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PubMed2005

Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma.

OBJECTIVE: Little is known about the causes of sporadic (noninherited) retinoblastoma. Rates seem to be somewhat higher among poorer populations in Mexico. Fruits and vegetables are important sources of carotenoids and folate. We examined whether decreased gestational maternal intake of fruits and vegetables may contribute to development of sporadic retinoblastoma. METHODS: At the Instituto Nacional de Pediatria in Mexico City, we conducted a hospital-based case-control study to evaluate prenatal maternal diet. We examined dietary intake of fruits and vegetables of mothers of 101 children with retinoblastoma and 172 control children using a dietary recall questionnaire and published food nutrient content tables. RESULTS: The reported number of mean daily servings of fruits and vegetables was lower among case mothers when compared with control mothers [vegetables: 2.28 in controls, 1.75 in cases (P < 0.01); fruits: 2.13 in controls, 1.59 in cases (P = 0.07)]. Mean daily maternal folate intake from both vegetables and fruits was higher in controls (103 microg) than in cases (48 microg; P < 0.05). Risk for having a child with retinoblastoma was increased for mothers consuming fewer than 2 daily servings of vegetables [odds ratios (OR), 3.4; 95% confidence interval (95% CI), 2.0-6.0] or with a low intake of folate (OR, 3.9; 95% CI, 2.1, 7.3), or lutein/zeaxanthin (OR, 2.6; 95% CI, 1.5-4.6) derived from fruits and vegetables. CONCLUSIONS: Decreased intake of vegetables and fruits during pregnancy and the consequent decreased intake of nutrients such as folate and lutein/zeaxanthin, necessary for DNA methylation, synthesis, and retinal function, may increase risk for having a child with sporadic retinoblastoma.

Adult↗
PubMed2006

Tobacco use in adult long-term survivors of retinoblastoma.

A significant risk of lung cancer was identified among hereditary, but not nonhereditary, retinoblastoma (Rb) patients. Tobacco use was investigated to determine whether differences in smoking prevalence might explain the lung cancer excess and to characterize smoking patterns in adult survivors of Rb. Subjects were 441 hereditary and 395 nonhereditary 1-year survivors of Rb, age >or=18 years, who responded to a telephone survey about current health behavior, including tobacco use. Response rates were 76% for hereditary and 73% for nonhereditary survivors. We compared patterns and predictors of current tobacco use among hereditary and nonhereditary survivors with other childhood cancer survivor studies and the U.S. population. Hereditary Rb survivors currently smoke cigarettes significantly less frequently than nonhereditary survivors (16. 8% versus 24.3%), although among current smokers, age at smoking initiation (17 years old) and average cigarettes (1.5 packs) smoked daily are similar. Predictors of current and ever cigarette smoking include nonhereditary Rb, older age, being female, less education, and use of other tobacco products. Rb survivors smoke cigarettes significantly less than the U.S. population (rate ratio, 0.63; 95% confidence interval, 0.5-0.8 for males; rate ratio, 0.75; 95% confidence interval, 0.6-0.9 for females), but Rb survivors have comparable smoking rates with other childhood cancer survivors. Smoking did not account for the increased risk of lung cancer among hereditary Rb patients, and this may point to an enhanced sensitivity to the carcinogenic effects of tobacco. Adult survivors of Rb should be encouraged to stop smoking.

Adolescent↗
PubMed2005

Topotecan combination chemotherapy in two new rodent models of retinoblastoma.

Chemotherapy combined with laser therapy and cryotherapy has improved the ocular salvage rate for children with bilateral retinoblastoma. However, children with late-stage disease often experience recurrence shortly after treatment. To improve the vision salvage rate in advanced bilateral retinoblastoma, we have developed and characterized two new rodent models of retinoblastoma for screening chemotherapeutic drug combinations. The first model is an orthotopic xenograft model in which green fluorescent protein- or luciferase-labeled human retinoblastoma cells are injected into the eyes of newborn rats. The second model uses a replication-incompetent retrovirus (LIA-E(E1A)) encoding the E1A oncogene. Clonal, focal tumors arise from mouse retinal progenitor cells when LIA-E(E1A) is injected into the eyes of newborn p53-/- mice. Using these two models combined with pharmacokinetic studies and cell culture experiments, we have tested the efficacy of topotecan combined with carboplatin and of topotecan combined with vincristine for the treatment of retinoblastoma. The combination of topotecan and carboplatin most effectively halted retinoblastoma progression in our rodent models and was superior to the current triple drug therapy using vincristine, carboplatin, and etoposide. Vincristine had the lowest LC50 in culture but did not reduce tumor growth in our preclinical retinoblastoma models. Taken together, these data suggest that topotecan may be a suitable replacement for etoposide in combination chemotherapy for the treatment of retinoblastoma.

Animals↗
PubMedDate not supplied

Further characterization of human mucin-like glycoprotein associated with photoreceptor cells by its introduction into Y79 retinoblastoma cells.

PURPOSE: To understand the function of a mucin- like glycoprotein associated with photoreceptor cells (MLGAPC), MLGAPC-transfected Y79 retinoblastoma cells were analyzed biochemically and morphologically. METHODS: The cDNA for the core protein of human MLGAPC was isolated, cloned into a mammalian expression vector, pCAGGSneo, and then transfected into Y79 retinoblastoma cells. The cells and the medium were analyzed by means of Western blotting, and the morphology of the transfectants and parental cells was compared. RESULTS: Western blot analysis of the culture medium revealed that the transfectants secreted MLGAPC into the medium. Lectin blot analysis of MLGAPC in the medium showed that it had a binding site for Maackia amurensis lectin II. No morphological difference was detected between the transfectants and parental cells. CONCLUSIONS: As expected from the deduced amino acid sequence of MLGAPC, it was secreted into the medium. The secreted MLGAPC was found to carry sialoglycans (rod type). The expression of MLGAPC had no effect on the adhesion or morphology of the cultured cells, which suggests that its interaction with other components may be required for these effects.

Binding Sites↗
PubMed1998

Congenital retinoblastoma: appearance of calcifications during short-term follow-up.

An echographic follow-up of a case of congenital retinoblastoma was performed by monitoring variations in the tumoral echostructure concomitant with the appearance of microcalcifications. A previously unreported echo-graphic aspect regarding the first phase of observation is described. The calcifications in the tumour were evidenced on the 41st day of the patient's life.

Calcinosis↗
PubMed1998

Retinal astrocytoma associated with hypertrophy of the retinal pigment epithelium: clinical report and follow-up.

Retinal astrocytoma is a rare and benign tumor of the retina most frequently seen in patients with tuberous sclerosis. We describe the case of a 12-year-old boy with solitary retinal astrocytoma in the right eye associated with hypertrophy of the retinal pigment epithelium in the left eye. In this work the instrumental examinations, the differential diagnosis and the follow-up of 7 years are described.

Astrocytoma↗
PubMed1998

Marker gene transfer and oncolysis of human Y79 retinoblastoma cells mediated by herpes simplex virus mutants.

Three different herpes simplex virus (HSV) mutants, designated hrR3, MGH-1 and R3616, were used to infect Y79 retinoblastoma cells grown in suspension. Two parameters were assayed: (a) vector-mediated gene expression, measured by histochemical staining of a transferred LacZ transgene, and (b) virus-mediated oncolysis, determined by the inability of infected cells to exclude trypan blue dye. The tested HSV mutants were found to infect cells grown in suspension at a relatively low multiplicity of infection (MOI = 0.01) and were capable of transferring the LacZ gene as early as 2 days after infection. Furthermore, differences in oncolytic activity were observed amongst the tested viruses: MGH-1 and R3616 exhibited 50% cell kill at a MOI of 0.1 over a period of 6 days, whereas hrR3-mediated oncolysis appeared less efficient. These studies provide a rationale for further exploitation of oncolytic herpes viruses as a potential treatment of intraocular tumors.

Cell Death↗
PubMed2000

Cloning and characterization of the breakpoint regions of a chromosome 11;18 translocation in a patient with hamartoma of the retinal pigment epithelium.

Mutations of various tumor suppressor genes, e.g., PTEN, TSC1, and TSC2, are known to be responsible for different inherited diseases presenting with multiple hamartomas, a benign tumor resembling neoplasia that results from faulty organ development. Combined hamartoma of the retinal pigment epithelium (RPE) and retina is a rare, congenital, focal malformation of the fundus. So far, no disease gene has been associated with this disorder. By molecular analysis of an apparently balanced and reciprocal translocation between the short arms of chromosomes 11 and 18, t(11;18)(p13;p11.31), in a patient with hamartoma of the RPE and retina, we selected PAC clones crossing the breakpoints on both derivative chromosomes 11 and 18. For the overlapping chromosome 11 clone, two EST clusters were identified, suggesting the existence of at least two genes in the breakpoint region. We constructed a PAC contig and showed that at least three exons of a novel gene map to the breakpoint region on chromosome 18. Based on the results of FISH analysis with the PAC clones of this contig, we suggest the occurrence of a complex rearrangement.

Adult↗
PubMed2003

Leiomyosarcoma of the bladder in a retinoblastoma patient.

We report a rare case of leiomyosarcoma in the bladder which occurred in an 18-year-old female with a prior history of retinoblastoma (RB). Molecular characterization of this tumor displayed a homozygous RB deletion and a reduced P53 expression. These results suggest that the loss of RB and P53 may have contributed to the initiation and/or progression of the leiomyosarcoma of the bladder in this patient.

Adolescent↗
PubMedDate not supplied

Visual outcome in macular retinoblastoma treated with primary chemotherapy.

In this prospective clinical study, we treated 8 patients (8 eyes, 11 tumors) of macular retinoblastoma with chemotherapy alone, with the aim of avoiding visual loss because of retinal damage by radiation or adjuvant therapy and to assess their final visual outcome. The mean basal dimension of the tumor was 5.0 +/- 2.6 mm and the mean height was 2.9 +/- 1.3 mm. The fovea was involved in 4 patients (50%) and foveal detachment was present in 3 patients (37.5%). All the patients required less than 6 cycles for tumor control. Four patients (50%) obtained visual acuities ranging from 20/25 to 20/200. Two patients (25%) could gain visual acuity of 20/20. The mean follow-up of patients was 3.24 +/- 0.9 years (range 2-5). No patient developed recurrence or metastatic disease. In conclusion, recent trends for ocular salvage have favored chemoreduction followed by focal therapy for the treatment of retinoblastoma. This study supports the consideration of chemotherapy alone as the primary treatment in eyes with macular retinoblastomas, under close supervision, with satisfactory visual outcome.

Antineoplastic Agents, Alkylating↗
PubMedDate not supplied

Ocular involvement in leukemia--a study of 288 cases.

Two hundred and eighty-eight newly diagnosed cases of leukemia (164 males and 124 females, 167 adults and 121 children, 245 acute and 43 chronic, 151 myeloid and 137 lymphoid), aged between 6 weeks and 78 years, were examined for eye changes in the oncology wards within 2 days of diagnosis before starting chemotherapy. Ocular lesions were present in 102 patients (35.4%)--retinal vascular changes in 91 (31.6%); infiltration of ocular tissues in 5 (1.7%), and neuro-ophthalmic signs in 6 (2.1%) cases. Some of the patients had more than one ocular lesion in one or both eyes. The eye changes were seen more often in adults (49.1%) than in children (16.5%), and in myeloid leukemia (41.0%) than in lymphoid leukemia (29.2%). Eye symptoms were present in 29 patients (10%) at initial diagnosis. Since ocular lesions were detected in many asymptomatic leukemia patients, eye examination should be included as a part of routine evaluation at initial diagnosis in these patients.

Adolescent↗
PubMedDate not supplied

Krypton laser membranotomy for premacular hemorrhage.

BACKGROUND: To evaluate the safety and effectiveness of krypton laser membranotomy. METHODS: Eleven patients (12 eyes) with premacular hemorrhage were enrolled from April 1998 to November 2002. The causes of premacular hemorrhage were proliferative diabetic retinopathy (7 patients, 8 eyes), Valsalva retinopathy (3 patients) and leukemia (1 eye). Krypton laser was used to create a membranotomy on the sloping edge of the premacular hemorrhage. Five eyes with proliferative diabetic retinopathy were treated with inferior panretinal photocoagulation and laser membranotomy simultaneously. After intravitreal dispersion of premacular blood, fundus examinations were performed in all eyes and fluorescein angiography in 5 patients to evaluate the retinal damage. RESULTS: Vision was improved within 2 weeks after surgery in all eyes with premacular hemorrhage, which received krypton laser membranotomy. No retinal damage was seen at the site of membranotomy. No eye needed vitrectomy postoperatively during the follow-up (mean, 17 months). CONCLUSION: Krypton laser membranotomy appears to be a safe and simple alternative procedure for treating selected cases of premacular hemorrhage. Further trials are necessary to evaluate its benefit.

Adolescent↗
PubMed2004

The RB protein family in retinal development and retinoblastoma: new insights from new mouse models.

The Rb gene was isolated almost 20 years ago, but fundamental questions regarding its role in retinal development and retinoblastoma remain. What is the normal function of RB protein in retinogenesis? What is the cell-of-origin of retinoblastoma? Why do retinoblastoma tumors have recurrent genetic lesions other than Rb inactivation? Why is retinoblastoma not induced by defects in cell cycle regulators other than Rb? Why is the retina so sensitive to Rb loss? Recently developed conditional Rb knockout models provide new insight into some of these issues. The data suggest that RB protein may not control the rate of progenitor division, but is critical for cell cycle exit when dividing retinal progenitors differentiate into postmitotic transition cells. This finding focuses attention on the ectopically dividing transition cell, rather than the progenitor, as the cell-of-origin. Cell-specific analyses in the RB-deficient retina reveal that ectopically dividing photoreceptors, bipolar and ganglion cells die, but amacrine, horizontal and Muller cells survive and stop dividing when they terminally differentiate. Rare amacrine transition cells escape cell cycle exit and generate tumors. These data suggest that post-Rb mutations are required to overcome growth arrest associated with terminal differentiation, rather than apoptosis as previously suggested. To explain why perturbing cell cycle regulators other than RB does not initiate retinoblastoma, we speculate that mutations in other components of the RB pathway perturb cell cycle arrest, but only RB loss triggers genome instability in retinal transition cells, which may be critical to facilitate post-Rb mutations necessary for transformation. Cell-specific differences in the effect of Rb loss on genome stability may contribute to the tremendous sensitivity of retinal transition cells to tumorigenesis. The new mouse models of retinoblastoma will be invaluable for testing these possibilities.

Animals↗
PubMed2005

Beta-ray brachytherapy of retinoblastoma: feasibility of a new small-sized ruthenium-106 plaque.

UNLABELLED: A non-comparative case observation study estimated the feasibility of brachytherapy for retinoblastoma with a newly designed ruthenium-106 plaque (label: CXS) with an 8-mm diameter of the irradiation zone. METHODS: The new CXS plaque was used between 2001 and 2003 for brachytherapy of 13 retinoblastomas. Indications were recurrences after preceding local treatment or endophytic retinoblastoma with an impending vitreous tumour cell seeding. The prescribed radiation dose at the apex was 88 Gy (NIST-calibrated dosimetry). RESULTS: The mean age at brachytherapy was 1.2 years (standard deviation, SD: 1.1 years), and the mean follow-up was 1.7 years (SD: 0.6 years). The treated tumours had a mean diameter of 2.3 mm (SD: 0.7 mm) and a mean height of 1.5 mm (SD: 0.6 mm) with a mean distance to the optic disc of 9.9 mm (SD: 2.2 mm). The mean duration of irradiation was 29.3 h (SD: 9.9 h) with a mean dose at the sclera of 213 Gy (SD: 80 Gy). Surgery was uneventful in all cases. Complete regression developed after 3.1 months (SD: 2.8 months) in all cases without a recurrence or a progression of the vitreous tumour cell seeding. The eyes developed no further side-effects besides a temporary circumscribed intra-ocular haemorrhage that emerged from the regressive tumour remnants. CONCLUSION: Brachytherapy with the CXS plaque seems to be a safe and reliable treatment option for small-sized retinoblastoma when laser or cryocoagulation failed to control the tumour growth or for small retinoblastoma with an incipient local tumour cell seeding on the tumour surface.

Beta Particles↗
PubMed1997

Demonstration of S-100 protein immunoreactivity in normal human retina and retinoblastoma.

Specimens of 24 enucleated eyes from patients with retinoblastomas in situ were examined by labelled streptavidin biotin (LSAB) method to ascertain the distribution of S-100 protein and compared with 28 normal developing eyes. Polyclonal anti-S-100 antiserum and monoclonal alpha and beta chain anti-S-100 antibodies were used in this study. In the normal retina a weak reaction was observed in astrocytes and ganglion cells at 24 gestational weeks (GW) and there was an increase in the intensity of staining with increasing age. In the morphologically normal retina with retinoblastoma, astrocytes, ganglion cells and Müller cells showed positive reactions for S-100 protein. Examined tumors showed S-100 protein-positive glial cells that were interpreted as reactive astrocytes. No reaction product was detected in the tumor cells. These findings support the concept that in the retinoblastoma, only glial cells are positive for S-100 protein.

Antibodies, Monoclonal↗
PubMed2004

Expression of cone-photoreceptor-specific antigens in a cell line derived from retinal tumors in transgenic mice.

PURPOSE: To examine an immortalized mouse retinal cell line (661W) for markers characteristic of photoreceptor cells and validate its photoreceptor origin. METHODS: The 661W cells were cloned from retinal tumors of a transgenic mouse line that expresses the simian virus (SV) 40 T antigen under control of the human interphotoreceptor retinol-binding protein (IRBP) promoter. Morphologic, immunocytochemical, and immunoblot analyses were performed to characterize these cells. Total cellular protein was used for immunoblot analysis of various photoreceptor-specific proteins. RESULTS: 661W cells grew as a monolayer and exhibited processes characteristic of neuronal cells. Immunoblot analysis showed that 661W cells expressed SV40 T antigen, blue and green cone pigments, transducin, and cone arrestin. Immunocytochemical detection of blue and green opsins showed distribution throughout the cell, the nucleus included. However, these cells did not express rod-specific antigens, such as opsin and arrestin or rod- and cone-specific proteins such as phosducin, peripherin/rds, and ROM1. Furthermore, the cells did not express RPE65, a cone- and RPE-cell-specific protein. CONCLUSIONS: 661W cells demonstrate cellular and biochemical characteristics exhibited by cone photoreceptor cells. These cells also resemble neuronal cells with their spindlelike processes and should serve as a useful alternative in vitro model for the study of cone photoreceptor cell biology and associated diseases.

Animals↗