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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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Eye Cancers

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Latest Research Publications

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

Yunoki T, Tabuchi Y, Hayashi A, Kondo T
Inhibition of polo-like kinase 1 promotes hyperthermia sensitivity via inactivation of heat shock transcription factor 1 in human retinoblastoma cells.
Invest Ophthalmol Vis Sci. 2013; 54(13):8353-63 [PubMed] Related Publications
PURPOSE: Hyperthermia (HT) has been recognized as an effective focal treatment in retinoblastoma. However, one of the problems with HT therapy is that cells acquire acquisition. The purpose of this study was to evaluate whether the inhibition of polo-like kinase 1 (PLK1) would promote HT sensitivity in human retinoblastoma cells.
METHODS: We examined the effects of PLK1 knockdown by small interfering RNA (siRNA) or by the inhibition of PLK1 activity with PLK1 inhibitor (BI-2536) on the sensitivity to HT (44°C, 1 hour) in human retinoblastoma Y79 and WERI-Rb-1 cells by evaluating apoptosis and cell proliferation using flow cytometry, Western blotting, real-time quantitative polymerase chain reaction, and WST-8 assay. Furthermore, we investigated the effects of activating heat shock transcription factor 1 (HSF1) through a combination of PLK1 knockdown and HT using Western blotting and immunocytochemistry.
RESULTS: The combination of PLK1 inhibition and HT enhanced sensitivity to HT synergistically. Furthermore, PLK1 knockdown inhibited HT-induced phosphorylation of HSF1, the nuclear translocation of HSF1 from the cytoplasm, and nuclear granule formation of HSF1. Heat shock transcription factor 1, inactivated by the silencing of PLK1, reduced the expression of heat shock proteins (HSPs), such as HSP70 and HSP40, as well as the expression of Bcl-2-associated athanogene 3 (BAG3).
CONCLUSIONS: Polo-like kinase 1 inhibition may attenuate the thermoresistance of HT through the inactivation of HSF1 concomitant with reductions in HSPs and BAG3. The combination of PLK1 inhibition and HT may become an option for HT therapy in patients with retinoblastoma.

Related: Apoptosis

Barot M, Gokulgandhi MR, Pal D, Mitra AK
In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management.
Exp Eye Res. 2014; 118:61-71 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Retinoblastoma (RB) is a common malignant intraocular tumor primarily affecting children. Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in treatment of RB. Ocular cells have shown good tolerability against moxifloxacin (MFX). Hence, the aim of present study was to investigate the effect of moxifloxacin on the functionality of MDR proteins. Furthermore, we have also examined an interaction of MFX with anticancer agents (Topotecan, etoposide and vinblastine) for RB treatment. For interaction of MFX with efflux transporter, model cell lines transfected with the efflux transporters (MDCK-MDR1 and MDCK-MRP2) were used to perform uptake and bi-directional transport experiments. Modulation of anticancer induced cell cytotoxicity, pro-inflammatory cytokines (IL-6 and IL-8) release and caspase-3 enzyme activity in presence of MFX was also evaluated. Result indicates that MFX is a substrate of both MDR1 and MRP2 efflux transporters. Furthermore elevation of anticancer uptake and bi-directional transport, reduction in IC50 cytotoxic value and modulation of antiproliferative and cytokines release in presence of MFX by anticancer agents was observed. Our results demonstrate that MFX may not only modulate the permeability of anticancer agents at efflux sites but it may also potentiate antiproliferative activity of anticancer agents in retinoblastoma cells. This study may be further extended to explore in vivo outcome of this finding.

Martin A, Jones A, Bryar PJ, et al.
MicroRNAs-449a and -449b exhibit tumor suppressive effects in retinoblastoma.
Biochem Biophys Res Commun. 2013; 440(4):599-603 [PubMed] Related Publications
Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment.

Villegas VM, Hess DJ, Wildner A, et al.
Curr Opin Ophthalmol. 2013; 24(6):581-8 [PubMed] Related Publications
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.

Zafar SN, Ahmad SQ, Zafar N
Retinoblastoma in an adult.
BMC Res Notes. 2013; 6:304 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
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.

Batra R, Abbott J, Jenkinson H, et al.
Long-term retinoblastoma follow-up with or without general anaesthesia.
Pediatr Blood Cancer. 2014; 61(2):260-4 [PubMed] Related Publications
BACKGROUND: Children with treated retinoblastoma undergo frequent examinations to monitor for recurrent or new tumours. Examinations under anaesthesia allow a more complete examination in younger children, however they are stressful for the family, subject the child to medical risk and consume resources. The risk of recurrent or new tumours declines with age and it is common practice to examine older children without general anaesthesia. There are no studies on the safety and cost effectiveness of this practice, or guidelines on when examination without anaesthesia (EWA) can be safely commenced.
PROCEDURE: Retrospective case note review of 128 sequential patients treated for retinoblastoma in a national referral centre over 10 years.
RESULTS: Following exclusions, 113 eyes of 84 children were analysed. The mean age at diagnosis was 20 months (range birth to 71 months). There were 55 unilateral and 29 bilateral cases. The mean follow-up was 77.7 months (range 12-178 months). EWA was commenced at a mean age of 53 months (range 12-98 months). The age of conversion to EWA was largely dependent on child cooperation and disease activity. Tumour activity was detected on EWA in one child at the age of 86 months, 9 months after the last active treatment and treated successfully.
CONCLUSIONS: Examination without general anaesthesia does not appear to expose children to an increased risk of undetected tumour growth. This study highlights the important factors to be considered when deciding a safe time to commence EWA.

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.

Related: Melphalan

Li Z, Li BQ, Jiang M, et al.
Prediction and analysis of retinoblastoma related genes through gene ontology and KEGG.
Biomed Res Int. 2013; 2013:304029 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
One of the most important and challenging problems in biomedicine is how to predict the cancer related genes. Retinoblastoma (RB) is the most common primary intraocular malignancy usually occurring in childhood. Early detection of RB could reduce the morbidity and promote the probability of disease-free survival. Therefore, it is of great importance to identify RB genes. In this study, we developed a computational method to predict RB related genes based on Dagging, with the maximum relevance minimum redundancy (mRMR) method followed by incremental feature selection (IFS). 119 RB genes were compiled from two previous RB related studies, while 5,500 non-RB genes were randomly selected from Ensemble genes. Ten datasets were constructed based on all these RB and non-RB genes. Each gene was encoded with a 13,126-dimensional vector including 12,887 Gene Ontology enrichment scores and 239 KEGG enrichment scores. Finally, an optimal feature set including 1061 GO terms and 8 KEGG pathways was obtained. Analysis showed that these features were closely related to RB. It is anticipated that the method can be applied to predict the other cancer related genes as well.

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.

Related: Brachytherapy

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 01/01/2015 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.

Related: Apoptosis

Islam F, Zafar SN, Siddiqui SN, Khan A
Clinical course of retinoblastoma.
J Coll Physicians Surg Pak. 2013; 23(8):566-9 [PubMed] Related Publications
OBJECTIVE: To determine the clinical manifestations and results of current treatment for patients with retinoblastoma (Rb) in a tertiary care eye hospital in the north west of Pakistan.
STUDY DESIGN: Case series.
PLACE AND DURATION OF STUDY: Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from January 2006 and December 2009.
METHODOLOGY: The data of 139 patients diagnosed as having retinoblastoma was collected. Gender, age at diagnosis, laterality, presenting sign, classification of tumour, treatment modality and outcome were noted.
RESULTS: The mean age of presentation in this patients ranged from 6 to 50 months (mean: 24.05 ± 10.74 months). The most common presenting sign was leucocoria in 78 eyes (44.1%). One hundred and one (72.7%) patients had unilateral retinoblastoma. Using the International Classification of Retinoblastoma (ICRB), 135 (76.3%) eyes were placed in group-E. one hundred and twenty four (77.5%) eyes were enucleated or exenterated while globe preservation was achieved by chemoreduction and/or focal therapy in the rest of the treated eyes (n = 36, 22.5%). Twenty three (16.5%) cases were lost to follow-up before one year. Ninety two (66.2%) patients survived, being free of tumour, at least one year after the completion of treatment.
CONCLUSION: Most children with Rb showed an advanced stage of tumour at the time of diagnosis. Measures to improve the rate of globe preservation and patient survival by early diagnosis and intervention are the need of the hour.

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.

Related: USA

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.

Related: Childhood Brain Tumours Childhood Brain Tumors

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.

Related: Childhood Brain Tumours Childhood Brain Tumors

Shields CL, Kaliki S, Al-Dahmash S, et al.
Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation.
Retina. 2013 Nov-Dec; 33(10):2103-9 [PubMed] Related Publications
PURPOSE: To determine the efficacy of primary intravenous chemotherapy (IVC) plus secondary intraarterial chemotherapy (IAC) for patients with advanced retinoblastoma.
METHODS: Retrospective, nonrandomized interventional case series of 14 patients with retinoblastoma managed with primary systemic IVC (vincristine, etoposide, and carboplatin for 6 cycles) followed by secondary IAC (melphalan for 1-6 cycles).
RESULTS: Fourteen patients with advanced retinoblastoma classified by the International Classification of Retinoblastoma as Group D (n = 6, 43%) or Group E (n = 8, 57%) were treated with IVC as primary treatment and subsequent secondary IAC as rescue or consolidation therapy. The IAC was given for recurrent retinoblastoma and/or subretinal/vitreous seeds in 13 eyes (93%) and for persistent viable retinoblastoma in 1 eye (7%). Enucleation was the alternative option. The mean interval between IVC completion and IAC start was 40 weeks (median, 11 weeks; range, 2-170 weeks) and the mean number of IAC cycles was 3 (median, 3; range, 1-6). After primary IVC plus secondary IAC, globe salvage was achieved in 8 patients (57%) at mean 2-year follow-up. There was no evidence of retinoblastoma metastasis or death and no sign of second cancer or life-threatening complication.
CONCLUSION: For advanced retinoblastoma (Groups D and E) in which enucleation is the alternative option, primary systemic IVC followed by secondary focal IAC provides globe salvage in 57% of the eyes and with no metastatic event.

Related: Carboplatin Etoposide Melphalan Vincristine

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.

Related: Carboplatin Cyclophosphamide Etoposide Vincristine

Bond WS, Akinfenwa PY, Perlaky L, et al.
Tumorspheres but not adherent cells derived from retinoblastoma tumors are of malignant origin.
PLoS One. 2013; 8(6):e63519 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Verification that cell lines used for cancer research are derived from malignant cells in primary tumors is imperative to avoid invalidation of study results. Retinoblastoma is a childhood ocular tumor that develops from loss of functional retinoblastoma protein (pRb) as a result of genetic or epigenetic changes that affect both alleles of the RB1 gene. These patients contain unique identifiable genetic signatures specifically present in malignant cells. Primary cultures derived from retinoblastoma tumors can be established as non-adherent tumorspheres when grown in defined media or as attached monolayers when grown in serum-containing media. While the RB1 genotypes of tumorspheres match those of the primary tumor, adherent cultures have the germline RB1 genotype. Tumorspheres derived from pRb-negative tumors do not express pRb and express the neuroendocrine tumor markers synaptophysin and microtubule-associated protein 2 (MAP2). Adherent cells are synaptophysin-negative and express pRb, the epithelial cell marker cytokeratin that is expressed in the retinal pigmented epithelium and the vascular endothelial cell marker CD34. While tumorspheres are of malignant origin, our results cast doubt on the assumption that adherent tumor-derived cultures are always valid in vitro models of malignant cells and emphasize the need for validation of primary tumor cultures.

Related: Eye Cancer

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.

Related: Apoptosis

Venkataraghavan K, Patil S, Guvva S, et al.
Abnormal odontogenesis following management of childhood cancer (retinoblastoma): review and a new variant.
J Contemp Dent Pract. 2013 Mar-Apr; 14(2):360-4 [PubMed] Related Publications
A young child being diagnosed with cancer naturally generates a pretty melancholy reaction. Each cancer can be managed with a vast array of treatment options that are available either individually or as a combination, the final goal of which is total eradication of the condition in the affected individual. Since, most of these treatments are administered during the age of tooth formation, they may affect stages of odontogenesis. Most common treatment of childhood cancers includes--chemotherapy and radiotherapy. With recent advancements in cancer therapy additional treatment options like laser therapy, radiation in the form of brachytherapy or teletherapy, cryotherapy, thermochemotherapy, etc. are available. As treatment of childhood cancers starts at a very young age coinciding with dental development, a number of dental malformations have been reported in childhood cancer survivors. The most common ocular cancer in children is retinoblastoma. This is the first such reported case and unique one where microdontia has affected all the first premolars.

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.

Related: BIRC5

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.

Related: Rhabdomyosarcoma

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.

Related: CGH

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.

Francis JH, Abramson DH, Marr BP, Brodie SE
Ocular manipulation reduces both ipsilateral and contralateral electroretinograms.
Doc Ophthalmol. 2013; 127(2):113-22 [PubMed] Related Publications
PURPOSE: To determine the electroretinogram (ERG) changes in eyes manipulated in the course of local ablative therapy (transpupil thermotherapy (TTT), cryotherapy or both) or scleral depression and in un-manipulated fellow, healthy eyes.
METHODS: This prospective observational report summarizes 73 ERG studies in 42 patients with retinoblastoma; a study consisted of ERGs of one or both eyes (if present) followed by ocular manipulation (scleral depression, cryotherapy, transpupillary thermotherapy, pressure applied to orbital implant in an anophthalmic socket, or a 5- or 10-min delay without mechanical manipulation) followed by a repeat of the ERGs. Each patient was studied with only a single manipulation modality on any given date: 23 patients were studied only once, and 19 patients were included in more than one study occasion.
RESULTS: Following local ablative treatment of patients with unilateral retinoblastoma, the photopic response decreased significantly in both the treated eye and the untouched fellow, healthy eye. Following scleral depression of the diseased eye, the photopic response immediately decreased in the diseased eye by a mean of 16 μV (21 %, p = .006) and, in the fellow, healthy eye by 40 μV (23 %, p = .0005). Following scleral depression of the fellow, healthy eye, the photopic response immediately decreased by a mean of 11 μV (4 %, p = .37) in the fellow, healthy eye, and by 16 μV (28 %, p = .01) in the diseased eye.
CONCLUSIONS: Following physical ocular manipulation, the amplitude of the photopic response decreased in the manipulated, but also the untouched healthy, fellow eyes. These findings may account for some of the variation in clinical ERG recordings, particularly that observed following ocular manipulation by TTT, laser or even scleral depression.

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.

Serrano ML, Yunis JJ
Identification of three new mutations in the RB1 gene in patients with sporadic retinoblastoma in Colombia.
Biomedica. 2013 Jan-Mar; 33(1):53-61 [PubMed] Related Publications
INTRODUCTION: Retinoblastoma is a childhood cancer of the retina originated by altered or null retinoblastoma protein (pRb) expression. Genetic alterations in both RB1 alleles in the retinal cells are required for the development of retinoblastoma. In the sporadic form, non-hereditary RB1 gene mutations take place in a single retinoblast cell, and are therefore only present in tumor DNA (somatic mutations). Sporadic retinoblastoma is primarily unilateral, lacks family history and has no risk of transmission to descendants. Genetic tests for detection of RB1 mutation has improved the identification of carriers and facilitated accurate genetic counseling.
OBJECTIVE: To identify mutations in the RB1 gene in Colombian patients with sporadic retinoblastoma by PCR-SSCP followed by sequence.
MATERIALS AND METHODS: Four patients with sporadic retinoblastoma were analyzed by PCR-SSCP, followed by DNA sequencing to identify variations in the RB1 gene.
RESULTS: We identified five variations in RB1 gene: three new mutations (one germline and two somatic mutations), one new polymorphism and one already reported somatic mutation. Four mutations were found in three patients with unilateral retinoblastoma and one mutation was found in a patient with bilateral retinoblastoma. One of these was a germline mutation in a sporadic unilateral retinoblastoma that was not present in the parents or three siblings analyzed.
CONCLUSIONS: Our results emphasize the importance of identifying mutations for genetic counseling and clinical management of sporadic retinoblastoma patients. Description of a new RB1 gene variant is interesting since there have been a small number of polymorphisms reported for this gene.

Related: Eye Cancer

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