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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
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Latest Research Publications

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

Xu XL, Singh HP, Wang L, et al.
Rb suppresses human cone-precursor-derived retinoblastoma tumours.
Nature. 2014; 514(7522):385-8 [PubMed] Related Publications
Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.

Related: MDM2 gene RB1 RBL1 retinoblastoma-like 1 (p107) MYCN (n-myc)

Kumar N, Gangappa D, Gupta G, Karnati R
Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells.
BMC Complement Altern Med. 2014; 14:319 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Plants are the valuable source of natural products with important medicinal properties. Most of the approved anti cancer drugs have a natural product origin or are natural products. Retinoblastoma is the most common ocular cancer of children. Although chemotherapy is the preferred mode of therapy, a successful treatment for retinoblastoma requires enucleation. Chebulagic acid (CA) from Terminalia chebula was shown to have anti-proliferative properties in the studies on cancerous cell lines. Due to anti cancer properties of CA and due to limitation in treatment options for retinoblastoma, the present study is undertaken to understand the role of CA on the proliferation of retinoblastoma cells.
METHODS: Anti proliferative potential of CA was determined by MTT assay. The expression levels of various cell death mediators in retinoblastoma cells with CA treatment were assessed by Western blotting. Flowcytometer analysis was used to estimate the mitochondrial membrane potential (MMP) and to determine the percentage of cells undergoing apoptosis.
RESULTS: The present study showed CA inhibited the proliferation of retinoblastoma cells in a dose dependent manner. CA modulated MMP, induced release of Cytochrome c, activated caspase 3 and shifted the ratio of BAX and Bcl2 towards cell death. G1 arrest, noticed in CA treated cells, is mediated by the increase in the expression of CDK inhibitor p27. CA treatment also decreased the levels of NFκB in the nucleus. This decrease is mediated by suppression in degradation of IκBα.
CONCLUSION: CA has shown significant anti proliferative potential on retinoblastoma cells. Our findings clearly demonstrate that CA induces G1 arrest, inhibits NFκB and induces apoptosis of retinoblastoma cells.

Related: Apoptosis

He LQ, Njambi L, Nyamori JM, et al.
Developing clinical cancer genetics services in resource-limited countries: the case of retinoblastoma in Kenya.
Public Health Genomics. 2014; 17(4):221-7 [PubMed] Related Publications
BACKGROUND/AIMS: Clinical cancer genetics is an integral part of cancer control and management, yet its development as an essential medical service has been hindered in many low-and-middle-income countries. We report our experiences in developing a clinical cancer genetics service for retinoblastoma in Kenya.
METHODS: A genetics task force was created from within the membership of the existing Kenyan National Retinoblastoma Strategy group. The task force engaged in multiple in-person and telephone discussions, delineating experiences, opinions and suggestions for an evidence-based, culturally sensitive retinoblastoma genetics service. Discussions were recorded and thematically categorized to develop a strategy for the design and implementation of a national retinoblastoma clinical genetics service.
RESULTS: Discussion among the retinoblastoma genetics task force supported the development of a comprehensive genetics service that rests on 3 pillars: (1) patient and family counseling, (2) community involvement, and (3) medical education.
CONCLUSIONS: A coordinated national retinoblastoma genetics task force led to the creation of a unique and relevant approach to delivering comprehensive and accurate genetic care to Kenyan retinoblastoma patients. The task force aims to stimulate innovative approaches in cancer genetics research, education and knowledge translation, taking advantage of unique opportunities offered in the African context.

Related: Eye Cancer

Shields CL, Lally SE, Leahey AM, et al.
Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy.
Curr Opin Ophthalmol. 2014; 25(5):374-85 [PubMed] Related Publications
PURPOSE OF REVIEW: The management of retinoblastoma is complex and involves strategically chosen methods of enucleation, radiotherapy, chemotherapy, laser photocoagulation, thermotherapy, and cryotherapy. Chemotherapy has become the most common eye-sparing modality. There are four routes of delivery of chemotherapy for retinoblastoma, including intravenous, intra-arterial, periocular, and intravitreal techniques. The purpose of this review is to discuss the current rationale for each method and the anticipated outcomes.
RECENT FINDINGS: The diagnosis of retinoblastoma should be clinically established prior to embarking on a chemotherapy protocol. There are over 25 conditions that can closely simulate retinoblastoma in a young child. In addition, enucleation is an acceptable method for management, particularly with advanced retinoblastoma. Intravenous chemotherapy is generally used for germline mutation (bilateral, familial) retinoblastoma with excellent tumor control for groups A, B, and C and intermediate control for group D eyes. Intra-arterial chemotherapy is used as primary therapy in selected cases for nongermline mutation (unilateral) retinoblastoma with excellent control, and also used as secondary therapy for recurrent solid retinoblastoma, subretinal seeds, and vitreous seeds. Periocular chemotherapy is employed to boost local chemotherapy dose in advanced bilateral groups D and E eyes or for localized recurrences. Intravitreal chemotherapy is used for recurrent vitreous seeds from retinoblastoma. Patients at high risk for metastases should receive intravenous chemotherapy.
SUMMARY: Chemotherapy is effective for retinoblastoma and the targeted treatment route depends on the clinical features and anticipated outcomes.

Brodowska K, Al-Moujahed A, Marmalidou A, et al.
The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation.
Exp Eye Res. 2014; 124:67-73 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Verteporfin (VP), a benzoporphyrin derivative, is clinically used in photodynamic therapy for neovascular macular degeneration. Recent studies indicate that VP may inhibit growth of hepatoma cells without photoactivation through inhibition of YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human retinoblastoma cell lines. Verteporfin but not vehicle control inhibited the growth, proliferation and viability of human retinoblastoma cell lines (Y79 and WERI) in a dose-dependent manner and was associated with downregulation of YAP-TEAD associated downstream proto-oncogenes such as c-myc, Axl, and surviving. In addition VP affected signals involved in cell migration and angiogenesis such as CTGF, cyr61, and VEGF-A but was not associated with significant effect on the mTOR/autophagy pathway. Of interest the pluripotency marker Oct4 were downregulated by Verteporfin treatment. Our results indicate that the clinically used photosensitizer VP is a potent inhibitor of cell growth in retinoblastoma cells, disrupting YAP-TEAD signaling and pluripotential marker OCT4. This study highlights for the first time the role of the YAP-TEAD pathway in Retinoblastoma and suggests that VP may be a useful adjuvant therapeutic tool in treating Rb patients.

Francis JH, Schaiquevich P, Buitrago E, et al.
Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study.
Ophthalmology. 2014; 121(9):1810-7 [PubMed] Related Publications
PURPOSE: Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model.
DESIGN: Clinical and preclinical, prospective, cohort study.
PARTICIPANTS: In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye.
METHODS: Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated.
MAIN OUTCOME MEASURES: For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings.
RESULTS: By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina.
CONCLUSIONS: Weekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Related: Melphalan

Dean M, Bendfeldt G, Lou H, et al.
Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala.
Cancer Lett. 2014; 351(1):59-63 [PubMed] Related Publications
Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

Related: RB1

Ayari Jeridi H, Bouguila H, Ansperger-Rescher B, et al.
Genetic testing in Tunisian families with heritable retinoblastoma using a low cost approach permits accurate risk prediction in relatives and reveals incomplete penetrance in adults.
Exp Eye Res. 2014; 124:48-55 [PubMed] Related Publications
Heritable retinoblastoma is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk. In order to lower analytical efforts, we designed a stepwise mutation detection strategy that was adapted to the spectrum of oncogenic RB1 gene mutations. We applied this strategy on 20 unrelated patients with familial and/or de novo bilateral retinoblastoma from Tunisia. In 19 (95%) patients, we detected oncogenic mutations including base substitutions, small length mutations, and large deletions. Further analyses on the origin of the mutations showed mutational mosaicism in one unilaterally affected father of a bilateral proband and incomplete penetrance in two mothers. In a large family with several retinoblastoma patients, the mutation identified in the index patient was also detected in several non-penetrant relatives. RNA analyses showed that this mutation results in an in-frame loss of exon 9. In summary, our strategy can serve as a model for RB1 mutation identification with high analytical sensitivity. Our results point out that genetic testing is needed to reveal or exclude incomplete penetrance specifically in parents of patients with sporadic disease.

Related: RB1

Menda SA, Kim HJ, Bloomer MM, et al.
Papillary cystadenocarcinoma of the lacrimal gland after radiation for bilateral retinoblastoma.
Ophthal Plast Reconstr Surg. 2014 May-Jun; 30(3):e57-9 [PubMed] Related Publications
The authors report a case of papillary cystadenocarcinoma of the lacrimal gland after irradiation for bilateral retinoblastoma. A 32-year-old man with a history of bilateral retinoblastoma, diagnosed shortly after birth, was treated with enucleation of the OS and a single session of radiation to the OD. Over 30 years later, he presented with an orbital mass of the right lacrimal gland that on biopsy demonstrated papillary cystadenocarcinoma.

Related: Eye Cancer

Lee JA, Choi SY, Kang HJ, et al.
Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases.
Br J Ophthalmol. 2014; 98(10):1355-9 [PubMed] Related Publications
AIMS: To analyse clinical characteristics and treatment outcomes of osteosarcoma that developed in survivors of bilateral retinoblastoma.
METHODS: Three institutions participated in this retrospective study. Among survivors of bilateral retinoblastoma who were diagnosed and treated between 1995 and 2012, 8 cases (4 male, 4 female) of osteosarcoma were identified. Medical records were thoroughly reviewed.
RESULTS: Median age at diagnosis of bilateral retinoblastoma was 8.5 months (range 1.4-18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Median radiotherapy dose was 46.5 Gy (range 45-54 Gy). Median age at diagnosis of osteosarcoma was 8.9 years (range 5.4-20.3 years). Median interval between retinoblastoma and osteosarcoma was 8.2 years (range 5.0-20.0 years). Tumour locations were femur (n=5), tibia (n=1), mandible (n=1), and nasal cavity (n=1). Two patients presented with lung metastasis. Seven patients received multimodal treatment, and treatment was refused in 1 patient. After diagnosis of osteosarcoma, the patients were followed for a median of 17.3 months (range 4.4-56.4 months). The 2-year overall survival and event-free survival rates were 56.3 ± 19.9% and 33.3 ± 18.0%, respectively. At the time of analysis, 5 patients remained alive, and 2 of them were on therapy. Of the 3 surviving patients without evidence of disease, 2 received high dose chemotherapy with autologous peripheral blood stem cell support.
CONCLUSIONS: Our data could be used as a basis for future studies aimed at reaching consensus about long term follow-up and treatment guidelines for this genetically susceptible group of patients.

Related: Bone Cancers Osteosarcoma

He MY, An Y, Gao YJ, et al.
Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype-phenotype correlations.
Mol Vis. 2014; 20:545-52 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype-phenotype correlations.
METHODS: The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old.
RESULTS: Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations.
CONCLUSIONS: Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB.

Related: RB1

Little MP, Schaeffer ML, Reulen RC, et al.
Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.
Br J Cancer. 2014; 110(10):2623-32 [PubMed] Article available free on PMC after 13/05/2015 Related Publications
BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors.
METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls.
RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5).
CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

Related: Breast Cancer Male Breast Cancer Eye Cancer USA

Park SJ, Woo SJ, Park KH
Incidence of retinoblastoma and survival rate of retinoblastoma patients in Korea using the Korean National Cancer Registry database (1993-2010).
Invest Ophthalmol Vis Sci. 2014; 55(5):2816-21 [PubMed] Related Publications
PURPOSE: We determined the incidence of retinoblastoma and the long-term survival rate of retinoblastoma patients in South Korea.
METHODS: We reviewed retrospectively data from the Korea Central Cancer Registry recorded between 1993 and 2010 to identify the incidence of retinoblastoma and the survival rate of retinoblastoma patients in Korea. The incidence of retinoblastoma was estimated by population-based analysis of children aged 0 to 4 years and children aged 0 to 9 years, population-based analysis per live birth, and birth cohort analysis. Survival was analyzed using the Korea Central Cancer Registry database, which was crosschecked with the national death registry.
RESULTS: The overall incidence was 11.2 for children aged 0 to 4 years and 5.3 for children aged 0 to 9 years per 1,000,000 person-years, 5.9 per 100,000 live births, and 5.3 per 100,000 live births. Birth cohort analysis showed less variable results in incidence rates over 4 calendar-periods compared to the population-based analyses. The all-cause mortality rate was 7.9% at 5 years and 8.4% at 10 years. The rate improved from 12.5% for patients diagnosed in 1993 to 2000 to 4.5% for those diagnosed in 2001 to 2010.
CONCLUSIONS: The incidence of retinoblastoma in Korea was found to be similar to that in the United States, Europe, and Asia. The survival rate of retinoblastoma patients in Korea was significantly better during 2001 to 2010 than during 1993 to 2000.

Brown L
Recognising retinoblastoma: what health visitors need to know.
Community Pract. 2014; 87(3):42-5 [PubMed] Related Publications
Retinoblastoma is very rare, with between 40 and 50 cases in the UK each year. However, delays in diagnosis and treatment can lead to loss of vision or even death, while with prompt treatment the outcome is much more positive. This article aims to provide community practitioners with the correct information about retinoblastoma, ensuring that babies and young children with retinoblastoma are identified at the first sign of the disease and are referred promptly. The article will examine the signs and symptoms of retinoblastoma, consider treatment options, present a case study and explore the role of the health visitor.

Berry JL, Jubran R, Wong K, et al.
Factors predictive of long-term visual outcomes of Group D eyes treated with chemoreduction and low-dose IMRT salvage: the Children's Hospital Los Angeles experience.
Br J Ophthalmol. 2014; 98(8):1061-5 [PubMed] Related Publications
AIM: To evaluate clinical factors predictive of visual outcomes in Group D retinoblastoma eyes.
METHODS: Retrospective chart review of patients with Group D retinoblastoma from January 2000 to December 2009. All patients were treated with systemic chemoreduction and external beam radiation as salvage therapy when indicated. Primary outcome measure was visual acuity. Clinical factors evaluated include quadrants of subretinal fluid, extent of vitreous seeding, involvement of more/less than 50% of the macula, endophytic/exophytic tumour classification, and presence of tumour behind the lens at diagnosis.
RESULTS: Fifty-two Group D eyes of 41 patients were included; 10 eyes with visual acuity better than 20/80, 32 eyes with vision worse than 20/100 and 10 eyes with indeterminate vision (fix and follow). Complete retinal detachment (p=0.002), involvement of >50% of the macula (p=0.01), and seeding >3 quadrants (p=0.05) were associated with worse visual outcome. Average follow-up was 50.0 months (range: 10-118 months).
CONCLUSIONS: At presentation, it is difficult to predict which Group D eyes will be salvaged with useful vision following systemic chemotherapy. The presence of complete retinal detachment, macular involvement and extensive seeding on presentation were factors associated with a worse visual prognosis in this study. These findings can guide the ophthalmologist in clinical decision making, as well as in counselling parents.

Klump KE, McGinnis JF
The role of reactive oxygen species in ocular malignancy.
Adv Exp Med Biol. 2014; 801:655-9 [PubMed] Related Publications
Increased production of reactive oxygen species (ROS) is an attribute of malignant cells and is linked to the development of many of the characteristics considered "hallmarks of cancer (Hanahan and Weinberg, Cell 144(5), 2011, 646-674)." Among these are sustained proliferative signaling, induction of new vascular growth, promotion of invasion, and metastatic potential. Maintaining the balance between the beneficial biological functions of ROS and the dysregulation seen in human disease such as cancer, presents a daunting conundrum in the future of oncology research. ROS involvement is pervasive throughout the process of tumorigenesis and subsequent cancer growth, yet the response to both pro- and antioxidant based therapy is varied. We will review the ROS species in the pathogenesis of primary ocular malignancy with consideration of potential targets for therapeutic intervention.

Shields CL, Manjandavida FP, Lally SE, et al.
Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma.
Ophthalmology. 2014; 121(7):1453-60 [PubMed] Related Publications
OBJECTIVE: To analyze our 5-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma as primary or secondary therapy.
DESIGN: Retrospective interventional case series.
PARTICIPANTS: A total of 70 eyes of 67 patients.
INTERVENTION: Ophthalmic artery chemotherapy infusion under fluoroscopic guidance was performed using melphalan (3, 5, or 7.5 mg) in every case, with additional topotecan (1 mg) and/or carboplatin (30 or 50 mg) as necessary.
MAIN OUTCOME MEASURES: Tumor control and treatment complications.
RESULTS: The mean patient age at IAC was 30 months. The treatment was primary in 36 eyes and secondary in 34 eyes. Those primary therapy eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 1), C (n = 4), D (n = 17), or E (n = 14). The secondary therapy eyes had failed previous intravenous chemotherapy (n = 34) in every case. Each eye received a mean of 3 IAC sessions per eye (median, 3; range, 1-7 sessions). After IAC with a mean follow-up of 19 months, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases. Specifically, primary therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%). Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). After each catheterization (n = 198), the main complications included transient eyelid edema (5%), blepharoptosis (5%), and forehead hyperemia (2%). More lasting complications included vitreous hemorrhage (2%), branch retinal artery obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial choroidal ischemia (2%), and optic neuropathy (<1%). Over the past 3 years, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%. There was no patient with stroke, seizure, neurologic impairment, limb ischemia, secondary leukemia, metastasis, or death.
CONCLUSIONS: Five-year experience with IAC indicates that this technique is remarkably effective for the management of retinoblastoma as both a primary and a secondary treatment.

Related: Carboplatin Melphalan Topotecan

Ding Y, Wu M, Liu J, et al.
Seed-targeting anti-miR-21 inhibiting malignant progression of retinoblastoma and analysis of their phosphorylation signaling pathways.
Exp Eye Res. 2014; 122:1-8 [PubMed] Related Publications
MiR-21 acts as a ubiquitous oncogene in major classes of human cancers and is a potential target for therapeutic intervention. However, the relative expression of miR-21 in retinoblastoma is poorly understood. Here we detected miR-21 expression in HXO-RB44 cell line human normal retinal tissues and retinoblastoma (Rb) tissue specimens, and studied its function using an 8-mer tiny seed-targeting anti-miR-21 (t-anti-miR-21). RT-PCR revealed that miR-21 was highly overexpressed in HXO-RB44 cells and Rb tissue specimens compared with normal human retinal tissues. The localization and transfection efficiency of t-anti-miR-21 and the cell cycle distribution were detected by confocal microscopy and flow cytometry. In addition, we found that t-anti-miR-21 led to a significant inhibition of retinoblastoma cell proliferation, migration and colony formation in vitro, with a similar effect to anti-miR-21. Anti-miR-21 down-regulated the miR-21 level, whereas both 8-mer t-anti-miR-21 and 15-mer m-anti-miR-21 had no impact on miR-21 expression levels. Finally, the phosphorylation signaling pathway, down-regulated by t-anti-miR-21, was integrated by KEGG assay, which elucidated the potential mechanisms of inhibition of miR-21 in retinoblastoma. Taken together, knockdown of miR-21 in the HXO-RB44 cell is capable of inhibiting cancer progression in retinoblastoma. Seed-targeting t-anti-miR-21 was a novel strategy for mir-21-based therapeutics and drug discovery.

Related: Apoptosis Signal Transduction miR-21

de Jong MC, de Graaf P, Noij DP, et al.
Diagnostic performance of magnetic resonance imaging and computed tomography for advanced retinoblastoma: a systematic review and meta-analysis.
Ophthalmology. 2014; 121(5):1109-18 [PubMed] Related Publications
PURPOSE: To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard.
DESIGN: Systematic review and meta-analysis.
PARTICIPANTS: Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies.
METHODS: Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed.
MAIN OUTCOME MEASURES: Sensitivity and specificity of MRI and CT in detecting tumor extent.
RESULTS: Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%-78%), 74% (95% CI, 52%-88%), and 88% (95% CI, 20%-100%), respectively, and specificities of 94% (95% CI, 84%-98%), 72% (95% CI, 31%-94%), and 99% (95% CI, 86%-100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses.
CONCLUSIONS: Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few-mostly old-studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.

Sullivan EM, Wilson MW, Billups CA, et al.
Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation.
J Pediatr Hematol Oncol. 2014; 36(6):e335-40 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma.
MATERIALS AND METHODS: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated.
RESULTS: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y).
CONCLUSIONS: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.

Related: Carboplatin Cyclophosphamide Dactinomycin Teniposide Vincristine

Wong JR, Tucker MA, Kleinerman RA, Devesa SS
Retinoblastoma incidence patterns in the US Surveillance, Epidemiology, and End Results program.
JAMA Ophthalmol. 2014; 132(4):478-83 [PubMed] Related Publications
IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics. We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95% CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95% CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95% CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin.

Related: USA

Manjandavida FP, Honavar SG, Reddy VA, Khanna R
Management and outcome of retinoblastoma with vitreous seeds.
Ophthalmology. 2014; 121(2):517-24 [PubMed] Related Publications
PURPOSE: To report the treatment response of retinoblastoma with vitreous seeds to high-dose chemotherapy coupled with periocular carboplatin.
DESIGN: Retrospective, interventional case series.
PARTICIPANTS: Consecutive patients with retinoblastoma with vitreous seeds managed over 10 years at a comprehensive ocular oncology center and followed up for at least 12 months after the completion of treatment were included in this study. Institutional review board approval was obtained.
INTERVENTION: High-dose chemotherapy with a combination of vincristine, etoposide, and carboplatin in patients with focal vitreous seeds and additional concurrent periocular carboplatin in patients with diffuse vitreous seeds.
MAIN OUTCOME MEASURES: Tumor regression, vitreous seed regression, and eye salvage.
RESULTS: After excluding the better eye of bilateral cases, 101 eyes of 101 patients were part of the final analysis. All the patients belonged to Reese-Ellsworth group VB, but on the International Classification of Retinoblastoma (ICRB), 21 were group C, 40 were group D, and 40 were group E. The mean basal diameter of the largest tumor was 11.8 ± 4.7 mm. Mean tumor thickness was 7.5 ± 4.0 mm. Vitreous seeds were focal in 21 eyes and diffuse in 80 eyes. Chemotherapy cycles ranged from 6 to 12 (median, 6). Seventy-three eyes with diffuse vitreous seeds received a 15-mg posterior sub-Tenon carboplatin injection (range, 1-13 mg; median, 6 mg). Follow-up duration ranged from 13.4 to 129.2 months (median, 48 months). External beam radiotherapy (EBRT) was necessary in 33 eyes with residual tumor, vitreous seeds, or both. In all, 20 eyes (95%) with ICRB group C retinoblastoma, 34 eyes (85%) with group D retinoblastoma, and 23 eyes (57.5%) with group E retinoblastoma were salvaged. Of 77 eyes that were salvaged, 74 (96%) had visual acuity of 20/200 or better. Twenty-four of 33 chemotherapy failures (73%) regressed with EBRT. None of the patients demonstrated second malignant neoplasm or systemic metastasis. Factors predicting tumor regression and eye salvage were bilateral retinoblastoma and absence of subretinal fluid. Factors predicting vitreous seed regression were absence of subretinal fluid and subretinal seeds.
CONCLUSIONS: Intensive management with primary high-dose chemotherapy and concurrent periocular carboplatin, and EBRT selectively in chemotherapy failures, provides gratifying outcome in retinoblastoma with vitreous seeds.

Related: Carboplatin Etoposide Vincristine

Wang J, Liu XH, Yang ZJ, et al.
The effect of ROCK-1 activity change on the adhesive and invasive ability of Y79 retinoblastoma cells.
BMC Cancer. 2014; 14:89 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Retinoblastoma (Rb) is the most common intraocular tumor in childhood worldwide. It is a deadly pediatric eye cancer. The main cause of death in Rb patients is intracranial and systemic metastasis. ROCK is the main downstream effector of Ras-homologous (Rho) family of GTPases which are involved in many cellular functions, such as cell proliferation, invasion and metastasis. Overexpression of ROCK promotes invasion and metastasis of many solid tumors. However, the effect of ROCK in Rb is largely unknown.
METHODS: ROCK-1 and ROCK-2 mRNA expression in Y79 cell lines were examined by RT-PCR. Protein expression in the Y79 cell line were examined by western blot analyses. ROCK-1 and ROCK-2 siRNA were transfected into Y79 cells with Lipofectamine 2000. Cell proliferation was evaluated by CCK-8 assay after exposure to ROCK inhibitor (Y-27632). We examined the effect of ROCK inhibitors (Y-27632, ROCK-1 and ROCK-2 siRNA) on Y79 cell adhesive capacity by cell adhesion assay. Cell invasion assay through matrigel was used to study the effect of ROCK inhibitors on Y79 cell invasive capacity.
RESULTS: The expression of mRNA of ROCK-1 was more than that of ROCK-2 in the Y79 cell line. The protein expression levels of ROCK-1 and ROCK-2 were downregulated in the cells transfected with siRNA. Y-27632 treatment didn't lead to any changes of Y79 cells proliferation. Adhesive ability of Y79 cells was enhanced following Y-27632 or ROCK-1 siRNA treatment. The invasive capacity of Y79 cells showed an inverse relationship with increasing Y-27632 concentration. Invasiveness of Y79 cells also decreased in Y79 cells transfected with ROCK-1 siRNA. However, there was no change in adhesive ability or invasive capacity in Y79 cells transfected with siRNA against ROCK-2.
CONCLUSIONS: The findings of this study demonstrate that ROCK-1 protein plays a key role in regulating metastasis and invasion of Y79 cells, suggesting that the ROCK-1 dependent pathway may be a potential target for therapy of Rb.

Kalita D, Shome D, Jain VG, et al.
In vivo intraocular distribution and safety of periocular nanoparticle carboplatin for treatment of advanced retinoblastoma in humans.
Am J Ophthalmol. 2014; 157(5):1109-15 [PubMed] Related Publications
PURPOSE: To study the intraocular distribution and safety of polymethylmethacrylate nanoparticles loaded with carboplatin after posterior subtenon injection in humans.
DESIGN: Prospective, interventional, comparative case series.
METHODS: Six patients (mean age: 26.83 ± 7.5 years), scheduled to undergo planned uniocular enucleation in an institutional setting, were randomly divided into 3 groups. Each group received a 10 mg/mL posterior subtenon injection of nanoparticle carboplatin in the eye to be enucleated. Two eyes were enucleated 6, 24 and 72 hours post injection. Intravenous blood was collected during enucleation. The concentration of carboplatin reaching various intraocular tissues was determined by inductively coupled plasma atomic emission spectroscopy. The drug toxicity in the ocular tissues was assessed by histopathology and high-resolution transmission electron microscopy.
RESULTS: The highest level of carboplatin was detected in retinas (8.33 ± 1.69 mg/g), up to 24 hours post treatment. The intravitreal concentration continued to increase gradually until 72 hours (3.46 ± 0.26 mg/g). The choroids and lenses showed very low levels of carboplatin after 6 hours, with negligible amounts at 72 hours. No signs of tissue damage were observed on histopathology or electron microscopy. Intravenous concentration of carboplatin was undetectable in all patients.
CONCLUSION: Results may indicate an increased facilitated trans-scleral transport of nanoparticle carboplatin, with a sustained-release behavior but without any associated short-term ocular or systemic side effects in humans. The very high concentrations achieved in vitreous and retina after a single posterior subtenon injection may be clinically useful for adjunctive treatment of advanced intraocular retinoblastoma with vitreous seeds. However, further studies are needed to assess long-term toxicity and clinical efficacy.

Related: Carboplatin

Walther J, Schastak S, Dukic-Stefanovic S, et al.
Efficient photodynamic therapy on human retinoblastoma cell lines.
PLoS One. 2014; 9(1):e87453 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Photodynamic therapy (PDT) has shown to be a promising technique to treat various forms of malignant neoplasia. The photodynamic eradication of the tumor cells is achieved by applying a photosensitizer either locally or systemically and following local activation through irradiation of the tumor mass with light of a specific wavelength after a certain time of incubation. Due to preferential accumulation of the photosensitizer in tumor cells, this procedure allows a selective inactivation of the malignant tumor while sparing the surrounding tissue to the greatest extent. These features and requirements make the PDT an attractive therapeutic option for the treatment of retinoblastoma, especially when surgical enucleation is a curative option. This extreme solution is still in use in case of tumours that are resistant to conventional chemotherapy or handled too late due to poor access to medical care in less advanced country. In this study we initially conducted in-vitro investigations of the new cationic water-soluble photo sensitizer tetrahydroporphyrin-tetratosylat (THPTS) regarding its photodynamic effect on human Rb-1 and Y79 retinoblastoma cells. We were able to show, that neither the incubation with THPTS without following illumination, nor the sole illumination showed a considerable effect on the proliferation of the retinoblastoma cells, whereas the incubation with THPTS combined with following illumination led to a maximal cytotoxic effect on the tumor cells. Moreover the phototoxicity was lower in normal primary cells from retinal pigmented epithelium demonstrating a higher phototoxic effect of THPTS in cancer cells than in this normal retinal cell type. The results at hand form an encouraging foundation for further in-vivo studies on the therapeutic potential of this promising photosensitizer for the eyeball and vision preserving as well as potentially curative therapy of retinoblastoma.

Chawla B, Khurana S, Sen S, Sharma S
Clinical misdiagnosis of retinoblastoma in Indian children.
Br J Ophthalmol. 2014; 98(4):488-93 [PubMed] Related Publications
AIM: To determine the rate of clinical misdiagnosis in paediatric patients who were enucleated for retinoblastoma and report the clinicopathological features of cases that were misdiagnosed.
METHODS: Retrospective review of medical records of children who underwent a primary enucleation for advanced retinoblastoma was done. In all cases, the diagnosis of retinoblastoma was made on the basis of clinical presentation and imaging modalities. Clinicopathological features of eyes with discordant clinical and histopathological diagnosis were studied in detail.
RESULTS: Of 280 eyes (280 patients) that were enucleated over a 4-year period, histopathological diagnosis was consistent with retinoblastoma in 276 (98.6%) eyes. In 4 (1.4%) eyes, clinical and histopathological diagnoses were discordant. Histopathological features in misdiagnosed cases included one case each of granulomatous endophthalmitis, retinal astrocytoma, Coats' disease and persistent hyperplastic primary vitreous.
CONCLUSIONS: To the best of our knowledge, this is the first study to examine the rate of clinical misdiagnosis of retinoblastoma from South Asia. Despite the use of modern preoperative imaging modalities including MRI scans, benign lesions in end-stage conditions simulated retinoblastoma, resulting in potentially avoidable enucleation.

Mirakholi M, Mahmoudi T, Heidari M
MicroRNAs horizon in retinoblastoma.
Acta Med Iran. 2013; 51(12):823-9 [PubMed] Related Publications
In the retinoblastoma research, it is of great interest to identify molecular markers associated with the genetics of tumorigenesis. microRNAs (miRNAs) are small non-coding RNA molecules that play a regulatory role in many crucial cellular pathways such as differentiation, cell cycle progression, and apoptosis. A body of evidences showed dysregulation of miRNAs in tumor biology and many diseases. They potentially play a significant role in tumorigenesis processes and have been the subject of research in many types of cancers including retinal tumorigenesis. miRNA expression profiling was found to be associated with tumor development, progression and treatment. These associations demonstrate the putative applications of miRNAs in monitoring of different aspect of tumors consisting diagnostic, prognostic and therapeutic. Herein, we review the current literature concerning to the study of miRNA target recognition, function to tumorigenesis and treatment in retinoblastoma. Identification the specific miRNA biomarkers associated with retinoblastoma cancer may help to establish new therapeutic approaches for salvage affected eyes in patients.

Thériault BL, Dimaras H, Gallie BL, Corson TW
The genomic landscape of retinoblastoma: a review.
Clin Experiment Ophthalmol. 2014 Jan-Feb; 42(1):33-52 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Retinoblastoma is a paediatric ocular tumour that continues to reveal much about the genetic basis of cancer development. Study of genomic aberrations in retinoblastoma tumours has exposed important mechanisms of cancer development and identified oncogenes and tumour suppressors that offer potential points of therapeutic intervention. The recent development of next-generation genomic technologies has allowed further refinement of the genomic landscape of retinoblastoma at high resolution. In a relatively short period of time, a wealth of genetic and epigenetic data has emerged on a small number of tumour samples. These data highlight the inherent molecular complexity of this cancer despite the fact that most retinoblastomas are initiated by the inactivation of a single tumour suppressor gene. This review outlines the current understanding of the genomic, genetic and epigenetic changes in retinoblastoma, highlighting recent genome-wide analyses that have identified exciting candidate genes worthy of further validation as potential prognostic and therapeutic targets.

Abramson DH
Retinoblastoma: saving life with vision.
Annu Rev Med. 2014; 65:171-84 [PubMed] Related Publications
Retinoblastoma has gone from >95% mortality to >95% survival in the past 100 years. Once enucleation techniques were perfected, the majority of children survived, but without the eye (or vision in that eye). Over the past 100 years, progressively better techniques have been developed for salvaging vision without sacrificing patient survival. Presently, 99% of children treated at our center survive their cancer, >99% retain at least one eye, and >90% retain normal vision in at least one eye. The introduction of ophthalmic artery chemosurgery has been the most dramatic, non-radiation-based mode to maximally preserve vision.

D'Elia G, Grotta S, Del Bufalo F, et al.
Two novel cases of trilateral retinoblastoma: genetics and review of the literature.
Cancer Genet. 2013; 206(11):398-401 [PubMed] Related Publications
Retinoblastoma (RB) is the most common eye tumor in children; it originates from germline and/or somatic mutations that inactivate both alleles of the RB1 gene located on chromosome 13q14. Patients with unilateral or bilateral RB infrequently may develop an additional intracranial neuroblastic tumor, usually in the pineal gland, which characterizes the trilateral retinoblastoma (TRB) syndrome. The most common chromosomal abnormalities detected in TRB are deletions at 13q14, even if some rare cases of RB1 point mutations were described. In our report, we investigated two patients with TRB who showed a germline RB1 point mutation that has never been found to date and a large deletion involving RB1, respectively. Genetic data were compared to our in-house series and to current literature; these data suggested a role for other candidate regions in the pathogenesis of TRB. Moreover, our study highlights the need for new approaches allowing a multigenic analysis to clarify the genotype-phenotype correlation in TRB.

Related: Cancer Cytogenetics

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