Publications by authors named "Eva Biewald"

24 Publications

  • Page 1 of 1

Feasibility of Proton Beam Therapy as a Rescue Therapy in Heavily Pre-Treated Retinoblastoma Eyes.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Department of Ophthalmology, University Hospital Essen, University Duisburg Essen, 45122 Essen, Germany.

Despite the increased risk of subsequent primary tumors (SPTs) external beam radiation (EBRT) may be the only therapeutic option to preserve a retinoblastoma eye. Due to their physical properties, proton beam therapy (PBT) offers the possibility to use the effectiveness of EBRT in tumor treatment and to decisively reduce the treatment-related morbidity. We report our experiences of PBT as rescue therapy in a retrospectively studied cohort of 15 advanced retinoblastoma eyes as final option for eye-preserving therapy. The average age at the initiation of PBT was 35 (14-97) months, mean follow-up was 22 (2-46) months. Prior to PBT, all eyes were treated with systemic chemotherapy and a mean number of 7.1 additional treatments. Indication for PBT was non-feasibility of intra-arterial chemotherapy (IAC) in 10 eyes, tumor recurrence after IAC in another 3 eyes and diffuse infiltrating retinoblastoma in 2 eyes. Six eyes (40%) were enucleated after a mean time interval of 4.8 (1-8) months. Cataract formation was the most common complication affecting 44.4% of the preserved eyes, yet 77.8% achieved a visual acuity of >20/200. Two of the 15 children treated developed metastatic disease during follow-up, resulting in a 13.3% metastasis rate. PBT is a useful treatment modality as a rescue therapy in retinoblastoma eyes with an eye-preserving rate of 60%. As patients are at lifetime risk of SPTs consistent monitoring is mandatory.
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http://dx.doi.org/10.3390/cancers13081862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069965PMC
April 2021

Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Institute of Human Genetics, Medical Faculty, University Duisburg-Essen, 45122 Essen, Germany.

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013-2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality.
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http://dx.doi.org/10.3390/cancers13081876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070790PMC
April 2021

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

Clin Exp Ophthalmol 2021 Apr 17. Epub 2021 Apr 17.

Department of Ophthalmology, University Hospital of Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1111/ceo.13928DOI Listing
April 2021

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Constitutional haploinsufficiency of the gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant's predicted effects on the common causal mediator, protein pRB. For validation, the variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation's localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of variant.
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http://dx.doi.org/10.3390/cancers13071605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037437PMC
March 2021

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

Pediatr Blood Cancer 2021 Jun 15;68(6):e28963. Epub 2021 Mar 15.

The Goldschleger eye institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1002/pbc.28963DOI Listing
June 2021

Long-Term Clinical Results and Management following Vitrectomy in Undetected Retinoblastoma Eyes.

Ocul Oncol Pathol 2020 Aug 25;6(4):244-250. Epub 2020 Feb 25.

Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Introduction: Given the rarity of retinoblastoma and the consequences of accidental vitrectomy in the event of misdiagnosis, reporting on clinical experience in this area is important.

Objective: The aim of this study was to analyse the management and complications with a focus on local orbital recurrence and metastatic disease in 10 children vitrectomized in an undetected retinoblastoma eye.

Methods: This is a retrospective descriptive case series conducted in a single-centre referral university hospital.

Results: From October 1991 to June 2019, 10 patients with a vitrectomy in an unsuspected retinoblastoma eye were included in this study. The main preoperative diagnoses were unilateral inflammation with a suspected lymphoma, uveitis or toxocariasis in 5 cases, vitreous haemorrhage after trauma in 2 cases, and the last 3 were misdiagnosed with Coats disease, rhegmatogenous retinal detachment and congenital cataract. Mean age at surgery was 3 years, ranging from 14 months to 6 and a half years. Nine patients were suffering from unilateral retinoblastoma; these were enucleated and treated with 4-6 cycles of chemotherapy and/or radiation therapy. The sclerotomy sites were infiltrated with tumour cells in 3 cases. In 1 patient, the differential diagnosis of a malignant medulloepithelioma could not be excluded. One patient had bone marrow infiltration on initial presentation; all other patients are healthy without any signs of orbital recurrence or metastatic disease with a mean follow-up of 5.4 years.

Conclusion: In children, intraocular tumours, including retinoblastoma and medulloepithelioma, should be ruled out before pars plana vitrectomy is performed. If no doubtless preoperative diagnosis can be established, preoperative magnetic resonance imaging is mandatory. If a vitrectomy in a retinoblastoma eye has been performed, immediate enucleation of the eye with subsequent chemotherapy and orbital radiation is effective to avoid local recurrence and systemic metastases.
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http://dx.doi.org/10.1159/000505732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506289PMC
August 2020

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.

Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.

Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.

Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316613DOI Listing
September 2020

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.

Neuroradiology 2021 Mar 29;63(3):391-398. Epub 2020 Aug 29.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.

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 cm, AD 2.9 Gy cm, mean 3.5 Gy cm; (A3) DRL 7.0 Gy cm, AD 4.3 Gy cm, mean 6.0 Gy cm; (A4) DRL 14.5 Gy cm, AD 10.7 Gy cm, mean 10.8 Gy cm; (A5) AD 8.8 Gy cm, mean 8.8 Gy cm. 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.
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http://dx.doi.org/10.1007/s00234-020-02540-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880957PMC
March 2021

[Tumors and Pseudotumors of the Retina and the Ciliary Epithelium].

Klin Monbl Augenheilkd 2020 Nov 10;237(11):1359-1378. Epub 2020 Aug 10.

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.
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http://dx.doi.org/10.1055/a-1229-0946DOI Listing
November 2020

13q deletion syndrome resulting from balanced chromosomal rearrangement in father: the significance of parental karyotyping.

Mol Cytogenet 2020 23;13:31. Epub 2020 Jul 23.

Institute of Human Genetics, University Hospital Essen, Essen, Germany.

Background: Retinoblastoma is a malignancy of the eye in children characterized by biallelic inactivation of gene (), located at chromosome 13q14.2. Children with interstitial chromosome 13q deletions that include the gene show a predisposition to develop retinoblastoma and variable other features. Large 13q deletions with severe clinical phenotype are nearly always the result of a de novo mutation, i.e. the pathogenic alteration is not detected in parents. This results in a low risk for siblings to develop 13q deletion syndrome.

Result: Here, we describe a patient with profound muscle hypotonia, severe developmental delay and bilateral retinoblastoma carrying a large deletion in 13q13.3q14 with the size of 16 Mb, involving the gene. Neither parent showed retinoblastoma, muscle hypotonia or developmental delay. Chromosome analysis and Fluorescence in situ hybridization (FISH) showed a balanced complex chromosomal rearrangement (CCR) between chromosome 12 and 13 [ins(12;13)(q21.2;q12.3q14.3)] and an additional balanced translocation of chromosome 7 and 15 [t(7;15)(q31.2;q25.3)] in the healthy father. Malsegregation of the paternal insertional translocation involving chromosome 12 and 13 resulted in a 13q deletion syndrome of the child [46,XY,ins(12;13)(q21.2;q12.3q14.3)].

Conclusion: Balanced translocations in parents are a rare cause of de novo deletions in offspring. This case report emphasizes the need for parental chromosomal analysis and FISH in parents of children diagnosed with 13q deletion syndrome or large gene deletions to precisely determine the recurrence risk in siblings. Guidelines for genetic testing should be revised accordingly.
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http://dx.doi.org/10.1186/s13039-020-00500-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379829PMC
July 2020

[Uveitis Masquerade Syndrome: Typical Symptoms and Presentations].

Klin Monbl Augenheilkd 2020 May 20;237(5):614-620. Epub 2020 May 20.

Retinologie, Klinik für Augenheilkunde, Universitätsklinikum Essen.

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.
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http://dx.doi.org/10.1055/a-1120-8787DOI Listing
May 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

JAMA Oncol 2020 05;6(5):685-695

Imam Hussein Cancer Center, Karbala, Iraq.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.

Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.

Design, Setting, And Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.

Main Outcomes And Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

Conclusions And Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
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http://dx.doi.org/10.1001/jamaoncol.2019.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047856PMC
May 2020

Histopathology of retinoblastoma eyes enucleated after intra-arterial chemotherapy.

Br J Ophthalmol 2020 08 1;104(8):1171-1175. Epub 2019 Nov 1.

Department of Ophthalmology, University Hospital Essen, Essen, Germany.

Background: To demonstrate histopathological findings in retinoblastoma eyes enucleated after intra-arterial chemotherapy (IAC) with special emphasis on vascular toxicity and local tumour control.

Methods: Retrospective study with a consecutive series of 23 retinoblastoma eyes enucleated after IAC where histopathological work-up was available.

Results: From November 2010 to June 2019 23 eyes were enucleated after the attempt of eye salvaging therapy with IAC using melphalan. IAC was the first line treatment in nine and salvage treatment in 14 eyes. Doses of melphalan ranged from 3 to 7.5 mg, whereby a strict protocol with age-appropriate dosage was not used until 2015. The mean number of treatment cycles was 1.8. The main indications for enucleation were poor treatment response or tumour progression in 14 eyes, severe vascular complications in five eyes and a total exudative retinal detachment with amaurosis in the remaining four eyes. We found active disease in 15 eyes with an indication for adjuvant chemotherapy due to high risk factors for metastases in four eyes. To date none of these patients developed metastatic disease. Concerning vascular toxicity, we detected a central retinal artery occlusion in three eyes, severe vasculitis in another three, ischaemic outer retina atrophy and choroidal ischaemia in seven eyes with one eye developing a severe proliferative retinopathy.

Conclusion: IAC is a highly effective treatment option for advanced retinoblastoma, but the described potential risks should be kept in mind. These include severe vascular complications, as well as the possibility of persisting vital tumour cells fulfilling high-risk criteria for adjuvant chemotherapy.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315209DOI Listing
August 2020

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

Neuroradiology 2019 Mar 14;61(3):351-357. Epub 2019 Jan 14.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.

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.
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http://dx.doi.org/10.1007/s00234-019-02153-9DOI Listing
March 2019

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

Ocul Oncol Pathol 2018 Sep 16;4(2):122-128. Epub 2017 Sep 16.

Strahlenklinik, Universitätsklinikum Essen, Essen, Germany.

Brachytherapy with Ru 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 Ru eye plaques has been defined. For I plaques, the minimum dose required for tumor control should be at least 85 Gy. Concerning Ru 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.
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http://dx.doi.org/10.1159/000479558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167660PMC
September 2018

The Interdisciplinary Diagnosis and Treatment of Intraocular Tumors.

Dtsch Arztebl Int 2018 02;115(7):106-111

Department of Ophthalmology, Tumor Center Western Germany, Essen University Hospital; Department of Internal Medicine (Tumor Research), Tumor Center Western Germany, Essen University Hospital; Department of Pediatrics III, Tumor Center Western Germany, Essen University Hospital; Institute for Human Genetics, Tumor Center Western Germany, Essen University Hospital.

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.
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http://dx.doi.org/10.3238/arztebl.2018.0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842342PMC
February 2018

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

Retina 2018 Dec;38(12):2422-2428

Department of Neuroanatomy, Institute of Anatomy II, Medical Faculty, University of Duisburg-Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1097/IAE.0000000000001881DOI Listing
December 2018

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

Pediatr Blood Cancer 2017 01 27;64(1):71-80. Epub 2016 Aug 27.

Eye Oncogenetics Research Group, University Hospital Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1002/pbc.26193DOI Listing
January 2017

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

J Clin Oncol 2016 09 5;34(26):3183-8. Epub 2016 Jul 5.

Petra Temming, Marina Arendt, Anja Viehmann, Lewin Eisele, Claudia H.D. Le Guin, Michael M. Schündeln, Eva Biewald, Jennifer Mäusert, Regina Wieland, Norbert Bornfeld, Wolfgang Sauerwein, Dietmar R. Lohmann, and Karl-Heinz Jöckel, University Hospital Essen, Essen; Petra Temming, Dietmar R. Lohmann, and Karl-Heinz Jöckel, German Consortium for Translational Cancer Research, Heidelberg; and Angelika Eggert, Charité-Universitätsmedizin Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1200/JCO.2015.65.4012DOI Listing
September 2016

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

Br J Ophthalmol 2017 02 27;101(2):204-208. Epub 2016 Apr 27.

Department of Ophthalmology, University Hospital Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1136/bjophthalmol-2015-307076DOI Listing
February 2017

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

Ophthalmology 2016 Apr 4;123(4):898-907. Epub 2016 Feb 4.

Department of Ophthalmology, Poznán University of Medical Sciences, Poznán, Poland.

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.
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http://dx.doi.org/10.1016/j.ophtha.2015.12.024DOI Listing
April 2016

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

Ophthalmology 2016 Mar 12;123(3):635-45. Epub 2015 Dec 12.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany.

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.
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http://dx.doi.org/10.1016/j.ophtha.2015.10.054DOI Listing
March 2016

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

Pediatr Hematol Oncol 2015 3;32(7):455-66. Epub 2015 Aug 3.

d Department of Ophthalmology , Universitätsklinikum-Essen and the University of Duisburg-Essen , Essen, Germany.

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.
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http://dx.doi.org/10.3109/08880018.2015.1048912DOI Listing
September 2016

Sporadic unilateral retinoblastoma or first sign of bilateral disease?

Br J Ophthalmol 2013 Apr 26;97(4):475-80. Epub 2013 Jan 26.

Department of Paediatric Haematology and Oncology, University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany.

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.
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http://dx.doi.org/10.1136/bjophthalmol-2012-302666DOI Listing
April 2013