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

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Retinoblastoma Genetics
Eye Cancers

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Latest Research Publications

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

Quintero-Estades JA, Izquierdo NJ
Germline retinoblastoma without inherited gene mutation: a case report.
Bol Asoc Med P R. 2014; 106(3):32-5 [PubMed] Related Publications
Retinoblastoma is the most common primary ocular malignancy in childhood and can occur as a germline or somatic mutation. Recent studies have suggested a higher incidence of retinoblastoma in Hispanic children as compared to non-Hispanic white children of the same ages. We report the ocular findings of a 20 years old Hispanic male with a history of bilateral retinoblastoma. Although screening is currently performed with the red reflex test, analysis of current literature suggests the need to reassess screening recommendations for retinoblastoma.

Xu XL, Singh HP, Wang L, et al.
Rb suppresses human cone-precursor-derived retinoblastoma tumours.
Nature. 2014; 514(7522):385-8 [PubMed] Article available free on PMC after 16/04/2015 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)

Wong JR, Morton LM, Tucker MA, et al.
Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.
J Clin Oncol. 2014; 32(29):3284-90 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
PURPOSE: Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.
PATIENTS AND METHODS: In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.
RESULTS: Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).
CONCLUSION: This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.

Related: USA

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] Article available free on PMC after 10/10/2015 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 CASP3

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

Willard VW, Qaddoumi I, Chen S, et al.
Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation.
J Clin Oncol. 2014; 32(25):2788-93 [PubMed] Related Publications
PURPOSE: To determine the developmental trajectory of early cognitive and adaptive skills in young children with retinoblastoma from diagnosis to 5 years of age.
PATIENTS AND METHODS: Ninety-four patients with retinoblastoma treated according to an institutional protocol underwent serial assessments of cognitive and adaptive functioning at age 6 months and 1, 2, 3, and 5 years. Data were analyzed by treatment strata, with patients with 13q deletion analyzed separately.
RESULTS: At baseline, across all patients (except those with 13q deletion), developmental functioning was comparable with the normative mean, with mean scores for all strata within the average range. However, at age 5 years, developmental functioning was in the low average range and significantly below normative means. The trajectories of developmental functioning demonstrated significant decline over time, although this varied by treatment group/strata. Patients treated with enucleation only evidenced the greatest decline in cognitive functioning; significant change was not observed in patients treated with other modalities. Notable declines in parent-reported communication skills were observed in the majority of patients. Patients with 13q deletion evidenced delayed cognitive functioning at baseline, but minimal declines were observed through age 3 years. However, significant decreases in adaptive functioning were demonstrated over time for the 13q deletion subset.
CONCLUSION: The declines in functioning observed in this study were unexpected, as was the poorer performance of the enucleation-only group. This highlights the necessity of continuing to assess cognitive functioning in patients with retinoblastoma as they age. Additional research is necessary to determine the long-term trajectory of cognitive development in this population.

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.

Parareda A, Català J, Carcaboso AM, et al.
Intra-arterial chemotherapy for retinoblastoma. Challenges of a prospective study.
Acta Ophthalmol. 2014; 92(3):209-15 [PubMed] Related Publications
PURPOSE: To report the efficacy and complications of intra-ophthalmic artery melphalan (IAM) for treatment of patients with advanced intra-ocular retinoblastoma.
METHODS: Patients with newly diagnosed, unilateral, group D retinoblastoma were included in a phase II protocol. Children with relapsed-refractory disease after systemic chemoreduction were later treated under the same guidelines.Melphalan (3–5 mg/procedure) was injected through a 1.2 F microcatheter placed into the ophthalmic artery every 21 days.
RESULTS: Eleven patients (12 eyes, eight as primary treatment) received 33 IAM procedures. The phase II protocol closed prematurely because of low accrual. The IAM technique was overall safe and could be performed successfully in 31 of 33(94%) attempts. After the second administration of IAM, very good partial response was achieved in all treated eyes. With a median follow-up time of 29.5 months (range 6–57), ocular salvage was achieved in 7 of 12 (58%) eyes. No systemic adverse events were observed. Two patients developed diffuse arteriolar sclerosis, hyperpigmentation of the retinal pigment epithelium and partial retinal atrophy after the second IAM. Both eyes were preserved with no tumour activity, good motility and perception of light, 56 and 30 months after the last IAM treatment. Multinucleated macrophages with intracytoplasmic foreign material were found in the choroid and the retina in 2 of 5 enucleated eyes.
CONCLUSION: Our study reports the activity and reproducibility of IAM in advanced retinoblastoma but also underlines the challenges of performing prospective studies on this treatment modality. Toxicity was limited to only ocular vascular events.

Related: Melphalan

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

Xia T, Cheng H, Zhu Y
Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions.
Ann Clin Lab Sci. 2014; 44(2):134-44 [PubMed] Related Publications
BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in tumor cell adaption to hypoxia by inducing the transcription of numerous genes. The role of HIF-1α in malignant retinoblastoma remains unclear. We analyzed the role of HIF-1α in WERI-Rb-1 retinoblastoma cells under hypoxic conditions.
METHODS: CoCl2 (125 mmol/L) was added to the culture media to mimic hypoxia. HIF-1α was silenced using siRNA. Gene and protein expression were measured by semi-quantitative RT-PCR and Western blotting. Cell cycle and apoptosis were analyzed by flow cytometry. Cell proliferation, adhesion and invasion were assayed using MTT, Transwell invasion, and cell adhesion assays respectively.
RESULT: Hypoxia significantly upregulated HIF-1α protein expression and the HIF-1α target genes VEGF, GLUT1, and Survivin mRNA. HIF-1α mRNA expression was not affected by hypoxia. Transfection of the siRNA expression plasmid pRNAT-CMV3.2/Neo-HIF-1α silenced HIF-1α by approximately 80% in hypoxic WERI-Rb-1 cells. The knockdown of HIF-1α under hypoxic conditions downregulated VEGF, GLUT1, and Survivin mRNA. It also inhibited proliferation, promoted apoptosis, induced the G0/G1 phase cell cycle arrest, and reduced the adhesion and invasion of WERI-Rb-1 cells.
CONCLUSION: HIF-1α plays a major role in the survival and aggressive phenotype of retinoblastoma cells under hypoxic conditions. Targeting HIF-1α may be a promising therapeutic strategy for human malignant retinoblastoma.

Related: Apoptosis SLC2A1 HIF1A VEGFA BIRC5

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

Saremi L, Imani S, Rostaminia M, Nadeali Z
Parental age-related risk of retinoblastoma in Iranian children.
Asian Pac J Cancer Prev. 2014; 15(6):2847-50 [PubMed] Related Publications
BACKGROUND: Retinoblastoma is a rare malignant intraocular neoplasm. About 90% of cases feature a germline mutation in the RB1 gene and these will develop retinoblastoma during their early childhood. An association between mutations in germline cells and aging has been demonstrated. This suggests a higher incidence of childhood cancer including retinoblastoma among children of older parents.
MATERIALS AND METHODS: In the present study we aimed to determine the association of paternal and maternal age with an increased risk of retinoblastoma in a case-control study in Iranian population. The study was carried out on 240 persons who were born during 1984-2012 in Mahak and Mofid hospitals in Tehran, Iran. The statistical analysis included studying the mean age of parents and in order to know whether parental age of patients is different from parental age of control group, (t-test) compare averages test is used perfectly. By binary logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
RESULTS: The results of statistical analysis including the study of mean parental age by the use of (t-test) compare averages test showed a significant difference between parental ages of patients and controls. Logistic regression showed that coefficients were significant for maternal but not paternal age.
CONCLUSIONS: Our findings indicate that advanced maternal age can increase the risk of retinoblastoma in offspring, but the paternal age has no significant effect.

Related: Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page

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

Baroni LV, Sampor C, Fandiño A, et al.
Anterior segment invasion in retinoblastoma: is it a risk factor for extraocular relapse?
J Pediatr Hematol Oncol. 2014; 36(8):e509-12 [PubMed] Related Publications
We report a retrospective review of patients with retinoblastoma and anterior segment invasion (ASI) as risk factors for extraocular relapse. Only those with ASI combined with postlaminar optic nerve invasion and/or scleral invasion received adjuvant chemotherapy and those with tumor at the resection margin received orbital radiotherapy. Those with only uveal invasion did not receive adjuvant therapy. Of 479 evaluable patients, 67 patients had pathologically confirmed ASI, including 52 with anterior chamber invasion and 47 with iris or ciliary body invasion. ASI occurred with other pathology risk factors (25 had concomitant posterior uveal invasion, 36 had postlaminar optic nerve invasion, 11 with cut-end invasion, and 25 with scleral invasion). The 5-year disease-free survival (pDFS) was 0.9 (95% CI, 0.8-0.95) for children with ASI with no significant differences among children with other pathology risk factors with and without ASI. ASI was not significantly associated with extraocular relapse in multivariate analysis. There were no significant differences in pDFS for patients with anterior chamber invasion and those with iris-ciliary body invasion (pDFS 0.89 [95% CI, 0.65-0.96] vs. 0.93 [95% CI, 0.61-0.98]). To conclude, ASI was seen with other pathology risk factors and it did not add a significant risk for extraocular relapse.

Moreno F, Sinaki B, Fandiño A, et al.
A population-based study of retinoblastoma incidence and survival in Argentine children.
Pediatr Blood Cancer. 2014; 61(9):1610-5 [PubMed] Related Publications
BACKGROUND: An increased incidence of retinoblastoma in some developing countries has been reported but no conclusive data are available from population-based studies at national level.
PURPOSE: To report the incidence and survival of retinoblastoma in Argentina from the National Pediatric Cancer Registry (ROHA) and the influence of socio-economical indicators on outcome.
PROCEDURE: Cases reported to the ROHA (2000-2009) were analyzed. Incidence rates were calculated using National Vital Statistics and survival was estimated. The extended human development index (EHDI) was used as a socio-economical indicator.
RESULTS: With 438 patients reported, an incidence of 5.0 cases per million children 0-14 years old (95% CI 3.5-6.4) was calculated. Median age at diagnosis was significantly higher for children from provinces with lower EHDI; (24 vs. 35 months for unilateral, (P = 0.003) and 9 versus 11.5 months for bilateral retinoblastoma (P = 0.027). The 3-year probability of survival was 0.87 and 0.94 for unilateral and bilateral retinoblastoma, respectively. Residents in provinces with higher EHDI had a better 3-year survival (0.93 vs. 0.77 for lower EHDI, P < 0.0001). Probability of survival was higher for patients treated at tertiary level institutions (P = 0.0015). The combination of low EHDI residence province with no treatment at a tertiary institution was associated with the worst survival outcome. For both, unilateral and bilateral disease, children who died were in average diagnosed at older age.
CONCLUSIONS: The incidence of retinoblastoma in Argentina is comparable to that of developed countries. Retinoblastoma is diagnosed later and survival is lower in the less developed areas of the country.

Ajioka I
Coordination of proliferation and neuronal differentiation by the retinoblastoma protein family.
Dev Growth Differ. 2014; 56(5):324-34 [PubMed] Related Publications
Once neurons enter the post-mitotic G0 phase during central nervous system (CNS) development, they lose their proliferative potential. When neurons re-enter the cell cycle during pathological situations such as neurodegeneration, they undergo cell death after S phase progression. Thus, the regulatory networks that drive cell proliferation and maintain neuronal differentiation are highly coordinated. In this review, the coordination of cell cycle control and neuronal differentiation during development are discussed, focusing on regulation by the Rb family of tumor suppressors (including p107 and p130), and the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitors. Based on recent findings suggesting roles for these families in regulating neurogenesis and neuronal differentiation, I propose that the Rb family is essential for daughter cells of neuronal progenitors to enter the post-mitotic G0 phase without affecting the initiation of neuronal differentiation in most cases, while the Cip/Kip family regulates the timing of neuronal progenitor cell cycle exit and the initiation of neuronal differentiation at least in the progenitor cells of the cerebral cortex and the retina. Rb's lack of involvement in regulating the initiation of neuronal differentiation may explain why Rb family-deficient retinoblastomas characteristically exhibit neuronal features.

Related: RB1

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 MicroRNAs Signal Transduction microRNA 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

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