Sunlight exposure in infancy decreases risk of sporadic retinoblastoma, extent of intraocular disease.

BACKGROUND: Prior ecologic studies suggest that UV exposure through sunlight to the retina might contribute to increased retinoblastoma incidence. AIMS: Our study objectives were (1) to examine the relationship between exposure to sunlight during postnatal retinal development (prior to diagnosis of sporadic disease) and the risk of retinoblastoma, and (2) to examine the relationship between sun exposure during postnatal retinal development, and the extent of disease among children with unilateral and bilateral retinoblastoma. METHODS AND RESULTS: We interviewed 511 mothers in the EpiRbMx case-control study about their child's exposure to sunlight during postnatal retinal cell division by examining three time periods prior to Rtb diagnosis coinciding with developmental stages in which outdoor activities vary. Weekly sun exposure was compared by age period, between unilateral (n = 259), bilateral (n = 120), and control (n = 132) children, accounting for two factors affecting UV exposure: residential elevation and reported use of coverings to shield eyes. For cases, association between sunlight exposure and clinical stage was examined by laterality at each age period. After adjusting for maternal education and elevation, sun exposure was lower in cases than controls in all three age periods especially during the first 6 months, and in children 12-23 months whose mothers did not cover their eyes when outdoors. In children diagnosed after 12 months of age, sun exposure during the second year of life (age 12-23 months) appeared inversely correlated (r = -0.25) with more advanced intraocular disease in bilateral Rtb children after adjusting for maternal education, residential elevation, and age of diagnosis (p < .09) consistent with effects of Vitamin D exposure on intraocular spread in earlier transgenic murine models of retinoblastoma, and suggesting potential chemopreventive strategies. CONCLUSION: Sun exposure in early childhood is protective for retinoblastoma and may decrease degree of intraocular spread in children with bilateral Rtb.

Secondary Prevention of Retinoblastoma Revisited: Laser Photocoagulation of Invisible New Retinoblastoma.

PURPOSE: Invisible retinoblastoma tumors are now detected with screening for retinal tumors in at-risk neonates (those inheriting RB1 pathogenic alleles from affected parents) using handheld OCT. Laser photocoagulation is challenging, requiring exact localization of a tumor invisible to indirect ophthalmoscopy and standard imaging. We describe OCT-guided localization and photocoagulation of these invisible tumors with 1-year follow-up. DESIGN: Retrospective, noncomparative, single-institutional, observational case series. PARTICIPANTS: Children with any clinically invisible retinoblastoma tumor that was detected on OCT posterior pole screening. METHODS: OCT revealed round homogeneous invisible tumors within the inner nuclear layer. Software calipers placed beside anatomic retinal landmarks (branched/curved vessels, fovea, or optic disc) mapped the tumor location and extent. A single laser (532 nm) burn flagged the location, and OCT evaluated the tumor-laser burn relationship; laser treatment was then continued in the correct location. Post-laser OCT ensured complete treatment. MAIN OUTCOME MEASURES: Accuracy (frequency of geographic miss and skip areas), effectiveness (recurrence rate), and burden (scar size and characteristics at final follow-up) of laser treatment. RESULTS: Eleven new invisible posterior pole tumors in 7 eyes of 5 children were treated by this technique. Localization and tumor-laser burn relationships were accurate in 11 of 11 tumors (100%, 95% confidence interval [CI], 49.9-100), and all showed swelling and hyper-reflectiveness of the tumor in post-laser OCT. Two photocoagulation sessions (2 weeks apart) were sufficient to successfully manage 9 of 11 tumors (82%, 95% CI, 37.4-100) with resulting permanent flat scars. One tumor (9%, 95% CI, 0.2-50.6) developed OCT-detected subclinical recurrences within 3 months, treated by 1 laser session. No treatment scar showed gliosis, foveal involvement, or retinal traction at 1-year follow-up. Scar expansion occurred in 1 tumor (9%, 95% CI, 0.2-50.6), and all scars (100%, 95% CI, 49.9-100) showed pigmentary changes. CONCLUSIONS: The OCT-guided localization and photocoagulation technique is valuable in achieving precision results in managing invisible new retinoblastoma tumors. This technique shows a potential to improve outcomes of secondary prevention screening for retinoblastoma.

LncRNA NKILA Inhibits Retinoblastoma by Downregulating lncRNA XIST.

Purpose: Although retinoblastoma is rare but can be deadly in some severe cases. To find novel therapeutic targets for retinoblastoma, we explored the potential role of lncRNA NKILA in retinoblastoma. Results: We found that, comparing to healthy controls, NKILA was downregulated, while lncRNA XIST was upregulated in plasma of retinoblastoma patients and they were inversely correlated. Downregulation of NKILA distinguished early-stage patients from healthy controls. Overexpression of lncRNA NKILA mediated the downregulation of XIST in retinoblastoma cells, while XIST overexpression failed to significantly affect NKILA. Overexpression of NKILA resulted in decreased, while XIST overexpression resulted in increased proliferation, migration and invasion rates of retinoblastoma cells. In addition, rescue experiment showed that XIST overexpression attenuated the effects of NKILA overexpression on cancer cell behaviors. Conclusions: Therefore, NKILA inhibits retinoblastoma possibly by downregulating XIST, but the causality has not been fully validated.

Integrating stages of change models to cast new vision on interventions to improve global retinoblastoma and childhood cancer outcomes.

BACKGROUND: Retinoblastoma, the most common intraocular tumor globally, represents a curable cancer when diagnosed early and treated promptly. Delay to diagnosis, lag time prior to treatment initiation, and abandonment of treatment including upfront treatment refusal, represent stark causes of high retinoblastoma mortality rates in low- and middle- income settings, particularly regions in Africa. While a health delivery-based approach has been a historic focus of retinoblastoma treatments globally and is essential to quality care, this is necessary but not adequate. Retinoblastoma is a compelling disease model to illustrate the potential insights afforded in theory-informed approaches to improve outcomes that integrate public health and oncology perspectives, prioritizing both health service delivery and social efficacy for cure. DISCUSSION: Given that barriers to appropriate and timely diagnosis and treatment represent main contributors to mortality in children with retinoblastoma in resource-limited settings such as certain areas in Africa, an important priority is to overcome barriers to cure that may be predominantly socially influenced, alongside health delivery-based improvements. While Stages of Change models have been effectively utilized in cancer screening programs within settings of economic and cultural barriers, this application of health behavior theory has been limited to cancer screening rather than a comprehensive framework for treatment completion. Using retinoblastoma as a case example, we propose applying stage-based intervention models in critical stages of care, such as the Precaution Adoption Process Model to decrease delay to diagnosis and a Transtheoretical Model to increase treatment completion rates in resource-limited settings. SUMMARY: Stage-based theories recognize that improved cure and survival outcomes will require supportive strategies to progress households, communities, and social and economic institutions from being unaware and unengaged to committed and sustained in their respective roles. Applying a stage-based model lens to programmatic interventions in resource-limited settings has potential for visible improvement in outcomes for children with retinoblastoma and other cancers.

Seed-targeting anti-miR-21 inhibiting malignant progression of retinoblastoma and analysis of their phosphorylation signaling pathways.

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

Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma.

BACKGROUND: Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate, etoposide phosphate, and carboplatin showed no evidence of systemic metastasis in any case during a mean (range) follow-up of 66 (12-202) months. PURPOSE: To determine the efficacy of postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin in the prevention of metastasis for patients with high-risk retinoblastoma. METHODS: Retrospective, nonrandomized, interventional case series of 52 eyes in 51 patients with high-risk retinoblastoma consisting of tumor invasion into the anterior segment, posterior uvea 3 mm or greater, postlaminar optic nerve, or any combination of posterior uvea and optic nerve involvement. RESULTS: Of 51 consecutive patients with high-risk retinoblastoma, there were 30 males (59%) and 21 females (41%), with a median age of 28 months at diagnosis. All 52 eyes were classified as group E. The main histopathologic risk factors included anterior segment invasion (7 [13%]), isolated massive posterior uveal invasion of 3 mm or greater (6 [12%]), isolated postlaminar optic nerve invasion (15 [29%]), or any posterior uveal invasion with any optic nerve involvement (24 [46%]). There was additional invasion into the sclera (3 [6%]) and extrascleral structures, including the orbit (1 [2%]). A single histopathologic high-risk factor was present in 32 eyes (62%), whereas 20 eyes (38%) manifested 2 or more high-risk characteristics. Based on previously published series, untreated high-risk retinoblastoma carries at least a 24% risk for metastatic disease. In the present series, using vincristine, etoposide, and carboplatin in all cases, there was no metastasis during a mean follow-up of 66 months (median [range], 55 [12-202] months). CONCLUSIONS: Retinoblastoma with invasion into the postlaminar optic nerve and/or posterior uvea is at high risk for metastasis and death. In this study, postenucleation chemotherapy using vincristine, etoposide, and carboplatin was effective in preventing metastasis in every case (100%).

Loss of Id2 potentiates the tumorigenic effect of Rb inactivation in a mouse model of retinoblastoma.

PURPOSE: In some cancers, the oncogenic consequences of inactivating the retinoblastoma protein (Rb) appear to be mediated by unrestrained activity of the inhibitor of DNA binding protein Id2. The role of Id2 has not yet been investigated in the prototype cancer Rb-defective cancer, retinoblastoma itself. This study investigated whether loss of Id2 modified the effects of Rb inactivation in a mouse model of retinoblastoma. METHODS: Id2 was analyzed in cultured cells using qPCR, Western blot, and colony formation assays. LH beta-Tag transgenic mice were crossed with Id2 heterozygotes to obtain mice with all three Id2 genotypes. Intraocular tumors were assessed for size, degree of differentiation, mitotic index, and tumor vascular density at 15 weeks of age. RESULTS: Retinoblastoma cell lines expressed low levels of Id2 mRNA and protein. Depletion of Id2 in Rb-inactivated cells increased clonogenic activity. Id2-deficient tumors in vivo were significantly larger, less differentiated, and more vascularized than Id2-wild-type tumors (P = 0.02, P = 0.01, P = 0.0001, respectively). There was a dosage effect for loss of each Id2 allele with respect to differentiation and vascular density. CONCLUSIONS: Id2 suppresses rather than promotes tumor progression in this mouse model of retinoblastoma. Id2 can act as either an oncogene or a tumor suppressor depending on context.

Development of retinoblastoma programs in Central America.

BACKGROUND: Retinoblastoma, a curable eye tumor, is associated with poor survival in Central America (CA). To develop a retinoblastoma program in El Salvador, Guatemala, and Honduras, twinning initiatives were undertaken between local pediatric oncology centers, nonprofit foundations, St. Jude Children's Research Hospital, and the University of Tennessee Hamilton Eye Institute. PROCEDURE: The retinoblastoma program focused on developing early diagnosis programs in Honduras with national vaccination campaigns, developing treatment protocols suited to local conditions, building local networks of oncologists and ophthalmologists, training local healthcare providers, using modern donated equipment for diagnosis and treatment, and the ORBIS Cybersight consultation program and Internet meetings to further education and share expertise. Pediatric ophthalmologists and oncologists worked with foundations to treat patients locally with donated equipment and Internet consultations, or at the center in Guatemala. RESULTS: Number of patients successfully treated increased after the program was introduced. For 2000-2003 and 2004-2007, patients abandoning/refusing treatment decreased in Guatemala from 20 of 95 (21%) to 14 of 123 (11%) and in Honduras from 13 of 37 (35%) to 7 of 37 (19%). Survival in El Salvador was good and abandonment/refusal low for both periods. Of 18 patients receiving focal therapy for advanced disease, 14 have single remaining eyes. CONCLUSION: Development of the program in CA has decreased abandonment/refusal and enabled ophthalmologists at local centers to use modern equipment to provide better treatment. This approach might serve as a guide for developing other multispecialty programs.

Estimating the incidence of retinoblastoma in Texas.

The purpose of this study was to estimate the number of retinoblastoma cases anticipated each year in various urban and rural areas in Texas. We obtained the most recent data on the number of live births in Texas from the Texas Department of Health. Using those data and the retinoblastoma incidence rate of 1 in 15,000 live births, we estimated that 26 cases of the disease will be diagnosed in Texas each year. Nearly half of those cases will occur in infants in rural areas of the state. We compared those values with data from the Texas Cancer Registry. Primary care physicians, particularly in rural areas of Texas, must screen patients for retinoblastoma and consider arrangements for rapid referral when the diagnosis is suspected.

Outpatient clinic for genetic counseling and gene testing of retinoblastoma.

We report on the genetic counseling and gene testing of patients with retinoblastoma who visited the National Cancer Center Hospital, Tokyo, from April 1997 through September 2003. During this period, 73 probands visited the clinic, and gene testing was performed in 51 individuals. Germline mutations of the RBI gene were detected in 20 individuals (39%); the frequencies were 82% (9/11) in bilateral/familial retinoblastoma, 50% (2/4) in unilateral/familial retinoblastoma, 50% (8/16) in bilateral/nonfamilial retinoblastoma, and 5% (1/20) in unilateral/nonfamilial retinoblastoma. Gene testing is indicated in the medical practice of hereditary retinoblastoma for familial risk assessment, while prior counseling is important for an understanding of the risks and benefits of gene testing. With improvements in patient prognosis, counseling for adult survivors is increasing in importance. Assessment of genetic risk to the offspring and prevention of secondary cancer are the primary issues of concern. Presymptomatic diagnosis of infants is effective for the proper assessment of the genetic risk and for making follow-up schedules for the detection of the tumor at an early stage.

Screening for retinoblastoma: presenting signs as prognosticators of patient and ocular survival.

OBJECTIVE: To correlate 3 common presenting signs of retinoblastoma with patient and ocular survival and to assess the efficacy of current pediatric screening practices for retinoblastoma. METHODS: A retrospective study was conducted of 1831 retinoblastoma patients from our center (1914-June 2000). Patient survival (excluding deaths from other primary neoplasms) and ocular survival (presenting eyes) rates were calculated and analyzed using the Kaplan-Meier method. RESULTS: Leukocoria correlated with excellent patient survival (>86%, 5 years) but poor ocular survival in unilateral (4%, 5 years) and bilateral patients (29%, 5 years). A total of 308 (19%) of 1654 patients presented with strabismus: patient survival was excellent (90%, 5 years), and ocular survival was poor (17%, 5 years) yet better than leukocoria. Patients who had a family history of retinoblastoma and were clinically screened for retinal tumors from birth were diagnosed younger (8 months of age) and earlier (Reese Ellsworth group 1 = 26 [58%] of 45) and had better ocular survival than nonscreened patients with a family history. More patients were initially detected by family/friends (1315 [80%] of 1632) than pediatricians (123 [8%] of 1632) or ophthalmologists (156 [10%] of 1632). CONCLUSION: Most US children whose retinoblastoma is diagnosed initially present with leukocoria detected by a parent, despite routine pediatric screening for leukocoria via the red reflex test. Initial disease detection at the point of leukocoria or strabismus correlated with high patient survival rates and poor ocular survival rates for the presenting eye. Saving eyes and vision requires disease recognition before leukocoria, as demonstrated by the better ocular salvage rate among patients who had a positive family history and received clinical surveillance via early, routine dilated funduscopic examinations by an ophthalmologist.

Retinoblastoma tells the story of our health care system.

OBJECTIVE: To review cases of retinoblastoma. SETTING: Department of Pathology Aga Khan University Hospital Karachi. METHOD: Twenty-three specimens from cases of retinoblastoma received over a period of eight years were routinely processes and stained with haematoxylin and Eosin stain. Other stains were used for tuberculoses and melanin. Immunochemistry was resorted to in undifferentiated tumors. RESULTS: Over 60% cases of retinoblastoma were diagnosed after 5 years and nine cases showed involvement of optinerve. CONCLUSION: Late diagnosis of retinoblastoma effects the stage of the tumors and the prognosis.

Descolamento de retina após facoemulsificaçäo / Retinal detachment after phacoemulsification

Objetivo: Evidenciar a prevalência de descolamento de retina em pacientes pseudofácicos submetidos à facoemulsificaçäo.Local: IMO - Instituto de Moléstias Oculares - Säo Paulo - Brasil.Método: Foram analisados, retrospectivamente, 3038 prontuários de pacientes submetidos à facoemulsificaçäo e que evoluíram com descolamento de retina após a facectomia entre 01/92 e 05/99.Resultados: A prevalência foi de 0, 49 por cento (15/3038) com seguimento variando de 3 meses a 4 anos.Em 60 por cento dos olhos com DR houve ruptura de cápsula posterior e vitrectomia anterior.O tempo médio de aparecimento do descolamento de retina foi de 11, 33 meses.Conclusäo: A facoemulsificaçäo aparenta ser o procedimento mais seguro, o que torna menos freqüente a complicaçäo do descolamento de retina no pós-operatório da cirurgia da catarata.

[Structural features of retinoblastoma]. / Stukturnye osobennosti retinoblastomy.

The authors analyze the pathohistological archives of the Tashkent Research Institute of Ophthalmic Diseases for the years 1985-1994 and their own materials collected in recent years: 44 eyes enucleated for retinoblastoma. The microscopic picture of 44 tumors is as follows: retinoblastoma A in 12 (27.3%) cases, retinoblastoma B in 16 (36.3%), retinoblastoma C in 9 (20.4%), and mixed form in 7 (16%) cases. The total level of retinoblastoma A and B is almost 64%; this condition is positively life-threatening. The authors emphasize the necessity of health education of the population and improvement of primary health care and prophylactic check-ups of preschool children.