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Retinoblastoma is a rare tumour of the eye which develops in the cells of the retina, most patients are under 5 years old. Sometimes only one eye is affected (unilateral-retinoblastoma ), but in about two fifths of patients both eyes have the disease (bilateral-retinoblastoma ). Some cases are known to be hereditary.

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Retinoblastoma Genetics
Eye Cancers

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Zhang H, Zhong J, Bian Z, et al.
Long non-coding RNA CCAT1 promotes human retinoblastoma SO-RB50 and Y79 cells through negative regulation of miR-218-5p.
Biomed Pharmacother. 2017; 87:683-691 [PubMed] Related Publications
OBJECTIVE: To investigate the regulatory role and potential mechanism of long non-coding RNAs (lncRNA) in human retinoblastoma (RB).
METHODS: The lncRNA profile in RB tissues were analyzed by microarray and quantitative reverse transcription PCR (qRT-PCR). One of the identified lncRNAs (LncRNA CCAT1) was selected for further experiments. SO-RB50 and Y79 cells were transfected with negative control, siRNA targeting lncRNA CCAT1 (si-CCAT1) and si-CCAT1+miR218-5p inhibitor, respectively. lncRNA CCAT1 expression was measured by qRT-PCR. Cell proliferation, migration and invasion were detected by CCK8, wound scratching, and transwell assay, respectively. Apoptosis and cell cycle distribution were assessed by flow cytometry. Apoptosis- (cle-caspase-3, cle-caspase-9, Bax and Bcl-2) and cell cycle-related protein expression (cyclin B1, CDC2 and p-CDC2 (Thr161)) were analyzed by Western blot.
RESULTS: lncRNA CCAT1 expression in SO-RB50 and Y79 cells was significantly inhibited after si-CCAT1 transfection (P<0.01). Both RB cells exhibited significantly reduced proliferation, migration and invasion abilities, but markedly increased apoptosis at 48h after si-CCAT1 transfection (P<0.05 or 0.01). RB cells in si-CCAT1+miR218-5p inhibitor group had significantly higher proliferation, migration and invasion, but notably lower apoptosis compared with si-CCAT1 group at 24 and 48h after transfection (all P<0.05 or 0.01). si-CCAT1 significantly increased the expression of cle-caspase-3, cle-caspase-9, Bax, but decreased Bcl-2 expression (P<0.01). The proportion of G2/M SO-RB50 and Y79 cells in siCCAT1 group was significantly increased compared with negative control group (P<0.01). LncRNA CCAT1 interference significantly reduced the expression of cyclin B1, CDC2 and p-CDC2 (Thr161) (P<0.01).
CONCLUSION: LncRNA CCAT1 promotes the proliferation migration and invasion, and reduces cell apoptosis of SO-RB50 and Y79 cells, probably through negative modulation of miR-218-5p. Our study suggested lncRNA CCAT1 as a potential biomarker and therapeutic target for RB.

Related: Apoptosis CASP3 MicroRNAs

Shao Y, Yu Y, Zong R, et al.
Erlotinib has tumor inhibitory effect in human retinoblastoma cells.
Biomed Pharmacother. 2017; 85:479-485 [PubMed] Related Publications
AIM: In this study, we explored the effect of erlotinib on the development of retinoblastoma (RB) cells both in vitro and in vivo.
METHOD: RB cell lines, Y79 and WERI cells were treated with various concentrations of erlotinib in vitro to assess their cytotoxic profiles. In vitro proliferation, cell-cycle transition and migration were compared between RB cells treated with erlotinib and cells without erlotinib treatment. In in vivo tumorigenicity assay, mice were injected with Y79 cells and orally fed with erlotinib for 28days. The effect of erlotinib on in vivo tumor grafts was then assessed. Western blot analysis on EGFR, ERK, AKT proteins and their phosphorylated proteins was also performed to assess molecular signaling pathways of associated with erlotinib in RB cells.
RESULTS: In vitro erlotinib treatment induced cytotoxicity in Y79 and WERI cells in dose-dependent manner. While Y79 and WERI cells were treated with erlotinib close to EC50 concentrations for 3days, RB proliferation, cell-cycle transition and migration were all significantly inhibited. In in vivo tumorigenicity assay, oral induction of erlotinib also dramatically reduced the growth of Y79 tumor grafts. Western blot demonstrated that, in in vitro RB cells, erlotinib did not alter the protein expression levels of EGFR, ERK or AKT, but significantly reduced the expressions of phosphorylated EGFR, ERK and AKT proteins.
CONCLUSION: Erlotinib was shown to have tumor suppressive effect on RB growth in vitro and in vivo, possibly through the inhibition on EGFR, ERG/AKT signaling pathways.

Related: Apoptosis

Gao J, Zeng J, Guo B, et al.
Clinical presentation and treatment outcome of retinoblastoma in children of South Western China.
Medicine (Baltimore). 2016; 95(42):e5204 [PubMed] Free Access to Full Article Related Publications
To study the clinical presentation and treatment outcome among children in South Western China with retinoblastoma (RB) and to determine factors predictive of poor outcome.A retrospective review of children diagnosed with RB from 2006 to 2015 at West China Hospital was undertaken. Demographic and clinical characteristics and treatment outcomes were studied.A total of 253 patients (unilateral 80.2%, bilateral 19.8%) were studied. Twenty six patients (10.3%) were from minority ethnic groups of China. The median onset age was 21 months. Leukocoria was the most common presenting sign (71%). Tumors were intraocular in 91.3% cases, extraocular in 8.7% cases. Extraocular RB patients had a longer median lag period than intraocular patients (9 months vs 2 months, P < 0.0001). In the intraocular group, 89.5% were advanced group D or E diseases. Enucleation was the major treatment for intraocular RB. However, over 10 years, the enucleation rate decreased constantly while more patients received chemotherapy. The Kaplan-Meier survival probability was 87.8%, 81.4%, and 74.8% at 3 years, 5 years, and 10 years, respectively. On Cox regression analysis, extraocular RB (P = 0.0008) and treatment abandonment (P < 0.0001) were associated with poor outcome; bilateral RB (P = 0.0116) and advanced pathological grade pT4 (P = 0.0011) were associated with poor outcome of intraocular RB.Most RB patients from South Western China were diagnosed at advanced clinical stage. Delayed presentation is related to extraocular RB which is a risk factor for poor outcome. Chemotherapy increased the eye salvage but had no effects to overall survival. Education for parents and general physicians for the early signs of RB (such as leukocoria), therapeutic strategy and treatment outcomes of RB may promote early diagnosis, improve the compliance, and outcome.

Tuncer S, Sencer S, Kebudi R, et al.
Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey.
Acta Ophthalmol. 2016; 94(7):e644-e651 [PubMed] Related Publications
PURPOSE: To report our 4-year experience in Turkey, with advanced intra-ocular retinoblastoma managed primarily with intra-arterial chemotherapy (IAC).
METHODS: From October 2011 to September 2015, 26 group D eyes of 24 treatment-naïve retinoblastoma patients managed primarily with IAC were evaluated in this prospective study.
RESULTS: Of 76 procedures, ophthalmic artery cannulation failed in two patients with unilateral involvement. In the remaining 22 patients (24 eyes), the mean age at diagnosis was 18 months (range, 6-55 months). Each eye received a mean of 3 IAC sessions/eye (range, 2-5 sessions). After a median follow-up of 29 months (range, 6-55 months), complete regression of the main tumour was achieved in 23 of 24 eyes. One eye with partial regression required enucleation due to ciliary body involvement by the tumour. Overall, 16 eyes (66.6%) were salvaged with primary IAC with or without additional local treatments, and eight (33.3%) required enucleation. The main IAC-related periocular complications included transient eyelid oedema (n = 13), ptosis (n = 6) and forehead hyperpigmentation (n = 3), each resolving in 2 weeks to 4 months. Intra-ocular complications included chorioretinal atrophy (n = 9), newly noted retinal detachment (n = 5) and vitreous haemorrhage (n = 1). Kaplan-Meier eye estimates of enucleation-free survival rates were 83.3% (95% CI, 68.4-98.1%), 69.1% (95% CI, 49.8-88.3%) and 62.9 (95% CI, 41.9-83.8%) at 6 months, 1 and 2 years, respectively, and stable thereafter.
CONCLUSION: Our first 4-year experience in Turkey showed that enucleation or external-beam radiotherapy could be avoided in two-thirds of eyes with advanced intra-ocular retinoblastoma managed primarily with IAC.

Related: Melphalan

Thottian AG, Benson R, Kashyap S, et al.
Orbital medulloepithelioma in an adult patient: Radiation-induced second neoplasia?
Orbit. 2016; 35(6):313-316 [PubMed] Related Publications
Second cancers in survivors of hereditary retinoblastoma occur much more commonly than in the general population. This can be attributed both to the germline mutation of the RB gene and chemoradiation used for treatment of this paediatric cancer. Medulloepithelioma is an uncommon tumor of neuroectodermal origin, seen largely in the paediatric population and rarely reported in adults. Though the incidence of second malignancies is common in retinoblastoma, medulloepithelioma as a second malignancy in retinoblastoma survivors is rare, with only one case reported so far. Herein, we present a case of a 29-year-old patient presenting with medulloepithelioma of the right orbit, arising in the radiation field of previously treated retinoblastoma. This case was also peculiar in that though the origin of tumor was in the eyeball it had a very aggressive clinical course.

Singh U, Malik MA, Goswami S, et al.
Epigenetic regulation of human retinoblastoma.
Tumour Biol. 2016; 37(11):14427-14441 [PubMed] Related Publications
Retinoblastoma is a rare type of eye cancer of the retina that commonly occurs in early childhood and mostly affects the children before the age of 5. It occurs due to the mutations in the retinoblastoma gene (RB1) which inactivates both alleles of the RB1. RB1 was first identified as a tumor suppressor gene, which regulates cell cycle components and associated with retinoblastoma. Previously, genetic alteration was known as the major cause of its occurrence, but later, it is revealed that besides genetic changes, epigenetic changes also play a significant role in the disease. Initiation and progression of retinoblastoma could be due to independent or combined genetic and epigenetic events. Remarkable work has been done in understanding retinoblastoma pathogenesis in terms of genetic alterations, but not much in the context of epigenetic modification. Epigenetic modifications that silence tumor suppressor genes and activate oncogenes include DNA methylation, chromatin remodeling, histone modification and noncoding RNA-mediated gene silencing. Epigenetic changes can lead to altered gene function and transform normal cell into tumor cells. This review focuses on important epigenetic alteration which occurs in retinoblastoma and its current state of knowledge. The critical role of epigenetic regulation in retinoblastoma is now an emerging area, and better understanding of epigenetic changes in retinoblastoma will open the door for future therapy and diagnosis.

Related: MicroRNAs

Hiwatashi A, Togao O, Yamashita K, et al.
3D turbo field echo with diffusion-sensitized driven-equilibrium preparation technique (DSDE-TFE) versus echo planar imaging in evaluation of diffusivity of retinoblastoma.
Br J Radiol. 2016; 89(1067):20160074 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
OBJECTIVE: Compared with echoplanar (EP) diffusion-weighted imaging (DWI), three-dimensional (3D) turbo field echo with diffusion-sensitized driven-equilibrium (DSDE-TFE) preparation DWI obtains images with higher spatial resolution and less susceptibility artefacts. The purpose of this study was to evaluate the feasibility of DSDE-TFE to visualize retinoblastomas compared with EP imaging.
METHODS: This retrospective study was approved by our institutional review boards. Eight patients with retinoblastomas (five males and three females; age range 0-87 months; median 21 months) were studied. For the DSDE-TFE, motion-probing gradients (MPGs) were conducted at one direction with b-values of 0 and 500 s mm(-2) and a voxel size of 1.5 × 1.5 × 1.5 mm(3). For the EP imaging, MPGs were conducted at three directions with b-values of 0 and 1000 s mm(-2) and a voxel size of 1.4 × 1.8 × 3 mm(3). The apparent diffusion coefficients (ADCs) of each lesion were measured. Statistical analyses were performed with Pearson R and linear correlation coefficients.
RESULTS: Intraocular lesions were clearly visualized on the DSDE-TFE without obvious geometrical distortion, whereas all showed deformity on EP images. On the DSDE-TFE, the ADCs of the lesions ranged from 0.83 × 10(-3) to 2.93 × 10(-3) mm(2) s(-1) (mean ± standard deviation 1.73 ± 0.73 × 10(-3) mm(2) s(-1)). On the EP images, the ADCs ranged from 0.53 × 10(-3) to 2.03 × 10(-3) mm(2) s(-1) (0.93 ± 0.53 × 10(-3) mm(2) s(-1)). There was a significant correlation in ADC measurement between the DSDE-TFE and EP imaging (r = 0.81, p < 0.05).
CONCLUSION: With its insensitivity to field inhomogeneity and high spatial resolution, the 3D DSDE-TFE technique enabled us to assess diffusivity in retinoblastomas. Advances in knowledge: DSDE-TFE could enable us to assess the ADC of retinoblastomas without obvious geometrical distortion.

Francis JH, Levin AM, Abramson DH
Update on Ophthalmic Oncology 2014: Retinoblastoma and Uveal Melanoma.
Asia Pac J Ophthalmol (Phila). 2016 Sep-Oct; 5(5):368-82 [PubMed] Related Publications
PURPOSE: The aim of this study was to review peer-reviewed articles on ophthalmic oncology (specifically retinoblastoma and uveal melanoma) published from January to December 2014.
DESIGN: This study is a literature review.
METHODS: The terms retinoblastoma and uveal melanoma were used in a MEDLINE literature search. Abstracts were studied, and the most relevant articles were selected for inclusion and further in-depth review.
RESULTS: In retinoblastoma, more eyes are being salvaged due to intravitreal melphalan. The year 2014 marks a deepening in our understanding of the biological basis of the disease and the cell of origin. Knowledge on the genetic underpinnings of uveal melanoma has broadened to include other pathways, interactions, and potential therapeutic targets.
CONCLUSIONS: In 2014, there were valuable advancements in our knowledge of retinoblastoma and uveal melanoma. Some of these resulted in improved patient management.

Related: Melanoma Ocular Melanoma IntraOcular Melanoma

Gui F, Hong Z, You Z, et al.
MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.
Cell Biol Int. 2016; 40(12):1294-1302 [PubMed] Related Publications
MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

Related: Apoptosis MicroRNAs PTEN AKT1 Signal Transduction microRNA mir-21

Kaliki S, Tahiliani P, Iram S, et al.
Choroidal Infiltration by Retinoblastoma: Predictive Clinical Features and Outcome.
J Pediatr Ophthalmol Strabismus. 2016; 53(6):349-356 [PubMed] Related Publications
PURPOSE: To identify the clinical features predictive of choroidal infiltration by retinoblastoma on histopathology and to report the outcome in these patients.
METHODS: Retrospective study.
RESULTS: Of the 403 patients who underwent primary enucleation for retinoblastoma, 113 patients had choroidal tumor infiltration and 290 patients had no choroidal tumor infiltration. There was a higher incidence of metastasis and related death in the choroidal tumor infiltration group compared to the no choroidal tumor infiltration group (4% vs 1%; P = .02). On multivariate analysis, the clinical features predictive of histopathologic massive choroidal infiltration included prolonged duration of symptoms for more than 6 months (hazard ratio [HR] = 3.04; P = .001) and secondary glaucoma (HR = 2.24; P = .005).
CONCLUSIONS: In this study, the patients with retinoblastoma with prolonged duration of symptoms (> 6 months) had a three-fold greater risk and those with secondary glaucoma at presentation had a two-fold greater risk of massive choroidal tumor infiltration. [J Pediatr Ophthalmol Strabismus. 2016;53(6):349-356.].

Naru J, Aggarwal R, Singh U, et al.
Proteomic analysis of differentially expressed proteins in vitreous humor of patients with retinoblastoma using iTRAQ-coupled ESI-MS/MS approach.
Tumour Biol. 2016; 37(10):13915-13926 [PubMed] Related Publications
There is close proximity of vitreous humor with the tumor bulk in eyes with retinoblastoma. This renders vitreous humor a promising source to evaluate disease-specific protein targets in retinoblastoma. We studied the differential proteome of vitreous fluid in retinoblastoma tumors (n = 4) as compared to controls (n = 4). The vitreous humor was depleted off the high abundant fraction using MARS-6 affinity column. Subsequently, the tryptic peptides were derivatised with iTRAQ labels. The labelled peptides were pooled and subjected to fractionation using bRPLC. This was followed by protein identification and quantification using electrospray ionisation mass spectrometry (ESI-MS/MS) approach. The identified proteins were subjected to bioinformatics analysis utilizing PANTHER 7.0 and IPA software. Four hundred and thirty-one non-redundant (362 upregulated and 69 downregulated) proteins (≥2 unique peptides, ± 1.5 folds, p < 0.05) were identified. The majority of the proteins were cytoplasmic (40 %), majorly involved in catalytic (32.7 %) and binding activities (26.3 %). Highly deregulated proteins included MMP2, TNC, CD44, SUZ12 and CRABP1. The protein expression of GFAP, CRABP1, MMP2 and TNC was validated by western blotting. Pathway and network analyses revealed p38MAPK and Akt signalling to be the most significantly regulated pathways in retinoblastoma. This is the first report of differential vitreous proteome of retinoblastoma and highlights novel protein targets, such as MMP2, TNC and CRABP1. Further investigations into unravelling the biological role of the proteins and their prospects of being utilised as potential candidates in therapeutics are warranted.

Mallipatna A, Marino M, Singh AD
Genetics of Retinoblastoma.
Asia Pac J Ophthalmol (Phila). 2016 Jul-Aug; 5(4):260-4 [PubMed] Related Publications
Retinoblastoma is a malignant retinal tumor that affects young children. Mutations in the RB1 gene cause retinoblastoma. Mutations in both RB1 alleles within the precursor retinal cell are essential, with one mutation that may be germline or somatic and the second one that is always somatic. Identification of the RB1 germline status of a patient allows differentiation between sporadic and heritable retinoblastoma variants. Application of this knowledge is crucial for assessing short-term (risk of additional tumors in the same eye and other eye) and long-term (risk of nonocular malignant tumors) prognosis and offering cost-effective surveillance strategies. Genetic testing and genetic counseling are therefore essential components of care for all children diagnosed with retinoblastoma. The American Joint Committee on Cancer has acknowledged the importance of detecting this heritable trait and has introduced the letter "H" to denote a heritable trait of all cancers, starting with retinoblastoma (in publication). In this article, we discuss the clinically relevant aspects of genetic testing and genetic counseling for a child with retinoblastoma.

Magan T, Khoo CT, Jabbour PM, et al.
Intra-arterial Chemotherapy for Adult Onset Retinoblastoma in a 32-Year-Old Man.
J Pediatr Ophthalmol Strabismus. 2016; 53:e43-6 [PubMed] Related Publications
A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.].

Related: Brachytherapy Melphalan Topotecan

Shields CL, Alset AE, Say EA, et al.
Retinoblastoma Control With Primary Intra-arterial Chemotherapy: Outcomes Before and During the Intravitreal Chemotherapy Era.
J Pediatr Ophthalmol Strabismus. 2016; 53(5):275-84 [PubMed] Related Publications
PURPOSE: To compare outcomes of intra-arterial chemotherapy for retinoblastoma as primary therapy before (Era I) and during (Era II) the intravitreal chemotherapy era.
METHODS: In this retrospective interventional case series at a tertiary referral center, 66 eyes of 66 patients with untreated unilateral retinoblastoma were used. intraarterial chemotherapy into the ophthalmic artery under fluoroscopic guidance was performed using melphalan in every case, with additional topotecan as necessary. Intravitreal chemotherapy using melphalan and/or topotecan was employed as needed for active vitreous seeding. Globe salvage was measured based on the International Classification of Retinoblastoma (ICRB) during two eras.
RESULTS: The two eras encompassed 2008 to 2012 (intraarterial chemotherapy alone, Era I) and 2012 to 2015 (intraarterial chemotherapy plus intravitreal chemotherapy, Era II). Over this period, there were 66 patients with unilateral untreated retinoblastoma treated with primary intra-arterial chemotherapy. A comparison of features (Era I vs Era II) revealed no significant difference in mean patient age (24 vs 24 months), ICRB groups, mean largest tumor diameter (19 vs 17 mm), mean largest tumor thickness (10 vs 10 mm), vitreous seed presence (56% vs 59%), subretinal seed presence (67% vs 62%), retinal detachment (70% vs 66%), or vitreous hemorrhage (0% vs 5%). There was no significant difference in mean number of intra-arterial chemotherapy cycles (3 vs 3.1) or intraarterial chemotherapy dosages. Following therapy, there was a significant difference (Era I vs Era II) in the need for enucleation overall (44% vs 15%, P = .012), especially for group E eyes (75% vs 27%, P = .039). Four of the eyes that initiated therapy in Era I later required intravitreal chemotherapy during Era II. The enucleation rate was 0% for groups B and C in both eras and non-significant for group D (23% vs 13%). There were no patients with stroke, seizure, limb ischemia, extraocular tumor extension, secondary leukemia, metastasis, or death.
CONCLUSIONS: The current era of retinoblastoma management using intra-arterial chemotherapy plus additional intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma. [J Pediatr Ophthalmol Strabismus. 2016;53(5):275-284.].

Related: Melphalan Topotecan

Li X, Yang L, Shuai T, et al.
MiR-433 inhibits retinoblastoma malignancy by suppressing Notch1 and PAX6 expression.
Biomed Pharmacother. 2016; 82:247-55 [PubMed] Related Publications
Retinoblastoma (RB) is the most frequent primary intraocular cancer. It has been demonstrated by previous studies that retinoblastoma is initiated primarily by the inactivation of the retinoblastoma Rb1 gene in retinal cells. However, additional genetic alterations than Rb1 mutation could play important roles in the process of transforming benign retinal cells into retinoblastoma tumor cells. In this study, we identified that microRNA miR-433 is one of such genetic factors. We found that the expression levels of miR-433 were downregulated in RB tissues. We also determined that miR-433 negatively regulated RB cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis of RB cells. We used bioinformatics method to predict and confirmed that Notch1 and PAX6 were miR-433 target genes in RB cells. Importantly, we demonstrated that restoration of Notch1 and PAX6 expression partially rescued the inhibition of cell proliferation and metastasis induced by miR-433 overexpression, suggesting that miR-433 regulates RB cell proliferation and metastasis through suppressing the expression of Notch1 and PAX6.

Related: Apoptosis MicroRNAs

Fadakar P, Akbari A, Ghassemi F, et al.
Evaluation of SD-208, a TGF-β-RI Kinase Inhibitor, as an Anticancer Agent in Retinoblastoma.
Acta Med Iran. 2016; 54(6):352-8 [PubMed] Related Publications
Retinoblastoma is the most common intraocular tumor in children resulting from genetic alterations and transformation of mature retinal cells. The objective of this study was to investigate the effects of SD-208, TGF-β-RI kinase inhibitor, on the expression of some miRNAs including a miR-17/92 cluster in retinoblastoma cells. Prior to initiate this work, the cell proliferation was studied by Methyl Thiazolyl Tetrazolium (MTT) and bromo-2'-deoxyuridine (BrdU) assays. Then, the expression patterns of four miRNAs (18a, 20a, 22, and 34a) were investigated in the treated SD-208 (0.0, 1, 2 and 3 µM) and untreated Y-79 cells. A remarkable inhibition of the cell proliferation was found in Y-79 cells treated with SD-208 versus untreated cells. Also, the expression changes were observed in miRNAs 18a, 20a, 22 and 34a in response to SD-208 treatment (P<0.05). The findings of the present study suggest that the anti-cancer effect of SD-208 may be exerted due to the regulation of specific miRNAs, at least in this particular retinoblastoma cell line. To the best of the researchers' knowledge, this is the first report demonstrating that the SD-208 could alter the expression of tumor suppressive miRNAs as well as oncomiRs in vitro. In conclusion, the present data suggest that SD-208 could be an alternative agent in retinoblastoma treatment.

Related: MicroRNAs

Baker MS, McConnell LK, Kleinberg TT, et al.
Orbital sarcomas in retinoblastoma patients: recommendations for screening and treatment guidelines.
Curr Opin Ophthalmol. 2016; 27(5):443-8 [PubMed] Related Publications
PURPOSE OF REVIEW: Retinoblastoma is the most common primary ocular malignancy in children. Although currently retinoblastoma has an excellent survival rate in developed countries, hereditary retinoblastoma survivors as well as those with a history of radiation therapy as children are at an increased risk for second primary tumors (SPTs), and specifically, for orbital sarcomas. Despite the known increased risk for SPTs in retinoblastoma survivors and the associated morbidity and mortality, no screening or treatment guidelines exist.
RECENT FINDINGS: Understanding of retinoblastoma tumorigenesis and genomic expression has expanded significantly, and treatment has evolved with a shift away from radiotherapy. Until the last two decades, however, radiation was the therapy of choice for patients with bilateral disease. Because both hereditary retinoblastoma and radiation are independent risk factors for the development of SPTs such as sarcomas and these SPTs are often fatal, appropriate surveillance for retinoblastoma survivors is crucial.
SUMMARY: As a result of the excellent survival rates for retinoblastoma patients, it is important to: recognize the risk of sarcoma, particularly in patients with hereditary retinoblastoma and/or prior radiation therapy; establish a screening protocol, such as the one proposed, to maximize early detection; and discuss and develop treatment guidelines for high-risk patients. Future directions of research for these patients will involve the development of molecularly targeted agents and the use of proton radiotherapy.

Related: Soft Tissue Sarcomas

Chen C, Ma FW, Du CY, Wang P
Multiple Differential Networks Strategy Reveals Carboplatin and Melphalan-Induced Dynamic Module Changes in Retinoblastoma.
Med Sci Monit. 2016; 22:1508-15 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND Retinoblastoma (RB) is the most common malignant tumor of the eye in childhood. The objective of this paper was to investigate carboplatin (CAR)- and melphalan (MEL)-induced dynamic module changes in RB based on multiple (M) differential networks, and to generate systems-level insights into RB progression. MATERIAL AND METHODS To achieve this goal, we constructed M-differential co-expression networks (DCNs), assigned a weight to each edge, and identified seed genes in M DCNs by ranking genes based on their topological features. Starting with seed genes, a module search was performed to explore candidate modules in CAR and MEL condition. M-DMs were detected according to significance evaluations of M-modules, which originated from refinement of candidate modules. Further, we revealed dynamic changes in M-DM activity and connectivity on the basis of significance of Module Connectivity Dynamic Score (MCDS). RESULTS In the present study, M=2, a total of 21 seed genes were obtained. By assessing module search, refinement, and evaluation, we gained 18 2-DMs. Moreover, 3 significant 2-DMs (Module 1, Module 2, and Module 3) with dynamic changes across CAR and MEL condition were determined, and we denoted them as dynamic modules. Module 1 had 27 nodes of which 6 were seed genes and 56 edges. Module 2 was composed of 28 nodes and 54 edges. A total of 28 nodes interacted with 45 edges presented in Module 3. CONCLUSIONS We have identified 3 dynamic modules with changes induced by CAR and MEL in RB, which might give insights in revealing molecular mechanism for RB therapy.

Related: Carboplatin Melphalan

Singh G, Daniels AB
Disparities in Retinoblastoma Presentation, Treatment, and Outcomes in Developed and Less-Developed Countries.
Semin Ophthalmol. 2016; 31(4):310-6 [PubMed] Related Publications
Retinoblastoma (RB) is the most common intraocular malignancy in children. In the past century, RB survival rates in developed countries (DCs) have improved from <5% to as high as 99%. In contrast, in less developed countries (LDCs) where the tumor burden is greatest, survival rates remain poor, with some countries reporting survival rates as low as 0-5%. In addition, there are disparities between DCs and LDCs in RB presentation, treatment modalities, and prognosis. These disparities are due to many underlying causes, including delays in diagnosis, access to medical care, patient and physician familiarity with the disease, availability and cost of treatment, and patient acceptance of enucleation. It is our belief that attempts to extend the improvements in prognosis achieved in DCs to various LDCs must be culturally sensitive and tailored to each country's specific challenges, and thus, a "one-size-fits-all" approach to improving patient outcomes in LDCs is unlikely to work well. We discuss several culturally sensitive approaches that have been successfully implemented in various LDCs, including those that make use of telemedicine and "twinning" with centers of excellence around the world.

Kooi IE, Mol BM, Massink MP, et al.
A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression.
PLoS One. 2016; 11(4):e0153323 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes.
METHODS: We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310).
RESULTS: Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades.
INTERPRETATION: Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

Zhang Y, Xue C, Zhu X, et al.
Suppression of microRNA-125a-5p upregulates the TAZ-EGFR signaling pathway and promotes retinoblastoma proliferation.
Cell Signal. 2016; 28(8):850-60 [PubMed] Related Publications
Retinoblastoma is the most common intraocular malignancy that occurs during childhood; however, the mechanism underlying retinoblastoma proliferation and progression remains unclear. MicroRNAs (miRNAs) play an important role in the regulation of a myriad of biological processes in various types of cancer. In this study, we performed microarray analysis followed by qRT-PCR using four classes of retinoblastoma tissues with increasing cTNM classification stages to identify crucial miRNAs whose expression was correlated with retinoblastoma progression. miR-125a-5p was downregulated, and its expression levels were inversely correlated with cell proliferation in retinoblastoma compared with adjacent non-tumor retinal tissues. The overexpression of miR-125a-5p significantly suppressed cell proliferation and tumor formation in retinoblastoma. We further identified the transcriptional co-activator with PDZ binding motif (TAZ) as a direct target of miR-125a-5p. Importantly, TAZ levels were inversely correlated with miRNA-125a-5p expression, and TAZ promoted retinoblastoma cell proliferation. Moreover, the overexpression of miR-125a-5p led to a decrease in TAZ expression and downstream EGFR signaling pathway activation both in vitro and vivo. Finally, TAZ overexpression in retinoblastoma cells overexpressing miR-125a-5p restored retinoblastoma cell proliferation and EGFR pathway activation. Taken together, our data demonstrated that miR-125a-5p functions as an important tumor suppressor that suppresses the EGFR pathway by targeting TAZ to inhibit tumor progression in retinoblastoma. Thus, the miR-125a-5p/TAZ/EGFR axis may be a potential therapeutic target for retinoblastoma.

Related: MicroRNAs Signal Transduction

Venkatesan N, Kanwar JR, Deepa PR, et al.
Targeting HSP90/Survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma.
Chem Biol Interact. 2016; 252:141-9 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) is a childhood retinal malignancy. Effective therapeutic strategies are still being investigated in RB disease management. Here, the anti-cancer effect of shepherdin, a peptido-mimetic inhibiting heat shock protein (HSP90)-Survivin interaction has been analyzed.
METHODS: We analyzed HSP (HSP70/90) and Survivin protein expressions by immunohistochemistry (29 archival tumors), qRT-PCR, FACS and Western analysis (10 un-fixed RB tumors). We also analyzed cellular cytotoxicity and anti-proliferative effect in peptide treated RB cells (Y79, Weri Rb1) and MIO-M1 cells.
RESULTS: Heterogeneous expressions of HSP70/90 and Survivin with a significant association between HSP70 and HSP90 (r(2) = 0.59, p = 0.001) was observed. In RB cells, anti-tumor effects were detected with 0.42 μg/ml of shepherdin at 4 h s of serum starvation. Decreased Survivin, Bcl2, MMP-2 activity with increased Bax, Bim, and Caspase-9 protein expressions were noticed. No significant changes were observed in shepherdin treated non-neoplastic MIO-M1, nor in scramble-peptide treated RB cells.
CONCLUSION: The presence of HSPs (HSP70/90) and Survivin reveals multiple cellular mechanisms adopted by RB cells during cancer progression. Serum starvation induced HSP90 whose interactions with Survivin were specifically inhibited by shepherdin. The associated molecular shuffling has been reported. These findings strongly implicate the potential of targeting HSP90-Survivin interaction as an adjuvant therapy in RB management.

Related: Apoptosis MMP2

Hille S, Dierck F, Kühl C, et al.
Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling.
Cardiovasc Res. 2016; 110(3):381-94 [PubMed] Related Publications
AIMS: Down syndrome-associated dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) is a ubiquitously expressed protein kinase. Up to date a variety of targets have been identified, establishing a key role for Dyrk1a in selected signalling pathways. In cardiomyocytes, Dyrk1a acts as a negative regulator of hypertrophy by phosphorylating transcription factors of the NFAT family, but its mechanistic function in the heart remains poorly understood. This study was designed to investigate a potential protective role of Dyrk1a in cardiac hypertrophy in vivo.
METHODS AND RESULTS: We generated transgenic mice with cardiac-specific overexpression of Dyrk1a. Counterintuitively, these mice developed severe dilated cardiomyopathy associated with congestive heart failure and premature death. In search for the cause of this unexpected phenotype, we found that Dyrk1a interacts with all members of the D-cyclin family and represses their protein levels in vitro and in vivo. Particularly, forced expression of Dyrk1a leads to increased phosphorylation of Ccnd2 on Thr280 and promotes its subsequent proteasomal degradation. Accordingly, cardiomyocytes overexpressing Dyrk1a display hypo-phosphorylated Rb1, suppression of Rb/E2f-signalling, and reduced expression of E2f-target genes, which ultimately results in impaired cell cycle progression.
CONCLUSIONS: We identified Dyrk1a as a novel negative regulator of D-cyclin-mediated Rb/E2f-signalling. As dysregulation of this pathway with impaired cardiomyocyte proliferation leads to cardiomyopathy, dose-specific Dyrk1a expression and activity appears to be critical for the hyperplastic and hypertrophic growth of the developing heart.

Related: Signal Transduction

Ferrario A, Luna M, Rucker N, et al.
Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors.
PLoS One. 2016; 11(4):e0153011 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
Treatments for retinoblastoma (Rb) vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE) cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155). Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy.

Related: Apoptosis BIRC5

Selistre SG, Maestri MK, Santos-Silva P, et al.
Retinoblastoma in a pediatric oncology reference center in Southern Brazil.
BMC Pediatr. 2016; 16:48 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Retinoblastoma (Rb) is the most common intraocular tumor diagnosed in children in Brazil. However, detailed information is lacking regarding patient clinical demographics. This study aimed to determine the clinical profile of patients with Rb who were treated in a public university hospital in southern Brazil from 1983 to 2012.
METHODS: Patients' medical records were reviewed to retrospectively identify patients with a principal diagnosis of Rb. Rb was classified as hereditary or non-hereditary. Clinical staging was reviewed by an ophthalmologist. Statistical analysis was performed using SPSS.
RESULTS: Of 165 patients with a diagnosis of Rb during this period, 140 were included in the study. Disease was unilateral in 65.0 % of patients, bilateral in 32.9 %, and trilateral in 2.1 %. The mean age at onset of the first sign/symptom was 18.1 month, and 35.7 % of patients were diagnosed during the first year of life. The most common presenting signs were leukocoria (73.6 %) and strabismus (20.7 %). The mean age at diagnosis was 23.5 months, and time to diagnosis was 5.4 months. In patients with clinical features of hereditary Rb, both onset of the first sign/symptom and diagnosis were at an earlier age than in patients without these features (12.3 vs 21.6 months [P = 0.001] and 15.9 vs 28.0 months [P < 0.001], respectively). However, there was no significant difference in overall survival between the two groups. Ocular stage at diagnosis was advanced in 76.5 % (Reese V) and 78.1 % (International Classification D or E). Of patients with unilateral and bilateral disease, 35.2 % and 34.8 %, respectively, had extraocular disease at diagnosis; 10.7 % had metastatic disease at diagnosis. Enucleation was observed in 88.1 % and exenteration in 11.9 % of patients; 93.6 % patients were followed until 2012, and 22.9 % relapsed. Overall survival was 86.4 %.
CONCLUSIONS: Most Rb diagnoses are still diagnosed in advanced stages of the disease, considerably reducing overall survival time and the rate of eye and vision preservation.

Related: Cancer Screening and Early Detection

Zhang Y, Wu D, Xia F, et al.
Downregulation of HDAC9 inhibits cell proliferation and tumor formation by inducing cell cycle arrest in retinoblastoma.
Biochem Biophys Res Commun. 2016; 473(2):600-6 [PubMed] Related Publications
Histone deacetylase 9 (HDAC9) is a member of class II HDACs, which regulates a wide variety of normal and abnormal physiological functions. Recently, HDAC9 has been found to be overexpressed in some types of human cancers. However, the role of HDAC9 in retinoblastoma remains unclear. In this study, we found that HDAC9 was commonly expressed in retinoblastoma tissues and HDAC9 was overexpressed in prognostically poor retinoblastoma patients. Through knocking down HDAC9 in Y79 and WERI-Rb-1 cells, the expression level of HDAC9 was found to be positively related to cell proliferation in vitro. Further investigation indicated that knockdown HDAC9 could significantly induce cell cycle arrest at G1 phase in retinoblastoma cells. Western blot assay showed downregulation of HDAC9 could significantly decrease cyclin E2 and CDK2 expression. Lastly, xenograft study in nude mice showed that downregulation of HDAC9 inhibited tumor growth and development in vivo. Therefore, our results suggest that HDAC9 could serve as a novel potential therapeutic target in the treatment of retinoblastoma.

Azary S, Ganguly A, Bunin GR, et al.
Sporadic Retinoblastoma and Parental Smoking and Alcohol Consumption before and after Conception: A Report from the Children's Oncology Group.
PLoS One. 2016; 11(3):e0151728 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Retinoblastoma is the most frequent tumor of the eye in children and very little is known about the etiology of non-familial (sporadic) retinoblastoma. In this study we examined whether parental tobacco smoking or alcohol consumption (pre- or post-conception) contribute to the two phenotypes (bilateral or unilateral) of sporadic retinoblastoma.
METHODS: Two large multicenter case-control studies identified 488 cases through eye referral centers in the United States and Canada or through the Children's Oncology Group. Controls (n = 424) were selected from among friends and relatives of cases and matched by age. Risk factor information was obtained via telephone interview. We employed multivariable logistic regression to estimate the effects of parental tobacco smoking and alcohol consumption on retinoblastoma.
FINDINGS: Maternal smoking before and during pregnancy contributed to unilateral retinoblastoma risk in the child: year before pregnancy conditional Odds Ratio (OR), 8.9; 95% confidence interval (CI) 1.5-51, and unconditional OR, 2.4; 95% CI, 1.3-4.7; month before or during pregnancy, conditional OR, 3.3; 95% CI, 0.5-20.8, and unconditional OR, 2.8; 95% CI, 1.1-7.0. No association was found for maternal or paternal alcohol consumption.
CONCLUSION: The results of this study indicate that maternal active smoking during pregnancy may be a risk factor for sporadic retinoblastoma. Our study supports a role for tobacco exposures in embryonal tumors.

Related: Canada USA

Chao A, Kao LY, Liu L, Wang NK
Diffuse chorioretinal atrophy after a single standard low- dose intravitreal melphalan injection in a child with retinoblastoma: a case report.
BMC Ophthalmol. 2016; 16:27 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
BACKGROUND: Controlling retinoblastoma with seeding is challenging despite advances in treatment modalities. Intravitreal melphalan is an alternative to external beam radiation or enucleation for recurrent or refractory vitreous seeds. Significant ocular side effects following intravitreal melphalan injections are uncommon. Complications have been reported in eyes receiving higher concentrations of melphalan and repetitive injections. We report a case in which diffuse chorioretinal atrophy was developed at the injection site after a single, standard low-dose intravitreal melphalan injection.
CASE PRESENTATION: A 12-month-old female child without a family history of retinoblastoma presented with unilateral group C retinoblastoma in her right eye. A solitary tumour with retinal breaks on the tumour surface, and vitreous seeds overlying the tumour were observed at the 8 o'clock position of the retina. After two cycles of intra-arterial chemotherapy with melphalan, the main tumour displayed significant regression, but the vitreous seeds overlying the main tumour were still active. Because of the persistence of vitreous seeds and the inadequate response to intra-arterial melphalan treatment, intravitreal melphalan (8 μg in 0.05 mL) was injected using a 32-gauge needle 2.5 mm from the 5 o'clock position of the limbus, the meridian opposite to the vitreous seeds. After 1 month, the retina around the injection site demonstrated diffuse retinal pigment epithelium alterations with dense hard exudates. Although the main retinal mass, and vitreous seeds resolved, the hard exudates persisted for more than 2 years after the single low-dose melphalan injection.
CONCLUSIONS: Intravitreal melphalan injections should be cautiously used for eyes with refractory seeds, particularly when multiple injections are required to control retinoblastoma seeds. Dose- related retinal toxicity could occur in pre-treated eyes even when a relatively low standard dose is used. Such patients should be followed up closely to monitor the treatment response and to assess potential delayed toxicity.

Related: Melphalan

Delhiwala KS, Vadakkal IP, Mulay K, et al.
Retinoblastoma: An update.
Semin Diagn Pathol. 2016; 33(3):133-40 [PubMed] Related Publications
Retinoblastoma is the most common ocular malignancy in children, and is initiated by mutation of the RB1 gene. The tumor may be unilateral or bilateral and can be inherited. Overall survival, eye salvage, and preservation of vision are largely dependent on the stage of disease at presentation. Despite a recently enhanced understanding of the etiology of retinoblastoma, the mortality associated with it remains high worldwide. This may relate to a continuing lack of awareness of the lesion by laypersons, and unavailability of modern treatment facilities. Adverse outcomes are also caused by the occurrence of secondary malignancies after treatment of retinoblastoma in childhood. Early diagnosis, multidisciplinary treatment, and genetic counseling are all priorities in the management of this tumor.

Stagner AM, Jakobiec FA
Updates on the Molecular Pathology of Selected Ocular and Ocular Adnexal Tumors: Potential Targets for Future Therapy.
Semin Ophthalmol. 2016; 31(1-2):188-96 [PubMed] Related Publications
Ophthalmic pathologic studies of retinoblastoma first definitively elucidated a genetic etiology for cancer three decades ago. Advances in DNA sequencing, protein expression profiling, and the exploration of epigenetics have since led to categorization of tumors and clinical prognostication based on genetic aberrancy. There are now many neoplasms that are defined by a characteristic genetic signature. In the past several years alone, much has been discovered in regard to the original tumor-suppressor gene initially defined in retinoblastoma as well as in other intraocular tumors such as medulloepithelioma. Our further understanding of ocular adnexal tumors that result in substantial morbidity and mortality, such as sebaceous carcinoma, has also benefited from a genetic approach. In this article, we review the clinicopathologic features of the foregoing three entities--retinoblastoma, medulloepithelioma, and sebaceous carcinoma--in order to highlight discoveries in their underlying abnormal molecular genetic functioning.

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