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Cancers
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Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches
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Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 52659

Special Issue Editors

Prof. Dr. Nicole Dünker

E-Mail Website
Guest Editor
Institute for Anatomy II, Department of Neuroanatomy, University of Duisburg-Essen, University Medicine Essen, 45122 Essen, Germany
Interests: genes and miRNAs involved in retinoblastoma etiology and progression; mechanisms underlying RB chemoresistance; adjuvant RB treatment strategies; nanoparticle-mediated treatment approaches; role of trefoil factor family (TFF) peptides in RB; CAM assay as in vivo pre-screening model
Prof. Dr. Norbert Bornfeld

E-Mail Website
Guest Editor
Department of Ophthalmology, University Hospital Essen, 45122 Essen, Germany
Interests: retinoblastoma; biopsy techniques in the management of intraocular tumors; development and optimization of techniques for radiotherapy of intraocular tumors (brachytherapy, proton radiation therapy
Prof. Dr. Francis L. Munier

E-Mail Website
Guest Editor
Hôpital Ophtalmique Jules-Gonin, University of Lausanne, Switzerland
Interests: retinoblastoma; chemotherapy in situ; liquid biopsy; tumor progression; high resolution imaging; epigenetics

Special Issue Information

Dear Colleagues,

Retinoblastoma (RB) is the most common primary intraocular tumor with an incidence of 1 in 14000 to 1 in 20000 per childbirths. Untreated, the tumor expands, may extend beyond the eye and develop metastatic spread. The advent of novel routes of chemotherapy administration, including intra-arterial, intravitreal and intracameral injections, has considerably improved the overall eye survival rate, eradicating the need for external beam radiotherapy, eliminating the risk of radio-induced malignancies, and reducing the indications for systemic chemotherapy. These new therapeutic frontiers in the conservative management of RB can be further extended provided that new biological markers are validated to detect minimally disseminated disease, promoting tolerance zero for metastasis, and that new strategies and drugs are developed to overcome drug resistance, multi drug resistances and toxicities, as well as to improve the visual outcome and quality of life. Here, we aim at providing an overview on retinoblastoma by highlighting the progress made in treatment regimens. In this context, we welcome reviews and research articles summarizing the current state of the art in RB screening and treatment and future challenges as well as basic, preclinical and clinical studies. We are looking for studies on genes and miRNAs involved in the etiology and progression of RB, the potential impact of liquid biopsy and the development of chemoresistances. Other possible topics are promising new approaches including charged particle treatment, toxic chorioretinopathies, tumor invasion, metastasis and recurrence.

Prof. Dr. Nicole Dünker
Prof. Dr. Norbert Bornfeld
Prof. Dr. Francis L. Munier
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • State of the art in RB treatment and future challenges including indications to primary and secondary enucleation
  • new genes involved in the etiology and progression of retinoblastoma
  • miRNAs regulating retinoblastoma development, progression and chemosensitivity
  • new strategies to overcome chemoresistance and multi drug resistances
  • new prognostic RB markers
  • refinement in radiotherapy, value of brachytherapy and potential role of proton beam therapy
  • advances in RB diagnosis and screening including “liquid biopsy” and automated evaluation of imaging methods
  • advances in management of tumor invasion, metastasis and recurrence
  • new combined therapy approaches
  • tumor predisposition and second cancers
  • retinoblastoma in developing countries
  • new drugs and new Galenic formulation of known drugs

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 195 KiB  
Editorial
Special Issue of Cancers: “Retinoblastoma: Current Challenges and Promising New Approaches”
by Francis L. Munier
Cancers 2023, 15(8), 2293; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082293 - 14 Apr 2023
Viewed by 1012
Abstract
Despite being a rare pediatric cancer arising in the developing retina from red/green cone precursors, retinoblastoma is the most common eye cancer worldwide and occupies an emblematic position in oncology and human genetics for the following reasons:-Historically, the discovery of RB1 and the [...] Read more.
Despite being a rare pediatric cancer arising in the developing retina from red/green cone precursors, retinoblastoma is the most common eye cancer worldwide and occupies an emblematic position in oncology and human genetics for the following reasons:-Historically, the discovery of RB1 and the recessive nature of its mutations led to the prototypic description of anti-oncogenes or tumor suppressor genes [...] Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)

Research

Jump to: Editorial, Review, Other

14 pages, 956 KiB  
Article
Eye Tumors in Childhood as First Sign of Tumor Predisposition Syndromes: Insights from an Observational Study Conducted in Germany and Austria
by Madlen Reschke, Eva Biewald, Leo Bronstein, Ines B. Brecht, Sabine Dittner-Moormann, Frank Driever, Martin Ebinger, Gudrun Fleischhack, Desiree Grabow, Dirk Geismar, Sophia Göricke, Maja Guberina, Claudia H. D. Le Guin, Tobias Kiefer, Christian P. Kratz, Klaus Metz, Bert Müller, Tatsiana Ryl, Marc Schlamann, Sabrina Schlüter, Stefan Schönberger, Johannes H. Schulte, Selma Sirin, Daniela Süsskind, Beate Timmermann, Saskia Ting, Werner Wackernagel, Regina Wieland, Martin Zenker, Michael Zeschnigk, Dirk Reinhardt, Angelika Eggert, Petra Ritter-Sovinz, Dietmar R. Lohmann, Norbert Bornfeld, Nikolaos Bechrakis and Petra Ketteleradd Show full author list remove Hide full author list
Cancers 2021, 13(8), 1876; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081876 - 14 Apr 2021
Cited by 7 | Viewed by 2855
Abstract
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 [...] Read more.
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 DICER1 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. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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11 pages, 696 KiB  
Article
Feasibility of Proton Beam Therapy as a Rescue Therapy in Heavily Pre-Treated Retinoblastoma Eyes
by Eva Biewald, Tobias Kiefer, Dirk Geismar, Sabrina Schlüter, Anke Manthey, Henrike Westekemper, Jörg Wulff, Beate Timmermann, Petra Ketteler, Stefan Schönberger, Klaus A. Metz, Saskia Ting, Sophia Göricke, Nikolaos E. Bechrakis and Norbert Bornfeld
Cancers 2021, 13(8), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081862 - 13 Apr 2021
Cited by 7 | Viewed by 2635
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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11 pages, 704 KiB  
Article
Benign Tumors in Long-Term Survivors of Retinoblastoma
by Milo van Hoefen Wijsard, Sara J. Schonfeld, Flora E. van Leeuwen, Annette C. Moll, Armida W. Fabius, David H. Abramson, Johanna M. Seddon, Jasmine H. Francis, Margaret A. Tucker, Ruth A. Kleinerman and Lindsay M. Morton
Cancers 2021, 13(8), 1773; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081773 - 08 Apr 2021
Cited by 5 | Viewed by 1781
Abstract
Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., [...] Read more.
Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914–2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9–22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2–6.4%), corresponding to 4.9-fold (95%CI = 2.8–8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7–22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2–13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0–6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1–2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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21 pages, 2097 KiB  
Article
Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma
by Isabel Hülsenbeck, Mirjam Frank, Eva Biewald, Deniz Kanber, Dietmar R. Lohmann and Petra Ketteler
Cancers 2021, 13(7), 1605; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071605 - 31 Mar 2021
Cited by 4 | Viewed by 2004
Abstract
Constitutional haploinsufficiency of the RB1 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 RB1 are heterogeneous, and a few genotype-phenotype correlations have [...] Read more.
Constitutional haploinsufficiency of the RB1 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 RB1 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, RB1 protein pRB. For validation, the RB1 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 RB1 (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 RB1 variant. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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15 pages, 2221 KiB  
Article
Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy
by Liya Xu, Mary E. Kim, Ashley Polski, Rishvanth K. Prabakar, Lishuang Shen, Chen-Ching Peng, Mark W. Reid, Patricia Chévez-Barrios, Jonathan W. Kim, Rachana Shah, Rima Jubran, Peter Kuhn, David Cobrinik, Jaclyn A. Biegel, Xiaowu Gai, James Hicks and Jesse L. Berry
Cancers 2021, 13(6), 1282; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061282 - 13 Mar 2021
Cited by 30 | Viewed by 4349
Abstract
Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular [...] Read more.
Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular biomarkers from the first year of prospective validation data. Seven eyes from 6 RB patients who had AH sampled at diagnosis and throughout therapy with ≥12 months of follow-up were included. Cell-free DNA (cfDNA) from each sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing for pathogenic variants using a RB1 and MYCN custom hybridization panel. Tumoral genomic information was detected in 100% of diagnostic AH samples. Of the seven diagnostic AH samples, 5/7 were positive for RB SCNAs. Mutational analysis identified RB1 variants in 5/7 AH samples, including the 2 samples in which no SCNAs were detected. Two eyes failed therapy and required enucleation; both had poor prognostic biomarkers (chromosome 6p gain or MYCN amplification) present in the AH at the time of diagnosis. In the context of previously established pre-analytical, analytical, and clinical validity, this provides evidence for larger, prospective studies to further establish the clinical utility of the AH liquid biopsy and its applications to precision oncology for RB. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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0 pages, 1302 KiB  
Article
Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma
by Rosario Aschero, Jasmine H. Francis, Daiana Ganiewich, Soledad Gomez-Gonzalez, Claudia Sampor, Santiago Zugbi, Daniela Ottaviani, Lauriane Lemelle, Marcela Mena, Ursula Winter, Genoveva Correa Llano, Gabriela Lamas, Fabiana Lubieniecki, Irene Szijan, Jaume Mora, Osvaldo Podhajcer, François Doz, François Radvanyi, David H. Abramson, Andrea S. Llera, Paula S. Schaiquevich, Cinzia Lavarino and Guillermo L. Chantadaadd Show full author list remove Hide full author list
Cancers 2021, 13(4), 673; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040673 - 08 Feb 2021
Cited by 11 | Viewed by 2365
Abstract
Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 [...] Read more.
Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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15 pages, 9055 KiB  
Article
MR Imaging Features to Differentiate Retinoblastoma from Coats’ Disease and Persistent Fetal Vasculature
by Robin W. Jansen, Christiaan M. de Bloeme, Hervé J. Brisse, Paolo Galluzzi, Liesbeth Cardoen, Sophia Göricke, Philippe Maeder, Nathalie Cassoux, Arnaud Gauthier, Sabrina Schlueter, Theodora Hadjistilianou, Francis L. Munier, Jonas A. Castelijns, Paul van der Valk, Annette C. Moll, Marcus C. de Jong and Pim de Graaf
Cancers 2020, 12(12), 3592; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123592 - 30 Nov 2020
Cited by 23 | Viewed by 3578
Abstract
Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best [...] Read more.
Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best differentiate between retinoblastoma and the most common pseudoretinoblastoma diagnoses: Coats’ disease and persistent fetal vasculature (PFV). Here, six expert radiologists performed retrospective assessments (blinded for diagnosis) of MR images of patients with a final diagnosis based on histopathology or clinical follow-up. Associations between 20 predefined imaging features and diagnosis were assessed with exact tests corrected for multiple hypothesis testing. Sixty-six patients were included, of which 33 (50%) were retinoblastoma and 33 (50%) pseudoretinoblastoma patients. A larger eye size, vitreous seeding, and sharp-V-shaped retinal detachment were almost exclusively found in retinoblastoma (p < 0.001–0.022, specificity 93–97%). Features that were almost exclusively found in pseudoretinoblastoma included smaller eye size, ciliary/lens deformations, optic nerve atrophy, a central stalk between optic disc and lens, Y-shaped retinal detachment, and absence of calcifications (p < 0.001–0.022, specificity 91–100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts (p < 0.001, 38% [9/24] in Coats’ disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion (p < 0.001, 30% [7/23] in Coats’ disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats’ disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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20 pages, 8382 KiB  
Article
Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma
by Santiago Zugbi, Daiana Ganiewich, Arpita Bhattacharyya, Rosario Aschero, Daniela Ottaviani, Claudia Sampor, Eduardo G. Cafferata, Marcela Mena, Mariana Sgroi, Ursula Winter, Gabriela Lamas, Mariona Suñol, Manuel Daroqui, Edgardo Baialardo, Beatriz Salas, Anirban Das, Adriana Fandiño, Jasmine H. Francis, Fabiana Lubieniecki, Cinzia Lavarino, Ralph Garippa, Osvaldo L. Podhajcer, David H. Abramson, François Radvanyi, Guillermo Chantada, Andrea S. Llera and Paula Schaiquevichadd Show full author list remove Hide full author list
Cancers 2020, 12(9), 2714; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092714 - 22 Sep 2020
Cited by 27 | Viewed by 4047
Abstract
An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) has only been described as intra-ocular cases treated with initial enucleation. [...] Read more.
An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNamplRB1+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNamplRB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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Review

Jump to: Editorial, Research, Other

15 pages, 1005 KiB  
Review
The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma
by Amy Gerrish, Helen Jenkinson and Trevor Cole
Cancers 2021, 13(7), 1570; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071570 - 29 Mar 2021
Cited by 16 | Viewed by 4636
Abstract
Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic [...] Read more.
Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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18 pages, 15756 KiB  
Review
Subsequent Malignant Neoplasms in Retinoblastoma Survivors
by Armida W. M. Fabius, Milo van Hoefen Wijsard, Flora E. van Leeuwen and Annette C. Moll
Cancers 2021, 13(6), 1200; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061200 - 10 Mar 2021
Cited by 10 | Viewed by 2591
Abstract
Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence [...] Read more.
Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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14 pages, 987 KiB  
Review
Retinoblastoma Tumor Suppressor Protein Roles in Epigenetic Regulation
by Frederick Guzman, Yasamin Fazeli, Meagan Khuu, Kelsey Salcido, Sarah Singh and Claudia A. Benavente
Cancers 2020, 12(10), 2807; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102807 - 29 Sep 2020
Cited by 24 | Viewed by 4224
Abstract
Mutations that result in the loss of function of pRB were first identified in retinoblastoma and since then have been associated with the propagation of various forms of cancer. pRB is best known for its key role as a transcriptional regulator during cell [...] Read more.
Mutations that result in the loss of function of pRB were first identified in retinoblastoma and since then have been associated with the propagation of various forms of cancer. pRB is best known for its key role as a transcriptional regulator during cell cycle exit. Beyond the ability of pRB to regulate transcription of cell cycle progression genes, pRB can remodel chromatin to exert several of its other biological roles. In this review, we discuss the diverse functions of pRB in epigenetic regulation including nucleosome mobilization, histone modifications, DNA methylation and non-coding RNAs. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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23 pages, 718 KiB  
Review
Retinoblastoma: Etiology, Modeling, and Treatment
by Rossukon Kaewkhaw and Duangnate Rojanaporn
Cancers 2020, 12(8), 2304; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082304 - 16 Aug 2020
Cited by 51 | Viewed by 9596
Abstract
Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the [...] Read more.
Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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18 pages, 325 KiB  
Guidelines
Current Indications of Secondary Enucleation in Retinoblastoma Management: A Position Paper on Behalf of the European Retinoblastoma Group (EURbG)
by Christina Stathopoulos, Livia Lumbroso-Le Rouic, Annette C. Moll, Manoj Parulekar, Philippe Maeder, François Doz, Helen Jenkinson, Maja Beck Popovic, Guillermo Chantada and Francis L. Munier
Cancers 2021, 13(14), 3392; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143392 - 06 Jul 2021
Cited by 6 | Viewed by 2616
Abstract
Secondary enucleation (SE) puts an irreversible end to eye-preserving therapies, whenever their prolongation is expected to violate the presumed state of metastatic grace. At present, it must be acknowledged that clear criteria for SE are missing, leading to empiric and subjective indications commonly [...] Read more.
Secondary enucleation (SE) puts an irreversible end to eye-preserving therapies, whenever their prolongation is expected to violate the presumed state of metastatic grace. At present, it must be acknowledged that clear criteria for SE are missing, leading to empiric and subjective indications commonly related to disease progression or relapse, disease persistence masking the optic nerve head or treatment-related complications obscuring the fundus view. This absence of evidence-based consensus regarding SE is explained by the continuously moving frontiers of the conservative management as a result of diagnostic and therapeutic advances, as well as by the lack of studies sufficiently powered to accurately stratify the risk of metastasis in conservatively treated patients. In this position paper of the European Retinoblastoma Group (EURbG), we give an overview of the progressive shift in the indications for SE over the past decades and propose guidelines to assist decision-making with respect to when SE becomes imperative or recommended, with corresponding absolute and relative SE indications. Further studies and validation of biologic markers correlated with the risk of metastasis are expected to set more precisely the frontiers of conservative management and thus consensual criteria for SE in the future. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
9 pages, 477 KiB  
Commentary
At What Age Could Screening for Familial Retinoblastoma Be Discontinued? A Systematic Review
by Milo van Hoefen Wijsard, Saskia H. Serné, René H. Otten, Machteld I. Bosscha, Charlotte J. Dommering, Armida W. Fabius and Annette C. Moll
Cancers 2021, 13(8), 1942; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081942 - 17 Apr 2021
Cited by 2 | Viewed by 1897
Abstract
The aim of this systematic review is to assess the latest age at diagnosis for detection of familial retinoblastoma in order to evaluate at what age screening of at-risk children could be discontinued. Extended screening beyond this age would result in unnecessary patient [...] Read more.
The aim of this systematic review is to assess the latest age at diagnosis for detection of familial retinoblastoma in order to evaluate at what age screening of at-risk children could be discontinued. Extended screening beyond this age would result in unnecessary patient burden and costs. However, discontinuing screening prematurely would have the adverse effect of missing tumors. We performed a literature search (PubMed, Embase, CINAHL and the Cochrane Library) up until February of 2021 and systematically included studies where patients had a family history of retinoblastoma, a known age at diagnosis, and who were ophthalmologically screened for retinoblastoma from birth. A total of 176 familial retinoblastoma patients from 17 studies were included in this review. Based on 48 months of age being the latest age of diagnosis, ophthalmological screening for familial retinoblastoma could safely be discontinued at age four years. Full article
(This article belongs to the Special Issue Retinoblastoma—Current Therapeutic Challenges and Promising New Approaches)
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