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.
A charity for families and individuals affected by retinoblastoma which aims to provide support, fund research and raise awareness. Initially registered as a charity in 1987 and formerly known as the Retinoblastoma Society. the site includes resources for both families and health professionals.
PubMed Central search for free-access publications about Retinoblastoma MeSH term: Retinoblastoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
A charity for families and individuals affected by retinoblastoma which aims to provide support, fund research and raise awareness. Initially registered as a charity in 1987 and formerly known as the Retinoblastoma Society. the site includes resources for both families and health professionals.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
PURPOSE OF REVIEW: Retinoblastoma is the most common malignant intraocular tumor of childhood. Treatment and diagnostic modalities associated to this condition are changing rapidly as our understanding of this condition crystallizes. The purpose of this review is to provide an update of the current understanding of retinoblastoma. RECENT FINDINGS: Knowledge on tumorigenesis and genomic expression has expanded tremendously with the development of a mouse model for retinoblastoma. Tumor hypoxia has been identified as a significant step in the tumor progression and a novel target for future treatments. Current globe-sparing therapies, including periocular carboplatin, selective ophthalmic artery chemoreduction, intravitreal melphalan, and focal consolidation are being used and investigated actively. Diagnosis and the management of retinoblastoma is also undergoing major advances including wide-field photography, autofluorescence, and high-resolution optical coherence tomography. SUMMARY: Progressive advances in the understanding of retinoblastoma pathogenesis continue to lead treatment strategies. Improvements in the diagnosis and management of retinoblastoma are improving morbidity and mortality associated to this condition in the developed nations. However, it is of outmost importance to flatten the international boundaries to offer prompt care to retinoblastoma children in underdeveloped communities.
Choi YJ, Park C, Jin HC, et al. Outcome of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma. Br J Ophthalmol. 2013; 97(12):1530-3 [PubMed] Related Publications
AIM: To evaluate the surgical outcome after the insertion of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma. METHODS: 44 consecutive children with retinoblastoma who underwent primary enucleation and Medpor SST implantation at Seoul National University Hospital from November 2004 to August 2009, with at least 24 months of follow-up were included. A retrospective review of cases was performed. RESULTS: Mean age at the time of surgery was 24.7 months (range 1-65 months). The diameter of the spherical implant was 20 mm in 36 patients (81.8%) and 18 mm in 8 patients (18.2%). During a mean follow-up period of 60.1 months (range 26-93 months), there were no cases of implant exposure, extrusion or infection. Transient conjunctival thinning developed in three patients, but all resolved with conservative treatment. Anophthalmic socket complications such as lower lid malposition (retraction or entropion) (n=10, 22.7%), blepharoptosis (n=8, 18.2%) and enophthalmos (n=2, 4.5%) developed, but most showed acceptable cosmesis. CONCLUSIONS: Medpor SST is relatively safe, allowing for a mean follow-up of 5 years in terms of implant exposure, and may be a good choice of orbital implant for children with retinoblastoma.
BACKGROUND: Retinoblastoma is the most common pediatric ocular tumour. It may rarely present in adults. The present case adds to the number of 26 cases already published in literature since 1919 till 2013. Our aim is to highlight the rare occurrence of retinoblastoma in adults along with its features which differentiate it from paediatric retinoblastoma. CASE PRESENTATION: We describe a case of adult onset retinoblastoma (group E, according to the international classification of retinoblastoma) occurring in a 25 year old male. He presented with decreasing visual acuity in the right eye of 4 months duration. He had neo-vascular glaucoma and pseudohypopyon. B scan ultrsonography of his right eye showed intraocular growth without any calcification. The CT scan of the orbits and brain showed intraocular growth in the right eye with no calcification. Enucleation of the right eye was carried out. Retinoblastoma was confirmed on histopathology of the enuleated globe. CONCLUSIONS: The present case adds to the number of adult Rb patients reported in literature. Early detection to salvage the life can be made possible if the clinician keeps a high index of suspicion when observing retinal mass of adult onset. Proper counselling of the patient in order to seek his full involvement in management may help in improving the prognosis of the disease.
Tsimpida M, Thompson DA, Liasis A, et al. Visual outcomes following intraophthalmic artery melphalan for patients with refractory retinoblastoma and age appropriate vision. Br J Ophthalmol. 2013; 97(11):1464-70 [PubMed] Related Publications
BACKGROUND/AIMS: To determine the frequency and cause of visual loss following intra-arterial melphalan (IAM) in patients with retinoblastoma with age appropriate vision. METHODS: Assessment of patients with refractory retinoblastoma that had undergone systemic chemotherapy, with or without local treatment, and were subsequently treated with IAM. Eyes of patients with a healthy foveola were assessed. The main outcome measures included visual, macular (including Pattern Visual Evoked Potentials and Fundus Fluorescein Angiography) and retinal functions (Electroretinograms). RESULTS: Five of twelve eyes (42%) demonstrated severe visual loss following IAM at last follow-up (median 21 months). This was due to either retinal detachment (1 eye, 20%) or choroidal ischaemia involving the foveola (4 eyes, 80%). All 3 eyes that had technical difficulties or vasospasm during catheterisation suffered visual loss. 8 out of 10 eyes that had a non-age adjusted dose of melphalan suffered visual loss. Electroretinograms post-IAM deteriorated in 4 of 8 eyes (50%) and Pattern Visual Evoked Potentials deteriorated in 3 (37%), though only one of these 3 showed concomitant visual acuity loss. CONCLUSIONS: Structural and vascular damage to the foveola limited visual acuity. Complications associated with catheterisation and high doses of melphalan may be contributory factors to visual morbidity. Although visual loss is described, no patient developed metastases and most retained good vision.
Francis JH, Barker CA, Wolden SL, et al. Salvage/adjuvant brachytherapy after ophthalmic artery chemosurgery for intraocular retinoblastoma. Int J Radiat Oncol Biol Phys. 2013; 87(3):517-23 [PubMed] Related Publications
PURPOSE: To evaluate the efficacy and toxicity of brachytherapy after ophthalmic artery chemosurgery (OAC) for retinoblastoma. METHODS AND MATERIALS: This was a single-arm, retrospective study of 15 eyes in 15 patients treated with OAC followed by brachytherapy at (blinded institution) between May 1, 2006, and December 31, 2012, with a median 19 months' follow-up from plaque insertion. Outcome measurements included patient and ocular survival, visual function, and retinal toxicity measured by electroretinogram (ERG). RESULTS: Brachytherapy was used as adjuvant treatment in 2 eyes and as salvage therapy in 13 eyes of which 12 had localized vitreous seeding. No patients developed metastasis or died of retinoblastoma. The Kaplan-Meier estimate of ocular survival was 79.4% (95% confidence interval 48.7%-92.8%) at 18 months. Three eyes were enucleated, and an additional 6 eyes developed out-of-target volume recurrences, which were controlled with additional treatments. Patients with an ocular complication had a mean interval between last OAC and plaque of 2.5 months (SD 2.3 months), which was statistically less (P=.045) than patients without ocular complication who had a mean interval between last OAC and plaque of 6.5 months (SD 4.4 months). ERG responses from pre- versus postplaque were unchanged or improved in more than half the eyes. CONCLUSIONS: Brachytherapy following OAC is effective, even in the presence of vitreous seeding; the majority of eyes maintained stable or improved retinal function following treatment, as assessed by ERG.
Zhang Q, Jiang Y, Toutounchian J, et al. Novel quinic acid derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling. Invest Ophthalmol Vis Sci. 2013; 54(9):5937-43 [PubMed] Article available free on PMC after 01/03/2014 Related Publications
PURPOSE: To determine whether a novel NF-κB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS: RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 μM KZ-41, following treatment with 4 μg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-κB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-κB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a Cell Death ELISA after melphalan + KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS: KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-κB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS: KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK-dependent pathways.
Shinohara ET, DeWees T, Perkins SM Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer. 2014; 61(1):116-9 [PubMed] Related Publications
BACKGROUND: As cure rates for retinoblastoma have improved, it is clear that patients with hereditary retinoblastoma experience increased risk of subsequent malignant neoplasms (SMNs). METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database, we evaluated risk of SMNs in survivors or retinoblastoma. Standardized mortality ratios (SMRs) were calculated to compare number of deaths observed to the expected number for the cohort. Cumulative incidence of SMNs and standardized incidence ratios (SIRs) of observed to expected SMNs were calculated RESULTS: A total of 595 patients were included in the analysis. Cumulative incidence of secondary malignancy at 30 years for patients with unilateral and bilateral disease was 1.7% and 28.5%, respectively (P < 0.001). SIRs of subsequent malignancies for patients with unilateral and bilateral disease were 2.1 (95% CI = 0.6-5.4) and 38.3 (95% CI = 24.3-57.5), respectively. Patients with bilateral disease treated with and without radiotherapy both experienced an increased risk of SMNs (SIRs = 45.9, 95% CI = 26.8-73.6 and 27.3, 95% CI = 10.0-59.4, respectively). The most common cause of death for the patients with bilateral disease was subsequent malignancy (52% of deaths). Beginning in the 1990s, there was a significant decrease in the use of radiotherapy as 30.5% of patients received radiotherapy in the 1980s compared to 2.6% after 1999 (P < 0.001). CONCLUSIONS: Survivors of bilateral retinoblastoma experience an increased risk of SMNs which adversely affects survival. The use of radiotherapy in the management of retinoblastoma has declined; however, patients with bilateral disease remain at an increased risk of subsequent cancers.
Shah I, Baig A, Razzaq A, et al. Trilateral retinoblastoma with unilateral eye involvement. J Pak Med Assoc. 2013; 63(7):910-2 [PubMed] Related Publications
Trilateral retinoblastoma (TRb) is a rare combination of unilateral or bilateral retinoblastoma with an ectopic midline intracranial neuroblastic neoplasm (primitive neuroectodermal tumour) usually in the area of pineal gland or sellar region. TRb can occur with both familial and sporadic forms of retinoblastoma. An occurrence of this rare tumour in a 12-year-old boy who had unilateral retinoblastoma in association with ectopic suprasellar primitive neuroectodermal tumour (PNET) is reported here. To the best of our knowledge, this is the first case report in Pakistan on TRb with suprasellar mass.
Ramasubramanian A, Kytasty C, Meadows AT, et al. Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol. 2013; 156(4):825-9 [PubMed] Related Publications
PURPOSE: To report on the frequency of cysts and tumors of the pineal gland in patients with retinoblastoma. DESIGN: Observational retrospective case control study.
Künkele A, Jurklies C, Wieland R, et al. Chemoreduction improves eye retention in patients with retinoblastoma: a report from the German Retinoblastoma Reference Centre. Br J Ophthalmol. 2013; 97(10):1277-83 [PubMed] Related Publications
BACKGROUND: Retinoblastoma is the most common intraocular childhood tumour. Although mortality is low in Western countries, long-term sequelae, including secondary tumours, compromised vision or loss of one or both eyes are common. Chemoreduction combined with focal treatment is currently the leading conservative treatment for retinoblastoma, with success rates of 50-75% reported. We assessed a new chemoreduction protocol using intravenous cyclophosphamide with reduced dose of carboplatin on eye retention in patients with retinoblastoma. PROCEDURE: The 40 patients with retinoblastomas in 56 eyes were treated between 1995 and 2004 at the German Retinoblastoma Reference Centre Essen. The 6-cycle chemotherapy used vincristine (days 1, 22, 43, 64, 85, 106), etoposide (days 22, 43, 85, 106), carboplatin (days 1, 43, 64, 106), and cyclophosphamide (days 1, 22, 64, 85). Mean follow-up was 101 months. Most patients received additional hyperthermia, some received local treatment with laser coagulation, cryotherapy and/or β-ray brachytherapy. Therapy failure was defined as progression requiring enucleation or external beam radiotherapy (EBRT). RESULTS: Primary chemotherapy was successful in 42 of 56 eyes (75%). Therapy success and visual acuity at age 6 years correlated with the International Classification of Retinoblastoma (ICRB) group. Age at diagnosis (> or <6 months) correlated with relapse, but not with therapy failure or visual acuity at 6 years of age. ICRB group did not correlate with occurrence of relapse. CONCLUSIONS: In this retrospective single-centre study, chemoreduction, including cyclophosphamide, with or without focal treatment, effectively controlled retinoblastoma progression without requiring enucleation or EBRT. Addition of cyclophosphamide is safe, and allows reduction of carboplatin.
Vandhana S, Coral K, Jayanthi U, et al. Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors. Biochim Biophys Acta. 2013; 1831(9):1458-66 [PubMed] Related Publications
Retinoblastoma (RB) is a malignant intra-ocular neoplasm that affects children (usually below the age of 5years). In addition to conventional chemotherapy, novel therapeutic strategies that target metabolic pathways such as glycolysis and lipid metabolism are emerging. Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is over-expressed in retinoblastoma cancer. The present study evaluated the biochemical basis of FASN inhibition induced apoptosis in cultured Y79 RB cells. FASN inhibitors (cerulenin, triclosan and orlistat) significantly inhibited FASN enzyme activity (P<0.05) in Y79 RB cells. This was accompanied by a decrease in palmitate synthesis (end-product depletion), and increased malonyl CoA levels (substrate accumulation). Differential lipid profile was biochemically estimated in neoplastic (Y79 RB) and non-neoplastic (3T3) cells subjected to FASN inhibition. The relative proportion of phosphatidyl choline to neutral lipids (triglyceride+total cholesterol) in Y79 RB cancer cells was found to be higher than the non-neoplastic cells, indicative of altered lipid distribution and utilization in tumor cells. FASN inhibitor treated Y79 RB and fibroblast cells showed decrease in the cellular lipids (triglyceride, cholesterol and phosphatidyl choline) levels. Apoptotic DNA damage induced by FASN inhibitors was accompanied by enhanced lipid peroxidation.
Sudhakar J, Venkatesan N, Lakshmanan S, et al. Hypoxic tumor microenvironment in advanced retinoblastoma. Pediatr Blood Cancer. 2013; 60(10):1598-601 [PubMed] Related Publications
PURPOSE: Retinoblastoma (RB) is a malignant tumor of infancy and childhood. Unfavorable therapeutic response is still a quest in many tumors, including retinoblastoma. Hypoxic tumor microenvironment is one of the factors that determine the therapeutic response in many tumors. The purpose of this study was to determine the presence of hypoxia and its related proteins; Hypoxia inducible factor-1α (HIF-1α), Carbonic anhydrase IX (CA IX) and survivin in RB and their association with clinicopathological features. MATERIALS AND METHODS: We evaluated the expression of HIF-1α and survivin by immunohistochemistry in 42 archival retinoblastoma tumors and CA IX; a hypoxia marker in 33 tumors in the same cohort. The expression was correlated with tumor groups based on invasion, differentiation and IIRC. RESULTS: Expression of HIF-1α, survivin and CA IX was observed in 83% (35/42), 86% (36/42), and 93% (31/33) of tumors respectively. We observed no significance between HIF-1α and CA IX expression in tumors with invasion, differentiation and in IIRC tumor groups. An increased survivin expression was observed in group E tumors than in group D tumors (P = 0.044). A significant association was observed between HIF-1α and survivin in differentiated (r = -0.582; P = < 0.01) and undifferentiated tumors groups (r = 0.513; P = <0.012). A similar significant association was observed between HIF-1α and CA IX in tumors with high immunoreactivity for HIF-1α (r = 0.833; P = <0.01). CONCLUSION: Based on these observations, we propose that HIF-1α pathway is deregulated in RB. The role of drug resistance and the potential of targeting HIF-1α, CA IX, and survivin in RB should further examined.
Earl JB, Minckler DS, Lee TC, Murphree AL Malignant teratoid medulloepithelioma with retinoblastic and rhabdomyoblastic differentiation. J AAPOS. 2013; 17(3):328-31 [PubMed] Related Publications
We describe an unusual case of malignant teratoid medulloepithelioma in which distinct populations of tumor cells with different immunohistochemical staining patterns existed within the same eye. A neuroblastic population exhibited atypical features of retinoblastoma, including organization into pseudo-Flexner-Wintersteiner and Homer-Wright rosettes. Other populations evolved in strikingly different patterns, with large fields of cells resembling astrocytes and intervening streams of spindle cells that suggested smooth muscle. The spindle cell population was negative for smooth muscle antigen but stained positively for desmin, myoglobin, and myogenin. Under high magnification, the desmin, myoglobin, and myogenin-staining cells exhibited striations consistent with skeletal muscle differentiation.
Walinjkar J, Krishnakumar S, Gopal L, et al. Retinoblastoma presenting with orbital cellulitis. J AAPOS. 2013; 17(3):282-6 [PubMed] Related Publications
PURPOSE: To study the effectiveness of pre-enucleation steroids in reducing inflammation in patients with retinoblastoma presenting as orbital cellulitis. METHODS: Medical records of consecutive retinoblastoma patients presenting at a single tertiary eye care center during a period of 3 years were retrospectively reviewed. For those who presented with orbital cellulitis, clinical, radiological, and histopathological variables were assessed. The effect of pre-enucleation steroids was noted in this group of patients. RESULTS: Of 260 retinoblastoma cases reviewed, 14 had retinoblastoma-associated cellulitis (5.39%). Of these 14 patients, 4 received neoadjuvant chemotherapy and were excluded from the series. Of the remaining 10 cases (mean age at presentation, 14.2 months; mean follow-up, 16.4 months), 9 presented with orbital cellulitis and were included in the study. Radiological imaging depicted intraocular tumors occupying 80% to 100% of the globe in each case. All patients underwent enucleation. Five children received pre-enucleation systemic steroids (mean, 5.4 days), which resulted in a prompt decrease in inflammation. Postenucleation chemotherapy was administered in 4 (6 cycles) and external beam radiation therapy in 1 patient with high-risk histopathological characteristics. CONCLUSIONS: Advanced necrotic retinoblastoma with anterior segment involvement may present as orbital cellulitis. Pre-enucleation systemic steroids can aid in the surgical management of these tumors.
Chantada GL, Sampor C, Bosaleh A, et al. Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol. 2013; 131(9):1127-34 [PubMed] Related Publications
IMPORTANCE: Different staging systems for extraocular retinoblastoma have been published, but to date they have not been validated in large cohorts. OBJECTIVE: To review 533 patients (and pathology slides) with retinoblastoma included in 4 protocols (January 1, 1988, to December 31, 2009) who received uniform treatment. DESIGN AND SETTING: Retrospective review in a hospital setting. A critical analysis for detecting inconsistencies and omissions was performed. PARTICIPANTS: Patients were reclassified according to the modified St Jude Children's Research Hospital staging system, Grabowski-Abramson staging system, International Retinoblastoma Staging System (IRSS), and American Joint Committee on Cancer TNM staging system. MAIN OUTCOME AND MEASURE: The main outcome measure was disease-free survival (DFS), considering only extraocular relapse as an event. RESULTS: In the IRSS and the St Jude system, higher stages correlated with poorer DFS. For intraocular disease, only the TNM system and the IRSS included pathological definitions, and all systems except for the IRSS included substages without differences in DFS. Omissions of factors significantly associated with lower DFS included scleral invasion by the TNM system and massive choroidal invasion by the Grabowski-Abramson system. The St Jude system omits postlaminar optic nerve involvement, but this omission did not correlate significantly with lower DFS because these patients received intensive therapy. No differences in DFS were observed among substages for metastatic disease except for the presence of central nervous system involvement. All staging systems had inconsistencies in definitions of extent of disease. No system provides guidelines for imaging. CONCLUSIONS AND RELEVANCE: Only the IRSS and the St Jude system allowed for grouping of patients with increasing risk of extraocular relapse. For lower stages, only the IRSS considers all unequivocal pathological prognostic factors. For higher stages, all systems had redundant information, resulting in an excess of substages.
Kapatai G, Brundler MA, Jenkinson H, et al. Gene expression profiling identifies different sub-types of retinoblastoma. Br J Cancer. 2013; 109(2):512-25 [PubMed] Article available free on PMC after 23/07/2014 Related Publications
BACKGROUND: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. METHODS: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. RESULTS: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. CONCLUSION: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.
Smith SJ, Smith BD Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol. 2013; 97(10):1231-6 [PubMed] Related Publications
BACKGROUND: Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following intravitreal penetration has limited its use. This review evaluates the risk of extraocular tumour spread in patients receiving therapeutic intravitreal injections for retinoblastoma. METHODS: PUBMED (1946-present), SCOPUS (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index--Science (1990-present) electronic databases were searched to identify all published reports of IViT for retinoblastoma in humans. RESULTS: 14 studies with original IViT data were included in this review. A total of 1304 intravitreal injections were given in 315 eyes of 304 patients, with one report of extraocular tumour spread and one patient in whom intravitreal treatment could not be excluded as a contributor to metastatic disease. The proportion of subjects with extraocular tumour spread potentially due to IViT in these combined reports was 0.007 (95% CI 0.0008 to 0.0236), with a mean follow-up of 72.1 months. In a subset of 61 patients receiving IViT via safety enhancing injection techniques (347 injections, 19.6 months mean follow-up), there were no reports of tumour spread. CONCLUSIONS: Local and systemic tumour spread following IViT in cases of retinoblastoma is rare, and this risk is potentially reduced by the use of safety enhancing injection techniques. These results suggest that the risk of tumour spread should not preclude IViT use for carefully selected patients as part of multi-modal globe salvaging therapy.
Khan ZN, Sabir M, Kayani MA, Saeed M Acetylation of retinoblastoma like protein2 (Rb2/p130) in tumor tissues. Asian Pac J Cancer Prev. 2013; 14(4):2255-8 [PubMed] Related Publications
The activity of Rb proteins is controlled by post-translational modifications, especially through phosphorylation. Acetylation of Rb2/p130 was reported recently in NIH3T3 cells but its physiological relevance in cell cycle control and tumorigenesis is still unknown. Efforts are underway to investigate possible interplay between Rb2/p130 phosphorylation and acetylation. Here we hypothesized that Rb2/p130 acetylation, like p53 acetylation, may play a role in development of the tumor phenotype. The proposed hypothesis regarding acetylation of Rb2/p130 in tumor VS normal cells was found to be true in our case study of 36 tumor samples. Statistical analysis of results suggest strong correlation among Rb2/p130 acetylation and cancer phenotype.
Laurent VE, Sampor C, Solernou V, et al. Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA. Eur J Cancer. 2013; 49(13):2892-9 [PubMed] Related Publications
AIM: To evaluate minimally disseminated disease (MDD) in cytologically negative cerebrospinal fluid (CSF) specimens of patients with high-risk retinoblastoma by the detection of the synthase of ganglioside GD2 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). METHODS: The CSF was evaluated in 26 patients with high risk for CSF relapse: 14 with postlaminar optic nerve invasion, five of them with tumour at the resection margin, five with massive choroidal invasion, three with overt orbital extension and four patients with systemic metastasis. Serial CSF examinations were repeated at different time intervals according to stage and in the event of suspected relapse. GD2 synthase mRNA was evaluated by RT and nested PCR at each procedure. RESULTS: MDD was present at diagnosis in six cases (23%) and it was significantly associated to massive optic nerve involvement or history of glaucoma (p<0.05). Three of the children with positive MDD had a CSF relapse. Thirteen patients had negative MDD at diagnosis and one had a CSF relapse. In seven children no ARN could be obtained for PCR analysis and two subsequently relapsed. The probability of CSF relapse was 0.50 (95% confidence interval (CI) 0.13-0.88) for children with MDD and 0.08 (95% CI 0.02-0.46) for those with negative RT-PCR examination of the CSF at diagnosis (p=0.03). CONCLUSIONS: MDD in the CSF detected by RT-PCR for GD2-synthase mRNA occurred in 31.7% of evaluable high-risk children with retinoblastoma with no initial central nervous system (CNS) involvement. It was significantly associated to optic nerve involvement and glaucoma and increased risk of CSF relapse.
Liu Q, Wang Y, Wang H, et al. Tandem therapy for retinoblastoma: immunotherapy and chemotherapy enhance cytotoxicity on retinoblastoma by increasing apoptosis. J Cancer Res Clin Oncol. 2013; 139(8):1357-72 [PubMed] Related Publications
PURPOSE: The goal of this study was to provide an experimental basis for the clinical application of cell immunotherapy on RB in combination with chemotherapy treatment and to explore the mechanism of their combined cytotoxicity. METHODS: We investigated the antitumor effect of cytokine-induced killer cells (CIK), co-cultivated with dendritic cells pulsed with tumor antigens (DC-Ag) and/or with carboplatin. Cytotoxicity was evaluated on a retinoblastoma cell line (RB-Y79) by FCM and immunofluorescence microscopy. Time-lapse video microscopy was used to follow the sequence of events during the carboplatin and CIK cytotoxicity. RESULTS: Our results showed that a small proportion of RB-Y79 cells died after a low-dose carboplatin application. The cell population recovered 5 days after carboplatin was removed from the culture medium. Three times fewer normal epithelium retina cell lines (hTERT-RPE1) died at the same carboplatin dose. CIK achieved 5 times more cytotoxicity against RB cells pre-treated with low dose of carboplatin, showing the highest antitumor activity in the tandem carboplatin-DC-Ag-CIK-carboplatin treatment. Time-lapse video microscopy revealed that carboplatin-preconditioned RB cells are more avidly engaged by CIK cells, increasing RB mortality and resulting in an overall increment in apoptosis. CONCLUSION: This study provides evidence that carboplatin combined with cell immunotherapy is superior to carboplatin alone to kill RB cells in vitro. We propose that a primary application of a low dose of a chemotherapeutic drug that is able to attack the tumor, and a subsequent treatment with highly effective immunotherapy based on DC-Ag-CIK cells could be a safe and selective treatment for RB.
Mitra M, Kandalam M, Rangasamy J, et al. Novel epithelial cell adhesion molecule antibody conjugated polyethyleneimine-capped gold nanoparticles for enhanced and targeted small interfering RNA delivery to retinoblastoma cells. Mol Vis. 2013; 19:1029-38 [PubMed] Article available free on PMC after 23/07/2014 Related Publications
BACKGROUND: Several nanoconjugates have been designed to deliver nucleic acids such as small interfering RNA (siRNA) and DNA to cells to study silencing and expression efficacies. In the present study, we prepared novel epithelial cell adhesion molecule (EpCAM) monoclonal antibody conjugated polyethyleneimine (PEI) capped gold nanoparticles (AuNPs) loaded with EpCAM-specific siRNA molecules to knock-down the EpCAM gene in retinoblastoma (RB) cells. We chose EpCAM as a target moiety to deliver siRNA because this molecule is highly expressed in various epithelial cancers and is an ideal target as it is highly expressed in the apical surface of tumor cells while showing basolateral expression in normal cells. METHODS: The EpCAM antibody was conjugated to AuNP-PEI loaded with siRNA molecules to specifically deliver siRNA to EpCAM-expressing RB cells. Conjugation efficiencies were confirmed with ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, and agarose and SDS-polyacrylamide gel electrophoresis. The size and zeta potential were measured using a Zeta sizer analyzer. Nanoparticle internalization and uptake were studied using fluorescent microscopy and flow cytometry. Gene silencing efficacy was monitored with western blot analysis and real-time quantitative PCR. RESULTS: Optimal size and neutral zeta potential properties of the AuNP-PEI- EpCAM antibody (EpAb) antibody were achieved for the transfection studies. The AuNP-PEI nanoparticles did not show any cytotoxicity to the cells, which means these nanomaterials are suitable for intracellular delivery of siRNA for therapeutic interventions. With EpCAM antibody conjugation, PEI-capped AuNPs loaded with EpCAM siRNA were significantly internalized in the Y79 cells as observed with fluorescence microscopy and flow cytometry and induced a highly significant reduction in the cell viability of the Y79 cells. Through increased binding of EpCAM antibody-conjugated AuNP-PEI nanoparticles, significant downregulation of EpCAM gene was observed in the Y79 cells when compared to the cells treated with the antibody-unconjugated AuNP-PEI nanoparticles. CONCLUSIONS: Thus, a novel antibody conjugated nanocarrier designed to deliver siRNA holds promise as an effective gene therapy strategy for retinoblastoma in the near future. In addition to serving as an siRNA delivery tool for therapy, gold nanoparticles can also serve as imaging modality in diagnosis.
MacCarthy A, Bayne AM, Brownbill PA, et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 2013; 108(12):2455-63 [PubMed] Article available free on PMC after 25/06/2014 Related Publications
BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.
Yang Y, Tian S, Brown B, et al. The Rb1 gene inhibits the viability of retinoblastoma cells by regulating homologous recombination. Int J Mol Med. 2013; 32(1):137-43 [PubMed] Related Publications
Retinoblastoma is a childhood ocular tumor caused by the inactivation of both alleles of the retinoblastoma gene (Rb1). Without Rb1 gene function, chromosomal aberrations are observed in retinoblastoma cells. The instability of the genome is closely associated with the repair of DNA double-strand breaks (DSBs). However, the precise molecular mechanism of action of Rb1 in DNA DSB repair remains unclear. Thus, in this study, we aimed to investigate whether the Rb1 gene affects DNA stability by assaying DNA DSB repair and also whether it regulates the proliferation of retinoblastoma cells. Rb1 immunofluorescence and RT-PCR were performed, demonstrating that the Rb1 gene is silenced in SO-Rb50 retinoblastoma cells, and the karyotype analysis of SO-Rb50 cells indicated that the loss of Rb1 function led to genomic instability; both numerical and structural chromosomal aberrations were observed in our study. In addition, the DNA DSB repair efficiency of the SO-Rb50 cells was measured by γ-H2AX immunofluorescence, a commonly used in situ marker of DNA DSBs, following exposure to ionizing radiation (IR) (2.5 and 5.0 Gy). We found that the DNA repair efficiency was significantly increased following IR-induced damage (P<0.01). However, there was no significant difference in DNA repair efficiency between the cells expressing exogenous Rb1 and the control (P>0.05). The assay for the screening of the effect of Rb1 on the sub-pathway of DNA DSB repair, non-homologous end joining (NHEJ) and homologous recombination (HR), indicated that Rb1 did not affect NHEJ activity, although it significantly promoted the HR pathway (HR levels increased by 2.46-fold) compared with the control (P<0.01). Furthermore, we found that the cell viability of the SO-Rb50 cells transfected with exogenous Rb1 was significantly inhibited (P<0.01) and cell cycle assay indicated that exogenous Rb1 induced S phase arrest (P<0.001) which also inhibited the proliferation of retinoblastoma cells (SO-Rb50) in vitro. Therefore, this study provides new insight into the mechanisms of action of the Rb1 gene in regulating the proliferation of retinoblastoma cells.
Wang J, Wang X, Wu G, et al. MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6. FEBS Lett. 2013; 587(12):1779-86 [PubMed] Related Publications
PAX6 contributes to the development and progression of retinoblastoma (RB), but the molecular mechanism underlying the regulation of PAX6 expression is unclear. Here we found that microRNA-365b-3p (miR-365b-3p) is downregulated in human RB tissues. Ectopic expression of miR-365b-3p significantly attenuates cell growth, induces cell cycle arrest in G1 phase and cell apoptosis through inhibiting the expression of PAX6 by directly binding its 3' untranslated regions. Furthermore, overexpression of miR-365b-3p upregulates p21 and p27 but downregulates cdc2 and Cyclin D1 protein levels. Elucidating the regulatory mechanism of PAX6 by microRNAs may give new clues to the therapy against RB.
Abeyratne LR, Kingston JE, Onadim Z, Dubrey SW Heritable retinoblastoma and accelerated aortic valve disease. BMJ Case Rep. 2013; 2013 [PubMed] Related Publications
Heritable retinoblastoma is associated with a germline mutation in the tumour suppressor gene RBI. The Rb protein (pRb) arises from the RB1 gene, which was the first demonstrated cancer susceptibility gene in humans. Second primary malignancies are recognised complications of retinoblastoma. Furthermore, pRb is implicated in valve remodelling in calcific aortic valve disease. We report a family with hereditary retinoblastoma and associated secondary primary malignancies. There are two interesting aspects to this family. The first is the concept of 'cancer susceptibility genes'; the RBI gene being the first reported in humans. A further feature of note is that two family members also have bicuspid aortic valves. We discuss a potential association between the gene defect responsible for retinoblastoma (with its associated propensity for further malignancies) and accelerated deterioration of the bicuspid aortic valve in the proband carrying this gene defect.
Patel N, Salchow DJ, Materin M Differentials and approach to leukocoria. Conn Med. 2013; 77(3):133-40 [PubMed] Related Publications
Leukocoria is an important clinical examination finding as it can be a sign of significant intraocular pathology, with the most common being retinoblastoma and congenital cataracts. The Brückner test is a quick, easy, and inexpensive way to assess the red reflex. When leukocoria is suspected, prompt referral to an ophthalmologist is necessary for further evaluation.
Ren R, Liu W, Huang L, et al. Role of B lymphoma Mo-MLV insertion region 1 in the oncogenic behavior of retinoblastomas. Mol Vis. 2013; 19:561-74 [PubMed] Article available free on PMC after 25/06/2014 Related Publications
PURPOSE: This study investigated the relationship between B lymphoma Mo-MLV insertion region 1 (BMI-1)--a polycomb protein for stem cell self-renewal and proliferation--and the clinicopathological parameters of human retinoblastomas, including differentiation status and retinal tissue invasion, as well as the effects of BMI-1 on retinoblastoma Y79 cells. METHODS: Thirty-four archived human retinoblastoma samples were recruited for BMI-1 immunohistochemistry. The percentage of BMI-1-expressing cells was scored by independent pathologists and the data were correlated with the clinical features. Y79 cells were transfected to overexpress or specifically inhibit BMI-1 for cell proliferation, propidium iodide cell cycle and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis analyses, multicellular sphere formation assay, and gene expression study. RESULTS: BMI-1 was widely expressed in human retinoblastomas. Higher percentages of BMI-1-expressing cells were selectively limited to undifferentiated tumors and those tumors undergoing invasion to the optic nerve and choroid. However, there was no difference in BMI-1 expression in retinoblastoma retinas with or without tumor invasion. In Y79 cells, BMI-1 stimulated cell proliferation and suppressed apoptosis with reduced p14ARF and p16INK4 expression, along with upregulation of proliferating cell nuclear antigens cyclin D1 and D2. In contrast, silencing BMI-1 reversed these changes. It also upregulated CHX10 and Rx, but not other retinal development-related genes, including nestin and neurofilament M. CONCLUSIONS: Our work indicates that BMI-1 might render important oncogenic property of retinoblastomas and it could be a therapeutic target for the cancer treatment.
Barbosa RH, Aguiar FC, Silva MF, et al. Screening of RB1 alterations in Brazilian patients with retinoblastoma and relatives with retinoma: phenotypic and genotypic associations. Invest Ophthalmol Vis Sci. 2013; 54(5):3184-94 [PubMed] Related Publications
PURPOSE: To identify constitutional alterations of the retinoblastoma 1 gene (RB1) in two cohorts of Brazilian patients with retinoblastoma and to analyze genotype-phenotype associations. METHODS: Molecular screening was carried out by direct sequencing of the 27 RB1 exons and flanking regions in blood DNA of 71 patients with retinoblastoma and 4 relatives with retinoma, and with multiplex ligation-dependent probe amplification (MLPA) in 21 patients. The presumed impact of nucleotide substitutions on the structure of the retinoblastoma protein (pRB) was predicted by Polymorphism Phenotyping-2 (PolyPhen-2). Kaplan-Meier and log-rank test were used for estimating 60-month survival rates. RESULTS: One hundred two nucleotide substitutions were detected, 92 substitutions in 59 patients with retinoblastoma and 10 substitutions in 4 individuals with retinoma. Eight substitutions were novel. The majority of substitutions were intronic (86.2%). More than one substitution was present in 37.3% of patients. Twenty-one duplications and 11 deletions were found in 12 patients; some of which with both types of alterations. Duplications/deletions were found in four patients lacking constitutional alterations when analyzed by sequencing, and in eight patients carrying one or more polymorphic intronic substitutions. The global 60-month survival rate in patients was 91.8% (Confidence Interval95% = 85.0 - 99.1). Significant, lower survival rates were found in extraocular presentation (81.0%) versus intraocular tumors (P = 0.014), first enucleation after 1 month following diagnosis (80.9%) versus earlier first enucleation (P = 0.020), and relapse (100.0%) versus absence of relapse (P = 0.0005). CONCLUSIONS: Fifteen substitutions (4 intronic and 11 exonic) were identified as probably or likely pathogenic. Four of these 11 exonic substitutions were novel. Survival rates, however, were not affected by presence of these probably or likely pathogenic alterations, most of which not found in patients with retinoblastoma from other Latin American countries. These differences might be related to the different ethnic composition of the Latin American cohorts. Portuguese Abstract.
PURPOSE: Retinoblastoma is usually seen in children before 5 years of age. We report an unusual case of retinoblastoma in an adult who presented to us with an orbital mass. METHODS: A 24 year-old-male presented to our centre with a history of protrusion of the right eye for 6 months, and associated loss of vision. Ultrasonography B-scan revealed an intraocular mass with calcification and MRI of the orbits showed extra-ocular spread. An incisional biopsy was taken from the orbital mass. RESULTS: On biopsy, histopathologic features and immunohistochemical stains were consistent with retinoblastoma. CONCLUSION: To our knowledge, this is the first report of retinoblastoma presenting as an orbital mass in adulthood and highlights the importance of considering this tumour in the differential diagnosis of an intraocular mass with orbital extension in an adult patient.
Abdolahi A, van Wijngaarden E, McClean MD, et al. A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma. Occup Environ Med. 2013; 70(6):372-9 [PubMed] Article available free on PMC after 01/06/2014 Related Publications
BACKGROUND: The risk factors for sporadic (ie, non-familial) retinoblastoma remain largely unknown. OBJECTIVES: We examined the relationship between paternal occupational exposures from jobs held 10 years and 1 year prior to conception and the risk of sporadic bilateral retinoblastoma in children. METHODS: Paternal occupational data were obtained for 198 incident cases diagnosed with sporadic bilateral retinoblastoma from January 1998 to May 2006 and 245 referral-based controls from the case child's relatives and friends who were matched to 135 of the cases on birth year. Industrial hygienists independently assigned exposure scores for nine agents. Adjusted ORs and 95% CIs were computed using logistic regression models, using the full sample of cases and controls as well as subset of cases with matched controls only. RESULTS: There was some indication of an elevated risk associated with paternal pesticide exposure in the 10 years prior to conception (OR=1.64; 95% CI 1.08 to 2.50) as well as in the year before conception (OR=2.12; 95% CI 1.25 to 3.61). However, results for pesticide exposure were inconsistent and varied by analysis approach. An increased risk was also observed for non-welding metal exposure during the 10 years prior to conception in the full (OR=1.35; 95% CI 0.86 to 2.12) and matched (OR=1.40; 95% CI 0.82 to 2.37) samples, but not in the year before conception. Exposure-response trends were observed for pesticides and non-welding metal exposures. CONCLUSIONS: Our findings suggest a potential role of paternal occupational exposures to non-welding metals and perhaps pesticides in the aetiology of childhood retinoblastoma.