathy and retinopathy, radiation-related vitreous hemorrhage, and retinal detachment, as well as secondary glaucoma and radiogenic cataract. In addition, the course of visual acuity was analyzed. PATIENTS/METHODS AND MATERIALS: This retrospective study included 608 patients treated with ruthenium-106 brachytherapy between January 2008 and December 2010 at the Department of Ophthalmology, University Hospital Essen. The follow-up time was 11 years. The occurrence of the radiation-induced complications was analyzed using the Kaplan-Meier method. Cox regression was used for univariate and multivariate risk factor analyses. Hazard ratios were calculated for each variable. RESULTS: Regarding the complications, 34% (N = 207) of the patients had no reported side effects or complications during follow-up. Radiation optic neuropathy was observed in 18.8% (N = 114) of the patients, with a median time to onset of 16 months (range: 3 - 78 months). Radiation maculopathy occurred in 8.2% (N = 50) after a median time of 17 months (range: 3 - 67 months). Radiation retinopathy was observed in 20.1% (N = 122), with a median time to onset of 21 months (range: 6 - 67 months). Secondary glaucoma developed in 9.7% of the patients (N = 53) and radiogenic cataract in 46.8% (N = 227). Vitreous hemorrhage (11.8%, N = 72) and scleral necrosis (2.1%, N = 13) occurred relatively rarely. CONCLUSION: The observed radiogenic complication rate is comparable with that reported in previous studies.

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.

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.

Uveal Melanoma - Standardised Procedure in Diagnosis, Therapy and Surveillance. / Das uveale Melanom ­ standardisiertes Vorgehen in Diagnostik, Therapie und Nachsorge.

BACKGROUND: Uveal melanoma is a rare intraocular tumour, for which there is currently no national evidence-based guideline in Germany. The aim of this project was to provide a common standard operating procedure (SOP) for the diagnosis, treatment and follow-up care of uveal melanoma, within the network of German leading oncology centres funded by German Cancer Aid. The SOP was created as part of a moderated consensus process. RESULTS AND CONCLUSION: In a multistage process, a common SOP was developed for the diagnosis, therapy and follow-up of uveal melanoma, as based on current knowledge of the subject.

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.

[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.

Chromosome 3 is a valid marker for prognostic testing of biopsy material from uveal melanoma later treated by brachytherapy.

PURPOSE: Monosomy 3 (M3) in uveal melanoma (UM) obtained after enucleation is significantly associated with metastatic death. With improved biopsy techniques, samples from patients treated with eye-preserving methods have become available. As the choice of treatment depends on tumour size, patients treated with eye-preserving brachytherapy tend to have smaller tumours. It has to be determined if M3 is a valid marker for prognosis of these patients. METHODS: Follow-up and clinical data were collected from a total of 451 UM patients: 291 patients were treated by brachytherapy. Tumour tissue was sampled by transretinal biopsy using the 23-gauge Essen biopsy forceps prior to therapy in 114 of them. Chromosome 3 status was determined by microsatellite analysis. Data were compared to those from 160 patients treated by enucleation. RESULTS: Chromosome 3 status correlates significantly with disease-related survival in both patient groups. The proportion of tumours with M3 is lower in the brachytherapy group compared to patients treated with enucleation (25/77 32% and 102/144 71%, respectively). CONCLUSIONS: M3 is a valid marker for poor prognosis in uveal melanoma later treated by brachytherapy. The higher proportion of D3 tumours might explain, at least in part, the more favourable prognosis of patients treated by brachytherapy.

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.

Diagnostic performance of blood culture bottles for vitreous culture compared to conventional microbiological cultures in patients with suspected endophthalmitis.

The purpose of this investigation was to evaluate the performance of blood culture bottles in comparison to conventional microbiological culture techniques in detecting causative microorganisms of endophthalmitis and to determine their anti-infective susceptibility profiles. All consecutive cases with clinically suspected endophthalmitis in a university-based ophthalmology department between January 2009 and December 2016 were analysed in this retrospective comparative case series. Samples from 247 patients with suspected endophthalmitis underwent microbiological diagnostic work-up. All three culture methods were performed from 140 vitreous specimens. Vitreous fluid specimens were inoculated in blood culture bottles, aerobic and anaerobic broth solutions, and on solid media. Anti-infective susceptibility profiles were evaluated by semi-automated methods and/or gradient diffusion methods. Microorganisms were grown in 82 of 140 specimens for which all methods were performed (59%). Microorganisms were more frequently grown from blood culture bottles (55%) compared to broth solution (45%, p = 0.007) and solid media (33%, p < 0.0001). Considerable differences in the performance among culture media were detected for fungal pathogens. All grown fungi were detected by blood culture bottles (11 of 11, 100%). Broth solution recovered 64% and solid media 46% of grown fungi. No Gram-positive bacterium was resistant to vancomycin and all Gram-negative pathogens except for one isolate were susceptible to third-generation cephalosporins. In suspected endophthalmitis patients, blood culture bottles have a higher overall pathogen detection rate from vitreous fluid compared to conventional microbiological media, especially for fungi. The initial intravitreal antibiotic therapy with vancomycin plus third-generation cephalosporins appears to be an appropriate treatment approach for bacterial endophthalmitis.

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.

[Primary Intraocular Lymphoma: Relevance of Diagnostic Vitrectomy]. / Primäres intraokuläres Lymphom: Relevanz der diagnostischen Vitrektomie.

Primary intraocular lymphomas are rare tumours that can be further subdivided into primary vitreoretinal and the even rarer primary uveal lymphoma. The incidence of primary vitreoretinal lymphoma (PVRL) has increased during the last few decades. Differential diagnostic distinction between lymphoma and posterior uveitis is often difficult, so that adequate diagnosis and treatment is often delayed. This is fatal, because PVRL is often associated with primary central nervous lymphoma. To confirm the diagnosis, prior treatment of cytological or histological detection of lymphoma cells is the gold standard. Therefore, a diagnostic vitrectomy should be performed with vitreous biopsy and sometimes transretinal biopsy. Cytokine analysis, as well as flow cytometry and molecular tests, are only additional methods that can be employed in case enough tumour material is available. After the diagnosis has been made, an interdisciplinary treatment concept must be developed by oncologists and ophthalmologists together.

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 second primary malignancies after retinoblastoma treatment.

BACKGROUND: Children with retinoblastoma carry a high risk to develop second primary malignancies in childhood and adolescence. This study characterizes the type of pediatric second primary malignancies after retinoblastoma treatment and investigates the impact of different treatment strategies and prognostic factors at presentation. PROCEDURE: All national patients treated for retinoblastoma at the German referral center with a current age of 6-27 years were invited to participate in a study to characterize late effects. RESULTS: Data on pediatric second primary malignancies were recorded from 488 patients. Ten developed a malignancy before the age of 18 years. For children with heterozygous oncogenic RB1 alteration (heritable retinoblastoma), the cumulative incidence to develop a second malignancy at the age of 10 years was 5.2% (95% CI 1.7; 8.7%). This results in an elevated risk for sarcoma (n = 4) (SIR 147.98; 95% CI 39.81; 378.87) and leukemia (n = 4) (SIR 41.38; 95% CI 11.13; 105.95). Neither the functional type of the RB1 alteration nor its origin showed a significant impact. Treatment modality influenced incidence, latency, and type of malignancy. Previous radiotherapy increased the risk for solid tumors and 3 of 91 children developed acute leukemia after chemotherapy. However, 2 of 10 malignancies were diagnosed in patients with heritable retinoblastoma but without previous chemotherapy or external beam radiotherapy. CONCLUSIONS: Screening for second primary malignancy is an important part of pediatric oncological follow-up in patients with heritable retinoblastoma. For patients with sporadic unilateral retinoblastoma, genetic information influences treatment decisions and allows tailoring of follow-up schedules.

High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma: Part 2: new vs. old imaging concept.

INTRODUCTION: High-resolution magnetic resonance imaging (MRI) is recommended for the evaluation of metastatic risk factors in children with retinoblastoma according to recent guidelines. The aim of this study was to compare diagnostic accuracy of a new imaging concept with two orbit surface coils to that of an old imaging concept with one orbit surface coil. METHODS: One hundred forty-three patients (148 eyes, 64 girls, 79 boys) underwent high-resolution MRI on 1.5 T scanners using orbit surface coils. The old imaging concept (one orbit surface coil focusing on the (most) effected eye additionally to the standard head coil) was used in 100 patients/103 eye; the new imaging concept (two orbit surface coils (each focusing on one eye) additionally to the standard head coil) in 43 patients/45 eyes. Image analysis was performed by two neuroradiologists in consensus. Histopathology served as gold standard. RESULTS: Detection rate for choroidal invasion was higher for the new compared to that for the old imaging concept (sensitivity/specificity 87.5/94.6 % vs. 57.1/96.1 % for choroidal invasion and 100/97.5 % vs. 58.3/97.7 % for massive choroidal invasion, respectively). Sensitivity and specificity for the detection of postlaminar optic nerve infiltration, peribulbar fat, and scleral invasion were comparable in both imaging concepts; however positive predictive value was higher in the new imaging concept (new vs. old imaging concept: 60 vs. 31.6 % for postlaminar and deep postlaminar optic nerve infiltration, respectively, and 100 vs. 66.7 % for scleral invasion). CONCLUSION: The new imaging concept shows a trend towards improving the accuracy of detecting metastatic risk factors in children with retinoblastoma and is therefore recommended for pretherapeutic imaging and follow-up.