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.
Childhood Eye Cancer Trust A charity for families and individuals affected by retinoblastoma which aims to provide support, fund research and raise awareness. Initially registered as a charity in 1987 and formerly known as the Retinoblastoma Society. the site includes resources for both families and health professionals.
PubMed Central search for free-access publications about Retinoblastoma MeSH term: Retinoblastoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
Childhood Eye Cancer Trust A charity for families and individuals affected by retinoblastoma which aims to provide support, fund research and raise awareness. Initially registered as a charity in 1987 and formerly known as the Retinoblastoma Society. the site includes resources for both families and health professionals.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
Larina IV, Syed SH, Sudheendran N, et al. Optical coherence tomography for live phenotypic analysis of embryonic ocular structures in mouse models. J Biomed Opt. 2012; 17(8):081410-1 [PubMed] Article available free on PMC after 14/05/2013
Mouse models of ocular diseases provide a powerful resource for exploration of molecular regulation of eye development and pre-clinical studies. Availability of a live high-resolution imaging method for mouse embryonic eyes would significantly enhance longitudinal analyses and high-throughput morphological screening. We demonstrate that optical coherence tomography (OCT) can be used for live embryonic ocular imaging throughout gestation. At all studied stages, the whole eye is within the imaging distance of the system and there is a good optical contrast between the structures. We also performed OCT eye imaging in the embryonic retinoblastoma mouse model Pax6-SV40 T-antigen, which spontaneously forms lens and retinal lesions, and demonstrate that OCT allows us to clearly differentiate between the mutant and wild type phenotypes. These results demonstrate that OCTin utero imaging is a potentially useful tool to study embryonic ocular diseases in mouse models.
Knudsen ES, Pajak TF, Qeenan M, et al. Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression. J Natl Cancer Inst. 2012; 104(23):1825-36 [PubMed] Article available free on PMC after 05/12/2013
BACKGROUND: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. METHODS: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. RESULTS: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. CONCLUSIONS: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of beneﬁt.
Francis JH, Abramson DH, Brodie SE, Marr BP Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol. 2013; 97(2):164-8 [PubMed]
PURPOSE: Review our experience in the use of indocyanine green (ICG) enhanced transpupillary thermotherapy (TTT) in combination with ophthalmic artery chemosurgery for retinoblastomas unresponsive to standard TTT. METHODS: Single centre, retrospective study of 16 eyes in 13 retinoblastoma patients treated with TTT and ICG via indirect ophthalmoscope: 23 treatments of 16 eyes, with a mean follow-up of 12.1 months (range 3-35 months). Outcome measures included tumour response and electroretinogram. RESULTS: Treatment resulted in significant tumour regression in all eyes: 13 eyes with well-differentiated characteristics, 2 with implanting vitreous seeds and 1 eye refractory to traditional TTT. ERG function was retained in all eyes. CONCLUSIONS: ICG-enhanced TTT with ophthalmic artery chemosurgery can effectively treat retinoblastoma refractory to conventional focal treatments without deleterious ocular side effects.
Temming P, Lohmann D, Bornfeld N, et al. Current concepts for diagnosis and treatment of retinoblastoma in Germany: aiming for safe tumor control and vision preservation. Klin Padiatr. 2012; 224(6):339-47 [PubMed]
Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.
Brualla L, Mayorga PA, Flühs A, et al. Retinoblastoma external beam photon irradiation with a special 'D'-shaped collimator: a comparison between measurements, Monte Carlo simulation and a treatment planning system calculation. Phys Med Biol. 2012; 57(22):7741-51 [PubMed]
Retinoblastoma is the most common eye tumour in childhood. According to the available long-term data, the best outcome regarding tumour control and visual function has been reached by external beam radiotherapy. The benefits of the treatment are, however, jeopardized by a high incidence of radiation-induced secondary malignancies and the fact that irradiated bones grow asymmetrically. In order to better exploit the advantages of external beam radiotherapy, it is necessary to improve current techniques by reducing the irradiated volume and minimizing the dose to the facial bones. To this end, dose measurements and simulated data in a water phantom are essential. A Varian Clinac 2100 C/D operating at 6 MV is used in conjunction with a dedicated collimator for the retinoblastoma treatment. This collimator conforms a 'D'-shaped off-axis field whose irradiated area can be either 5.2 or 3.1 cm(2). Depth dose distributions and lateral profiles were experimentally measured. Experimental results were compared with Monte Carlo simulations' run with the penelope code and with calculations performed with the analytical anisotropic algorithm implemented in the Eclipse treatment planning system using the gamma test. penelope simulations agree reasonably well with the experimental data with discrepancies in the dose profiles less than 3 mm of distance to agreement and 3% of dose. Discrepancies between the results found with the analytical anisotropic algorithm and the experimental data reach 3 mm and 6%. Although the discrepancies between the results obtained with the analytical anisotropic algorithm and the experimental data are notable, it is possible to consider this algorithm for routine treatment planning of retinoblastoma patients, provided the limitations of the algorithm are known and taken into account by the medical physicist and the clinician. Monte Carlo simulation is essential for knowing these limitations. Monte Carlo simulation is required for optimizing the treatment technique and the dedicated collimator.
Radhakrishnan V, Sharma S, Vishnubhatla S, Bakhshi S MRI findings at baseline and after neoadjuvant chemotherapy in orbital retinoblastoma (IRSS stage III). Br J Ophthalmol. 2013; 97(1):52-8 [PubMed]
BACKGROUND: Published findings on MRI results in retinoblastoma patients treated with neoadjuvant chemotherapy (NACT) are lacking. The present study evaluates the role of MRI in International Retinoblastoma Staging System (IRSS) stage III retinoblastoma treated with NACT. METHODS: 28 consecutive IRSS stage III retinoblastoma patients underwent MRI at baseline and after three cycles of NACT prior to enucleation. MRI films were reviewed retrospectively by an ophthalmic radiologist who was masked to patient outcome. Optic nerves were staged based on their thickness, contrast enhancement and length of involvement on MRI. Response evaluation criteria were based on optic nerve staging and changes in the size of the orbital mass on MRI after NACT. RESULTS: The proposed staging at baseline and after NACT was able to predict event-free-survival (EFS) (p=0.005 and p <0.001, respectively) and overall survival (OS) (p=0.002 and p=0.001, respectively) using the log-rank test for trends. Patients with complete or partial response according to the proposed response evaluation criteria had significantly better EFS (p<0.001) and OS (p=0.024) than those who had stable or progressive disease. CONCLUSIONS: The proposed MRI based optic nerve staging system and response evaluation criteria were able to predict EFS and OS at baseline and after NACT.
Shields CL, Schoenberg E, Kocher K, et al. Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation. Ophthalmology. 2013; 120(2):311-6 [PubMed]
PURPOSE: To determine the types and frequency of ocular conditions that simulate retinoblastoma (pseudoretinoblastoma) based on age at presentation. DESIGN: Retrospective case series. PARTICIPANTS: Two thousand seven hundred seventy-five patients. METHODS: Chart review. MAIN OUTCOME MEASURES: Conditions simulating retinoblastoma. RESULTS: Of 2775 patients referred for management of retinoblastoma, 2171 patients (78%) had confirmed retinoblastoma and 604 patients (22%) had simulating lesions (pseudoretinoblastomas). In the pseudoretinoblastoma cohort, the mean patient age at presentation was 4 years (median, 2 years). There were 27 different pseudoretinoblastoma conditions, and the 10 most common included Coats' disease (n = 244; 40%), persistent fetal vasculature (PFV; n = 158; 28%), vitreous hemorrhage (n = 27; 5%), ocular toxocariasis (n = 22; 4%), familial exudative vitreoretinopathy (FEVR; n = 18; 3%), rhegmatogenous retinal detachment (n = 18; 3%), coloboma (n = 17; 3%), astrocytic hamartoma (n = 15; 2%), combined hamartoma of retina and retinal pigment epithelium (n = 15; 2%), and endogenous endophthalmitis (n = 10; 2%). Simulating lesions differed based on age at presentation, and children younger than 1 year were most likely to have PFV (49%), Coats' disease (20%), or vitreous hemorrhage (7%); those 2 to 5 years of age were most likely to have Coats' disease (61%), toxocariasis (8%), or PFV (7%); and those older than 5 years were most likely to have Coats' disease (57%), toxocariasis (8%), or FEVR (6%). CONCLUSIONS: The most common pseudoretinoblastomas include Coats' disease, PFV, and vitreous hemorrhage, but the spectrum varies depending on patient age.
Rootman DB, Gonzalez E, Mallipatna A, et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol. 2013; 97(1):59-65 [PubMed]
PURPOSE: Hand-held spectral domain optical coherence tomography (HHSD OCT) has greatly expanded the imaging/diagnostic capacity for clinicians managing children with intraocular retinoblastoma. We present our early experience with HHSD OCT and conventional spectral domain OCT imaging in these patients. METHODS: In this retrospective cross-sectional observational study, infants were imaged during examination under anaesthesia with HHSD OCT in the supine position. Older cooperative retinoblastoma patients were additionally imaged with upright conventional OCT. Clinical data were derived from patient charts and from a prospectively maintained interinstitutional retinoblastoma database. Complementary imaging techniques, including RetCam™, fluorescein angiography and B-scan ultrasound, were assessed. RESULTS: Twenty-two intraocular lesions in 16 patients were imaged. HHSD OCT was used exclusively in 19 lesions, while conventional OCT was also performed in three cases. Small lesions were imaged in five cases, all of which were localised to the middle retinal layers. Clinical uses for HHSD OCT imaging identified included: diagnosis of new lesions, monitoring response to laser therapy and the identification of edge recurrences. CONCLUSIONS: Although indirect ophthalmoscopy remains the gold standard for diagnosis and treatment of retinoblastoma, HHSD OCT is a valuable tool in better understanding and managing retinoblastoma.
Martin J, Bryar P, Mets M, et al. Differentially expressed miRNAs in retinoblastoma. Gene. 2013; 512(2):294-9 [PubMed]
MicroRNAs (miRNAs) are short non-coding RNA transcripts that have the ability to regulate the expression of target genes, and have been shown to influence the development of various tumors. The purpose of our study is to identify aberrantly expressed miRNAs in retinoblastoma for the discovery of potential therapeutic targets for this disease, and to gain a greater understanding of the mechanisms driving retinoblastoma progression. We report 41 differentially expressed miRNAs (p<0.05) in 12 retinoblastomas as compared to three normal human retinae. Of these miRNAs, many are newly identified as being differentially expressed in retinoblastoma. Further, we report the validations of five of the most downregulated miRNAs in primary human retinoblastomas (p<0.05), human retinoblastoma cell lines, and mouse retinoblastoma cell lines. This serves as the largest and most comprehensive retinoblastoma miRNA analysis to date with corresponding clinical and pathological characteristics. This is an essential step in the discovery of miRNAs associated with retinoblastoma progression, and in the identification of potential therapeutic targets for this disease.
Yousef YA, Shroff M, Halliday W, et al. Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS. 2012; 16(5):481-3 [PubMed]
We present the case of a child affected with retinoblastoma and evolving optic nerve pathology detected by spectral domain optical coherence tomography (SD-OCT) before magnetic resonance imaging. At 6 months of age, the patient was diagnosed with bilateral retinoblastoma, which was managed with systemic chemotherapy and focal therapy. Six months after the third and final cycle of systemic chemotherapy, the right optic disk clinically appeared progressively edematous, raising concerns of tumor infiltration of the optic nerve head. Images obtained via magnetic resonance imaging could not confirm the presence of a tumor at the optic nerve head, whereas findings on SD-OCT were suggestive of optic nerve head disease. Histopathologic findings after enucleation revealed viable tumor over the optic nerve head, supporting the OCT findings.
Venkatesan N, Krishnakumar S, Deepa PR, et al. Molecular deregulation induced by silencing of the high mobility group protein A2 gene in retinoblastoma cells. Mol Vis. 2012; 18:2420-37 [PubMed] Article available free on PMC after 05/12/2013
AIM: To explore the molecular mechanisms deregulated by high mobility group protein A2 (HMGA2) gene silencing in retinoblastoma (RB) cells. METHODS: Synthetic anti-HMGA2 short interfering RNA (siRNA) was used to silence the HMGA2 gene in cultured Y79 RB cells that were subjected to whole genome microarray analysis. The expression of differentially regulated key genes was confirmed with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in post-silenced RB cell lines (Y79 and WERI Rb1). These deregulated genes were compared for their constitutive expression in primary RB tumors (n=10). Zymographic determination of matrix metalloproteinase (MMP) activity was performed in RB cells. A cell cycle assay and a proliferation assay were performed in post-transfected RB cells. RESULTS: HMGA2 gene silencing in cultured RB cells results in reduced cell proliferation and transition in the G1/S phase. The whole genome microarray analysis of HMGA2 silenced Y79 cells revealed overall upregulation of 1,132 genes (≥ 1.0 fold) and downregulation of 1,562 genes (≤ -1.0 fold). Specific quantitative pathway analysis of the deregulated genes (using Biointerpreter) revealed 150 upregulated genes and 77 downregulated genes (≥ 1.0 fold) involved in vital pathways, namely, mitogen-activated protein kinase, Janus kinase/signal transducers and activators of transcription, Ras pathway, Ras-induced extracellular signal-regulated protein kinases 1 and 2, and tumor protein p53. The differential expression of genes obtained from microarray analysis (Homo sapiens ELK1, member of ETS oncogene family [ELK1], Homo sapiens cyclin-dependent kinase 6 [CDK6], Homo sapiens E2F transcription factor 4, p107/p130-binding [E2F4], Homo sapiens G-2 and S-phase expressed 1 [GTSE1], Damage-regulated autophagy modulator [DRAM], Homo sapiens cadherin 1, type 1,E-cadherin (epithelial) [CDH1], Homo sapiens snail homolog 1 (Drosophila) [SNAI1], Homo sapiens matrix metallopeptidase 2 [MMP2], and Homo sapiens matrix metallopeptidase 9 [MMP9]) was confirmed with quantitative reverse-transcriptase polymerase chain reaction in post-silenced RB cells. Zymographic analysis revealed that the increase in MMP mRNA expression in the post-silenced RB cells did not correlate with corresponding enzyme activity. CONCLUSIONS: Our study revealed molecular regulatory changes induced by HMGA2 silencing in RB cancer cells, offering mechanistic insights into the anticancer potential. HMGA2 may be considered a promising candidate for gene silencing therapy in RB.
Sengupta S, Krishnakumar S, Sharma T, et al. Histopathology of retinoblastoma: does standardization make a difference in reporting? Pediatr Blood Cancer. 2013; 60(2):336-7 [PubMed]
The International Retinoblastoma Staging Working Group (IRSWG) provided guidelines for tissue handling of eyes enucleated for retinoblastoma. We adopted these guidelines from January 2009. Reviewing histopathology slides between January 2006 and December 2010 we found significantly more number of eyes with massive choroidal, optic nerve, and anterior segment invasion by tumor cells in the post-IRSWG era. The guidelines provided by the IRSWG; in addition to being standardized; recognize more eyes with histopathologic risk factors compared to techniques applied in the past. This may translate to more children receiving adjuvant chemotherapy and contribute to reduced mortality rates in the future.
Hu H, Deng F, Liu Y, et al. Characterization and retinal neuron differentiation of WERI-Rb1 cancer stem cells. Mol Vis. 2012; 18:2388-97 [PubMed] Article available free on PMC after 05/12/2013
PURPOSE: The evidence is increasing that cancer stem cells (CSCs) expressing embryonic and neuronal stem cell markers are present in human retinoblastoma (Rb). This study was conducted to determine whether stem-like cancer cells (SLCCs) in Rb express retinal stem cell-related genes and whether SLCCs can directly differentiate into retinal neurons. METHODS: The cancer stem cell characteristics in WERI-Rb1 cells were determined with Hoechst 33,342 staining, clone formation assay, and CD133 flow cytometry. The expression of embryonic stem cell and retinal stem cell-related genes was analyzed with real-time PCR and immunofluorescence. The SLCCs were induced to differentiate into retinal neurons by the addition of Dickkopf-related protein 1 and Lefty-A. RESULTS: A small but persistent population of cells excluding Hoechst dye in a verapamil-sensitive manner exhibited a cancer stem cell-like phenotype. The SLCCs displayed highly clonogenic abilities and increased CD133 expression with isolation and expansion in culture in serum-free medium. By comparing the expression of stem cell markers, we found Oct3/4 was more highly expressed in the SLCCs than in human embryonic stem cells. Together with the properties of intrinsic retinal stem cell-related gene expression, we found SLCCs can be induced into neuron-like cells that express glial fibrillary acidic protein and rhodopsin (a photoreceptor cell marker). CONCLUSIONS: These findings provide new insight into cancer stem cells and used a strategy of an artificial change of cancer stem cell fate with transcription factors.
Ghassemi F, Shields CL Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. 2012; 130(10):1268-71 [PubMed]
OBJECTIVE: To evaluate the efficacy and complications of intravitreal chemotherapy for viable vitreous seeding from retinoblastoma. METHODS: Intravitreal injection of melphalan (8-50 μg in 0.05 mL) followed by injection site cryotherapy. RESULTS: Among 12 treated cases, success with control of vitreous seeds was achieved in 10 of 12 cases at immediate follow-up (0-3 months), 8 of 10 cases at short-term follow-up (3-6 months), and 6 of 10 cases at long-term (>6 months) follow-up. Among those 8 cases that received an 8- to 10-μg dose, control was achieved in 6 of 8 cases at immediate follow-up, 5 of 7 cases at short-term follow-up, and 3 of 7 cases at long-term follow-up. Complications with the 8- to 10-μg dose were minor and included preretinal hemorrhage and retinal vasculitis with retinal pigment epithelial alterations. Of those 4 that received a 50-μg dose, immediate, short-term, and long-term control was 100%, but complications of cataract, vitreous hemorrhage, subretinal hemorrhage, severe hypotonia, and phthisis lead to enucleation in 2 cases. There was no case of orbital tumor recurrence or retinoblastoma metastasis (follow-up range, 8-66 months). CONCLUSIONS: Intravitreal melphalan for recurrent vitreous seeds from retinoblastoma appears to provide vitreous seed control in some patients. A high dose (50 μg) of melphalan is toxic and should be avoided.
Ghassemi F, Rahmanikhah E, Roohipoor R, et al. Regression patterns in treated retinoblastoma with chemotherapy plus focal adjuvant therapy. Pediatr Blood Cancer. 2013; 60(4):599-604 [PubMed]
PURPOSE: The aim of this study was evaluation of the regression patterns after 3, 6, and 8 months of treatment. METHODS: A total of 100 retinoblastoma tumors (57 eyes of 35 patients) were treated with 6 (n = 8) or 8 (n = 92) cycles of systemic chemoreduction and tumor consolidation (transpupillary thermotherapy [TTT] or cryotherapy) during this prospective study. RESULTS: After 3 months of treatment, type 3 was the predominant pattern (n = 57%, 57%), while after 6 and 8 months of treatment the tumors regressed to type 4 most often (44% and 52%, respectively). Smaller tumors and the peripheral tumors were likely to regress to type 4, whereas larger tumors and those nearer to fovea were more likely to become type 1 pattern. Tumors consolidated with cryotherapy mostly showed type 4 regression (3rd month: 40%, 6th month: 90%, and 8th month: 87.5%). Whereas, those treated with TTT rather regressed to type 3 after 3 months (57.9%) and to type 4 after 6 and 8 months of treatment (51.4% and 59.5%, respectively). Recurrence of the tumor was 40% in our cases with defined correlation with tumor location, size, and subretinal seeds. CONCLUSION: We conclude that regression patterns of tumors in patients undergoing systemic chemoreduction with focal adjuvant treatments predominantly changed over time and their changes are dependent on tumor size, location, and type of treatment. It appears that subretinal seeds, tumor size, and location of tumors are the most important factors predicting tumor recurrence.
Gobin YP, Dunkel IJ, Marr BP, et al. Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS One. 2012; 7(9):e44322 [PubMed] Article available free on PMC after 05/12/2013
BACKGROUND: Intra-arterial (i.a.) chemotherapy has more risks of procedural complications in neonates and young infants. For these reasons, we have developed a strategy of bridge intravenous single agent chemotherapy to postpone i.a. chemotherapy in these children PROCEDURE: Neonates and young infants with retinoblastoma who required chemotherapy were treated with systemic carboplatin chemotherapy (18.7 mg/kg i.v. every 3-4 weeks) until they reached the age of 3 months and a weight of 6 Kg. If necessary, i.a. chemotherapy was subsequently performed at 4 weeks intervals. Efficacy was judged by tumor regression on ophthalmological examination. Retinal toxicity was judged by electroretinography. RESULTS: Eleven children (19 eyes) were treated. All patients are alive and no patient has developed metastatic disease or second malignancies (mean follow-up 27 months, range 9-46 months). Intravenous carboplatin (median 2 cycles, range 1-5) combined with cryotherapy and laser was given to all children. This was effective for five eyes, which did not require i.a. chemotherapy. I.a. chemotherapy was administered to 14 eyes (median 3.5 cycles per eye, range 1 to 6). No radiation therapy was required. The Kaplan Meier estimate of ocular radiation-free survival was 94.7% at one year (95% confidence interval 68.1-99.2%). One eye was enucleated due to tumor progression. ERG showed no deterioration of retinal function. CONCLUSION: Bridge i.v.-i.a. chemotherapy was feasible and safe, and is a promising strategy to treat retinoblastoma in neonates and young infants.
Song HB, Park KD, Kim JH, et al. Tissue factor regulates tumor angiogenesis of retinoblastoma via the extracellular signal-regulated kinase pathway. Oncol Rep. 2012; 28(6):2057-62 [PubMed]
Retinoblastoma, a well-vascularized tumor that is dependent on a very robust angiogenic response, is the most common intraocular malignancy in children. Tissue factor (TF) is known to regulate tumor progression and in the present study we demonstrated that TF regulates tumor angiogenesis of retinoblastoma. In an orthotopic transplantation model of retinoblastoma, TF was selectively expressed in the proliferative area of retinoblastoma including tumor vessels as well as tumor cells, where TF expression was co-localized with endothelial cells of tumor vessels. TF expression progressively increased with fibroblast growth factor-2 (FGF-2)-induced proliferation of human umbilical vein endothelial cells (HUVECs), which was effectively inhibited by blockade of the TF pathway by TF pathway inhibitor (TFPI). In addition, FGF-2-induced angiogenic processes of migration and tube formation of vascular endothelial cells were also effectively suppressed by TFPI, which would be mediated by inhibition of extracellular signal-regulated kinase activation. Therefore, further to our previous report that TF is involved in tumor cell proliferation of retinoblastoma, our current data suggest that blockade of the TF pathway by TFPI could effectively inhibit tumor growth by suppressing tumor cell proliferation and tumor angiogenesis at the same time.
Berry JL, Jubran R, Kim JW, et al. Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer. 2013; 60(4):688-93 [PubMed]
BACKGROUND: To evaluate outcomes of Group D eyes of bilateral retinoblastoma patients treated with primary chemoreduction and external beam radiation as salvage. PROCEDURE: Retrospective chart review of patients diagnosed with bilateral retinoblastoma and designated Group D in at least one eye from January 1, 2000 to December 31, 2009. Overall, 62 Group D eyes of 49 patients were included; 13 had bilateral Group D disease. Primary chemoreduction with vincristine, etoposide, and carboplatin with local consolidation was administered, followed by external beam radiation in the form of intensity-modulated radiation therapy (IMRT) as salvage for recurrent tumor. Primary outcome measure was globe salvage. RESULTS: Of 62 Group D eyes, 7 were enucleated primarily; 55 were treated with systemic chemoreduction, and local therapy. Chemoreduction cured 26 of 55 eyes (47%). Recurrences were found in 29 eyes; 5 underwent enucleation and 24 were treated with IMRT at a dose of 24 Gy (2 eyes) or 36 Gy (22 eyes). Of the 24 irradiated eyes, 19 (79%) were salvaged and 5 required enucleation. Final visual acuity ranged from 20/20 to light perception with 10 eyes having 20/80 or better visual acuity. Average follow-up was 54.2 months. CONCLUSION: Kaplan-Meier estimates of eye survival of Group D eyes in bilateral patients at 12 months is 82% (95% confidence interval [CI] 70.1-89.7%); at 60 months eye survival is estimated to be 68% (95% confidence interval [CI] 55.4-82.8%). Systemic treatment for retinoblastoma demonstrated a high rate of globe preservation with acceptable complications and many eyes retaining functional vision.
Rauschecker AM, Patel CV, Yeom KW, et al. High-resolution MR imaging of the orbit in patients with retinoblastoma. Radiographics. 2012 Sep-Oct; 32(5):1307-26 [PubMed]
Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.
Kandalam MM, Beta M, Maheswari UK, et al. Oncogenic microRNA 17-92 cluster is regulated by epithelial cell adhesion molecule and could be a potential therapeutic target in retinoblastoma. Mol Vis. 2012; 18:2279-87 [PubMed] Article available free on PMC after 05/12/2013
PURPOSE: Several miRNAs have been reported as candidate oncogenes and tumor suppressors, which are involved in the pathways specifically altered during tumorigenesis or metastasis. The miR 17-92 cluster located in 13q31 locus might contribute to retinoblastoma (RB) oncogenesis as 13q31 is amplified often in RB. We attempted to identify the factors involved in the regulation of miR 17-92 cluster in RB. METHODS: Real-time quantitative reverse transcriptase PCR was performed to study the expression of the miR 17-92 cluster in primary RB tumors and in Y79 cells after epithelial cell adhesion molecule (EpCAM) silencing. EpCAM was silenced using siRNA and confirmed by western blotting. The Y79 cells were transfected with individual and mixed antagomirs and studied the cell viability by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, invasion by matrigel analysis and caspase-3 expression by flow cytometry. RESULTS: The relative expression of miR 17-92 cluster, compared to that of a normal retina, ranged from 25 to 220 fold (p<0.0001), miR-18 being highly expressed in RB. Post EpCAM silencing resulted in a significant decrease (p<0.01) in the expression of the miR 17-92 cluster by 4 to eightfold in Y79 cells. Y79 cells transfected with an antagomirs mix (all 5 miRNAs) showed decreased cell viability (p<0.001) and cell invasion (p<0.001). Similarly, Y79 cells treated with antagomirs mix showed increased expression of caspase-3 (p<0.001), which confirms the anti-proliferative effect of antagomirs. CONCLUSIONS: This study has showed varied expression of the miR17-92 cluster in primary RB tumors. EpCAM influences miR 17-92 cluster expression in retinoblastoma. In addition, we showed that the miR 17-92 cluster plays a role in RB cell proliferation and invasion. Therefore, targeting the miRNA 17-92 cluster may be beneficial for controlling Y79/RB cell proliferation and invasion.
Hou JH, Aakalu VK, Setabutr P Quantitative characterization of growth rate of an incidental deep dermoid cyst in a child using sequential magnetic resonance imaging. J AAPOS. 2012; 16(4):403-5 [PubMed]
When orbital lesions are discovered incidentally, some have advocated observation given the slow-growing nature of deep dermoids; however, little has been published regarding the true growth potential of these tumors. We describe a case of an incidental deep orbital dermoid cyst in a 7.5-month-old girl with retinoblastoma. The cyst was monitored with five sequential magnetic resonance imaging studies of the orbit over 23 months with careful documentation of growth. The cyst was surgically removed without complication, and histopathology confirmed the diagnosis of dermoid cyst. This case represents the first published quantitative measurement of dermoid growth potential and highlights the need for close early monitoring in incidentally discovered cases.
Friedman DN, Sklar CA, Oeffinger KC, et al. Long-term medical outcomes in survivors of extra-ocular retinoblastoma: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Pediatr Blood Cancer. 2013; 60(4):694-9 [PubMed]
BACKGROUND: Data on long-term outcomes of survivors of extra-ocular retinoblastoma are lacking. The authors sought to provide the first report characterizing long-term outcomes among survivors of extra-ocular retinoblastoma. PROCEDURE: Retrospective analysis of long-term medical outcomes in 19 survivors of extra-ocular retinoblastoma treated between 1992 and 2009. Severity of outcomes was graded using Common Terminology Criteria for Adverse Events. All patients received intensive multimodality therapy for their extra-ocular disease after management of their primary intra-ocular disease, including conventional chemotherapy (n = 19, 100%), radiotherapy (n = 15, 69%), and/or high-dose chemotherapy with autologous stem cell transplant (n = 17, 89%). RESULTS: The median follow-up was 7.8 years from diagnosis of extra-ocular retinoblastoma (range 2-17.8 years). The most common long-term non-visual outcomes were hearing loss (n = 15, 79%), short stature (n = 7, 37%), and secondary malignancies [SMN] (n = 6, 31%). Sixty-eight percent of survivors exhibited ≥2 non-visual long-term outcomes of any grade. Except short stature, which was not graded for severity, Grade 3-4 outcomes were limited to: ototoxicity (n = 8; n = 4 require hearing aids), SMNs (n = 6), and unequal limb length (n = 1). Five patients who developed SMNs carried a known RB1 mutation. SMNs developed at a median of 11.1 years after initial diagnosis; two patients died of their SMN. Long-term cardiac, pulmonary, hepatobiliary, or renal conditions were not identified in any survivors. CONCLUSION: Long-term outcomes are commonly seen in extra-ocular retinoblastoma survivors but the majority are mild-moderate in their severity. Longer comprehensive follow-up is needed to fully assess treatment-related outcomes but the information collected to date may affect management decisions for children with extra-ocular disease.
Nittner D, Lambertz I, Clermont F, et al. Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. Nat Cell Biol. 2012; 14(9):958-65 [PubMed]
Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.
Marr BP, Brodie SE, Dunkel IJ, et al. Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results. Br J Ophthalmol. 2012; 96(10):1300-3 [PubMed]
AIMS: To report outcomes with selective intra-arterial chemotherapy (SIAC) using simultaneous carboplatin, topotecan, and melphalan for advanced intraocular retinoblastoma. METHODS: A retrospective chart review was conducted of patients who received three-drug (melphalan, topotecan, and carboplatin) SIAC during 2006-2011. RESULTS: Twenty-six eyes of 25 patients received the three-drug chemotherapy for treatment of advanced retinoblastoma. Reese-Ellsworth group was 5b in 21 eyes, 5a in 2, 4a in 2, and 3a in 1. Seventeen patients (68%) had recurrence after prior intravenous chemotherapy with or without radiotherapy. In the three-drug therapy, dose ranges were 2.5-7.5 mg for melphalan, 0.3-0.6 mg for topotecan, and 25-50 mg for carboplatin, and median infusions per eye was 2 (range 1-4). At a mean follow-up of 14 months (range 1-43 months), all patients are alive and no patient developed metastatic disease. Twenty-three of 26 eyes (88%) survived. Eleven of the 26 eyes (35%) developed recurrent disease and were treated with enucleation (n=3) or with focal therapy (n=8) with or without plaque brachytherapy (n=3). The Kaplan-Meier estimate of ocular survival at 24 months was 75% (95% CI). Electroretinogram showed improvement greater than 25 µV in 4 eyes (15%), loss greater than 25 µV in 12 eyes (46%), and no change greater than 25 µV in 10 eyes (39%). CONCLUSIONS: Three-drug SIAC has been used successfully to rescue eyes after treatment failure of intravenous chemotherapy and/or single- or double-agent SIAC. Twenty-three of 26 eyes avoided both enucleation and external beam radiotherapy and retained electroretinogram function.
Heck JE, Lombardi CA, Meyers TJ, et al. Perinatal characteristics and retinoblastoma. Cancer Causes Control. 2012; 23(9):1567-75 [PubMed] Article available free on PMC after 01/09/2013
PURPOSE: The etiology of retinoblastoma remains poorly understood. In the present study, we examined associations between perinatal factors and retinoblastoma risk in California children. METHODS: We identified 609 retinoblastoma cases (420 unilateral, 187 bilateral, and 2 with laterality unknown) from California Cancer Registry records of diagnoses 1988-2007 among children < 6 years of age. We randomly selected 209,051 controls from California birth rolls. The source of most study data was birth certificates. Multivariable logistic regression was used to examine associations between retinoblastoma and perinatal characteristics. RESULTS: Bilateral retinoblastoma was associated with greater paternal age [for fathers over 35, crude odds ratio (OR) = 1.73, 95 % confidence interval (CI) 1.20, 2.47] and with twin births (OR = 1.93, 95 % CI 0.99, 3.79). Among unilateral cases, we observed an increased risk among children of US-born Hispanic mothers (OR = 1.34, 95 % CI 1.01, 1.77) while a decreased risk was observed for infants born to mothers with less than 9 years of education (OR = 0.70, 95 % CI 0.49, 1.00), a group that consisted primarily of mothers born in Mexico. We observed that maternal infection in pregnancy with any STD (OR = 3.59, 95 % CI 1.58, 8.15) was associated with bilateral retinoblastoma. CONCLUSIONS: This study supports the findings of previous investigations reporting associations between parental age, HPV infection, and retinoblastoma.
Paunksnis A, Imbrasienė D, Liutkevičienė R, et al. Coats' retinitis or retinoblastoma in a 3-year-old girl: a case report. Medicina (Kaunas). 2012; 48(4):224-7 [PubMed]
Coats' disease is an idiopathic disorder defined by an abnormal development of retinal vessels with a progressive deposition of intraretinal or subretinal exudates, leading to exudative retinal detachment. The most difficult task is to differentiate Coats' disease from retinoblastoma. We present a rare case of Coats' disease diagnosed in a 3-year-old girl. From the age of 6 months, the girl was followed up 2 times a year at the Department of Ophthalmology, Hospital of Lithuanian University of Health Sciences, due to congenital convergent strabismus and refractive errors. At the age of 3.6 years, a routine examination of the fundus of the right eye revealed hard exudates, telangiectasia and tortuosity, gray color lesion below the optic nerve disc, submacular exudation in the inferior nasal part of the retina, and exudative retinal detachment, which extended from the 7-o'clock position to the 4-o'clock position. Before this examination, no abnormalities were found in the fundus of her both eyes. The girl was not treated with laser photocoagulation, cryocoagulation, or intravitreal injections, as the diagnosis of retinoblastoma could not be excluded; therefore, only eye drops were prescribed. In order to exclude the diagnosis of retinoblastoma, ultrasonography, magnetic resonance imaging, and computed tomography were carried out, and an appointment to see an ophthalmic oncologist was scheduled. Due to early and appropriate treatment, the progression of Coats' disease in patients could be arrested. However, in some cases, when the diagnosis is ambiguous, it is better to follow up the patient and to treat only with eye drops.
Nagarkatti-Gude N, Wang Y, Ali MJ, et al. Genetics of primary intraocular tumors. Ocul Immunol Inflamm. 2012; 20(4):244-54 [PubMed] Article available free on PMC after 01/09/2013
Primary intraocular neoplasms are tumors that originate within the eye. The most common malignant primary intraocular tumor in adults is uveal melanoma and the second is primary intraocular lymphoma or vitreoretinal (intraocular) lymphoma. The most common malignant intraocular tumor in children is retinoblastoma. Genetics plays a vital role in the diagnosis and detection of ocular tumors. In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas. The retinoblastoma gene RB1 is the prototype tumor suppressor gene-mutations in RB1 alleles lead to inactivated RB protein and the development of retinoblastoma. Immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement is observed in B-cell or T-cell primary vitreoretinal lymphoma, respectively. Other factors related to the genetics of these three common malignancies in the eye are discussed and reviewed.
Jaradat I, Mubiden R, Salem A, et al. High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review. Hematol Oncol Stem Cell Ther. 2012; 5(2):107-17 [PubMed]
BACKGROUND AND OBJECTIVES: In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. DESIGN: Systematic literature review. METHODS: We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma. RESULTS: We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up. CONCLUSIONS: Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control.
Makky A, Daghildjian K, Michel JP, et al. Assessment of the relevance of supported planar bilayers for modeling specific interactions between glycodendrimeric porphyrins and retinoblastoma cells. Biochim Biophys Acta. 2012; 1818(11):2831-8 [PubMed]
Glycodendrimeric porphyrins seem promising photosensitizers usable in photodynamic therapy. Evidence of their ability to interact with an artificial supported bilayer membrane exhibiting a model sugar receptor has been previously shown. In the present work, the interaction of the glycodendrimeric porphyrins with retinoblastoma cells bearing the actual sugar receptor has been assessed by both classical cell cultures and an original approach using the quartz crystal microbalance (QCM-D). Our results showed that unlike cell cultures, QCM-D allowed analyzing the mechanism of interaction of the glycodendrimeric porphyrins with the sugar receptor. Not only was molecular recognition demonstrated, but our methodology also proved efficient to discriminate between the studied compounds, depending on the presence of carbohydrate, and the spacer length.
Rodjan F, de Graaf P, Brisse HJ, et al. Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol. 2012; 109(3):535-44 [PubMed] Article available free on PMC after 01/09/2013
Trilateral retinoblastoma (TRb) is a rare disease associating intraocular retinoblastoma with intracranial primitive neuroectodermal tumor. Treatment is difficult and prognosis is poor. This multicenter study evaluates clinical findings and MR imaging characteristics of associated intracranial tumors in Rb patients. Clinical data of 17 patients (16 TRb and 1 quadrilateral Rb patients) included time intervals between Rb and TRb diagnosis and presence of baseline brain-imaging (BBI). Two reviewers reviewed all images individually and one reviewer per center evaluated their images. Consensus was reached during a joint scoring session. Studies were reviewed for tumor location, size and imaging characteristics (signal intensity (SI) on T1- and T2-weighted images, enhancement pattern and cystic appearance). Of 18 intracranial tumors, 78 % were located in the pineal gland and 22 % suprasellar. All tumors showed well-defined borders with mostly heterogenous enhancement (72 %) and isointense SI on T1- (78 %) and T2-weighted images (72 %) compared to gray matter. The majority of pineal TRbs showed a cystic component (57 %). TRb detected synchronously with the intraocular tumors on BBI (n = 7) were significantly smaller (P = 0.02), and mainly asymptomatic than TRb detected later on (n = 10). Overall, 5-year-survival of TRb patients detected on BBI was 67 % (95 % CI 29-100 %) compared to 11 % (95 % CI 0-32 %) for the group with delayed diagnosis. TRb mainly develops in the pineal gland and frequently presents with a cystic appearance that could be misinterpreted as benign pineal cysts. Routine BBI in all newly diagnosed Rb patients can detect TRb at a subclinical stage.
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