Eva Biewald

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

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.

Sporadic unilateral retinoblastoma or first sign of bilateral disease

Background A small number of children with unilateral retinoblastoma later develop retinoblastoma in the contralateral eye (metachronous bilateral retinoblastoma). Methods We analysed the clinical and genetic characteristics of children with sporadic unilateral retinoblastoma to identify risk factors for the development of metachronous bilateral disease. Results Fifteen (3.1%) of 480 children with unilateral retinoblastoma later developed metachronous bilateral retinoblastoma (latency period >30 days). The maximum latency period was 2.3 years after initial diagnosis. Nine (22.5%) of 40 children with a RB1 mutation detectable in blood developed metachronous bilateral disease while all 155 children proved to be without a germline RB1 mutation remained unilaterally affected. Clinically, the risk of developing metachronous bilateral retinoblastoma was higher for age at diagnosis ≤0.5 years compared with >0.5 years (19.6% vs 1.2%), and for multifocal compared with unifocal unilateral retinoblastoma (17.1% vs 2.2%). Conclusions This study shows that an oncogenic RB1 mutation in the blood is a risk factor for metachronous bilateral retinoblastoma. Additional clinical risk factors for metachronous bilateral disease are diagnosis at young age (≤0.5 years) and multifocal unilateral retinoblastoma. Early genetic analysis may identify children at high risk of developing metachronous bilateral disease and may help to preserve vision using risk-adapted follow-up and early treatment.

Endoresection of large uveal melanomas: clinical results in a consecutive series of 200 cases

Background To report eye salvaging rate, visual acuity (VA), local recurrences, complications and the potential benefit of adjuvant brachytherapy after endoresection of large uveal melanomas. Methods 200 patients were included in this retrospective study. They were treated from March 1999 to December 2010 with preoperative stereotactic gamma knife radiosurgery followed by endoresection and adjuvant brachytherapy in most cases. Results A total of 200 patients were included in this study (113 male, 87 female). Mean tumour height was 9.4 mm and the largest basal diameter ranged from 6.3 to 20 mm. The median follow-up time was 32.3 months. In 13.4% the eye was retained with a VA of 20/50 or better, in 33.6% VA was ranging from 20/400 to 20/50 and 53% had a VA of less than 20/400. In almost 90% of the cases the eye was preserved at the final visit. In 15.5% additional major surgery was required. In terms of survival 15.5% of our patients developed liver metastases during follow-up and died. Local tumour recurrence was observed in 10 out of 200 patients (5%) and was mainly treated with enucleation. The use of an adjuvant ruthenium-106 plaque did not lower the recurrence or enucleation rate significantly. Conclusions Eyes with a large uveal melanoma can be preserved by stereotactic radiotherapy followed by endoresection with the chance to obtain useful vision in approximately half of the cases. Adjuvant brachytherapy has no beneficial effect except a reduction of the frequency for major revision surgery.

How Eye-Preserving Therapy Affects Long-Term Overall Survival in Heritable Retinoblastoma Survivors

PURPOSE Intraocular retinoblastoma is curable, but survivors with a heritable predisposition are at high risk for second malignancies. Because second malignancies are associated with high mortality, prognostic factors for second malignancy influence long-term overall survival. This study investigates the impact of all types of eye-preserving therapies on long-term survival in the complete German cohort of patients with heritable retinoblastoma. PATIENTS AND METHODS Overall survival, disease staging using international scales, time period of diagnosis, and treatment type were analyzed in the 633 German children treated at the national reference center for heritable retinoblastoma. RESULTS The 5-year overall survival of children diagnosed in Germany with heritable retinoblastoma between 1940 and 2008 was 93.2% (95% CI, 91.2% to 95.1%), but long-term mortality was increased compared with patients with nonheritable disease. Overall survival correlated with tumor staging, and 92% of patients were diagnosed with a favorable tumor stage (International Retinoblastoma Staging System stage 0 or I). Despite a 5-year overall survival of 97.4% (95% CI, 96.0% to 98.8%) in patients with stage 0 or I, only 79.5% (95% CI, 74.2% to 84.8%) of these patients survived 40 years after diagnosis. Long-term overall survival was reduced in children treated with eye-preserving radiotherapy compared with enucleation alone, and adding chemotherapy aggravated this effect. CONCLUSION The benefits of preserving vision must be balanced with the impact of eye-preserving treatments on long-term survival in heritable retinoblastoma, and the genetic background of the patient influences choice of eye-preserving treatment. Germline RB1 genetic analysis is important to identify heritable retinoblastoma among unilateral retinoblastoma cases. Eye-preserving radiotherapy should be carefully considered in patients with germline RB1 mutations. Life-long oncologic follow-up is crucial for all retinoblastoma survivors, and less detrimental eye-preserving therapies must be developed.

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.

Ocular masquerade syndrome due to sarcoidosis

Die Sarkoidose ist eine systemische Erkrankung des Bindegewebes mit Granulombildung bislang ungeklärter Ursache. Eine Augenbeteiligung wird mit einer Häufigkeit von 20–30% angegeben [4], wobei sich die Erkrankung als Uveitis, periphere retinale Vaskulitis, multifokale Chorioiditis, durch Veränderungen der retinalen Pigmentepithel mit Granulomen am Nervus opticus oder eine Skleritis manifestieren kann. Eine Beteiligung der Tränendrüse wird ebenfalls häufig genannt [2]. Als Akutform der Erkrankung ist das Löfgren-Syndrom bekannt, das ein lebensbedrohliches Krankheitsbild darstellen kann [2]. Eine kausale Therapieform existiert nicht. Eine Therapie mit Kortikosteroiden kann aber die Symptome unterdrücken, ein Ausschleichen der Therapie führt allerdings meist zu Rezidiven [1]. Oftmals wird eine Kombination aus Steroiden und Immunsuppressiva angewendet, um die Prednisolondosis möglichst gering zu halten [5]. Wir möchten in unserer Kasuistik einen Patienten mit einer seltenen ophthalmologischen Manifestationsform bei systemischer Sarkoidose vorstellen.

Dose Distributions and Treatment Margins in Ocular Brachytherapy with 106 Ru Eye Plaques

Brachytherapy with 106Ru eye plaques is the most common treatment modality for small to medium-sized uveal melanomas in Europe. So far, no standardized or widely accepted dose prescription protocol for the irradiation of intraocular tumors with 106Ru eye plaques has been defined. For 125I plaques, the minimum dose required for tumor control should be at least 85 Gy. Concerning 106Ru plaques, the dose prescriptions at the University Hospital of Essen foresees minimum doses of 700 Gy to the tumor base and 130 Gy to the tumor apex. These dose prescriptions are expected to ensure sufficient treatment margins. We apply these dose prescriptions to different eye plaque types and tumor sizes and discuss the resulting treatment margins. These investigations are based on Monte Carlo simulations of dose distributions of 3 different eye plaque types. The treatment margin in apical direction has an expansion of at least 0.8 mm for all investigated eye plaques. For symmetrically formed eye plaques, the treatment margin at the base of the tumor goes beyond the visible edge of the plaque. This study focuses on the shape of 85-Gy isodose lines and on treatment margins for different eye plaque types and tumor sizes and shall help exchange knowledge for ocular brachytherapy.

The Interdisciplinary Diagnosis and Treatment of Intraocular Tumors

BACKGROUND Recent years have seen major changes in the diagnosis and treatment of solid intraocular tumors, mainly owing to an improved molecular biological understanding of their pathogenesis, new therapeutic approaches for the local treatment of tumors in children, and long-term follow-up observations in clinical trials. METHODS This review is based on pertinent publications retrieved by a selective search in PubMed. RESULTS Retinoblastoma is the most common type of primary intraocular tumor, with approximately 8000 new cases per year around the world, while malignant melanoma of the uvea is the most common primary intraocular tumor in adults, with approximately 7000 new cases per year around the world. Intraocular metastases of malignant tumors are ten times more common, in terms of incidence, than primary intraocular tumors and are therefore the most common intraocular tumors overall. Improved methods of intraocular biopsy, diagnostic imaging, and molecular genetic investigation have led to steady improvement in clinical and predictive diagnostic assessment. In the treatment of retinoblastoma, local techniques including brachytherapy and intra-arterial and intravitreal chemotherapy play a prominent role. Prognostic molecular-genetic testing now enables the highly selective identification of uveal melanomas that have a high potential to metastasize. Cutaneous and uveal melanomas differ both in their clinical behavior and in their basic biological features; to date, effective systemic treatment has been established for melanoma of the skin, but not for metastatic melanoma of the uvea. Intraocular metastases are common and often the initial manifestation of an extraocular tumor, particularly lung cancer. CONCLUSION Modern diagnostic and therapeutic concepts for intraocular tumors can only be implemented through the close interdisciplinary collaboration of ophthal - mologists, oncologists, radiologists, radiotherapists, pathologists, and human geneticists.