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At least 613 records · Page 34Linked to original sources
PubMed2003

Optic nerve tissue shrinkage during pathologic processing after enucleation for retinoblastoma.

OBJECTIVES: To quantify and analyze the differences between the length of the optic nerve as measured by the ophthalmologist in the operating room after enucleation and the length as measured by the pathologist after fixation. METHODS: The authors performed a retrospective review of patients who underwent either primary or secondary enucleation for retinoblastoma at the Ophthalmic Oncology Center of the New York-Presbyterian Hospital-Cornell campus between November 1979 and August 2001. Intraoperative notes and pathologic reports were reviewed to determine the length of the resected optic nerve as recorded by both the surgeon and pathologist. RESULTS: Sufficient data for inclusion in the study were available from 100 enucleation specimens belonging to 96 patients. A significant degree of shrinkage of the optic nerve occurred after fixation, with a mean shrinkage of 30.3% from the time of enucleation to the time of measurement by the pathologist. Age at enucleation affected the degree of optic nerve shrinkage; nerves from younger children underwent more shrinkage than nerves from older patients. Sex of the patient and the laterality of disease did not significantly affect optic nerve shrinkage. CONCLUSIONS: A significant degree of shrinkage of the optic nerve occurs in retinoblastoma enucleation specimens after fixation prior to pathologic analysis. This finding must be taken into account when comparing different series and making recommendations for chemoprophylaxis based solely on histopathologic examination.

Child↗
PubMed2003

Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma.

BACKGROUND: Focal subtenon carboplatin injections have recently been used as a presumably toxicity-free adjunct to systemic chemotherapy for intraocular retinoblastoma. OBJECTIVE: To report our clinical experience with abnormal ocular motility in patients treated with subtenon carboplatin chemotherapy. METHODS: We noted abnormal ocular motility in 10 consecutive patients with retinoblastoma who had received subtenon carboplatin. During ocular manipulation under general anesthesia, we assessed their eyes by forced duction testing, comparing ocular motility after tumor control with ocular motility at diagnosis. Eyes subsequently enucleated because of treatment failure (n = 4) were examined histologically. RESULTS: Limitation of ocular motility was detected in all 12 eyes of 10 patients treated for intraocular retinoblastoma with 1 to 6 injections of subtenon carboplatin as part of multimodality therapy. Histopathological examination revealed many lipophages in the periorbital fat surrounding the optic nerve in 1 eye, indicative of phagocytosis of previously existing fat cells and suggesting prior fat necrosis. The enucleations were technically difficult and hazardous for globe rupture because of extensive orbital soft tissue adhesions. CONCLUSIONS: Subtenon carboplatin chemotherapy is associated with significant fibrosis of orbital soft tissues, leading to mechanical restriction of eye movements and making subsequent enucleation difficult. Subtenon carboplatin is not free of toxicity, and its use is best restricted to specific indications.

Adolescent↗
PubMed2004

External beam radiation "salvage" therapy in transgenic murine retinoblastoma.

OBJECTIVE: To determine the efficacy of low-dose "salvage" external beam radiation therapy (EBRT) following failed subconjunctival carboplatin chemotherapy in a murine model of heritable retinoblastoma. METHODS: Eighty-four eyes from 8-week-old, simian virus 40, T-antigen-positive mice were treated with 6 serial subconjunctival carboplatin injections (100 microg/25 microL). At 12 weeks of age, 64 eyes received EBRT for a total dose of 480 (4.8 Gy), 1200 (12.0 Gy), 1560 (15.6 Gy), or 3000 (30.0 Gy) rad. Twenty eyes received no additional therapy following subconjunctival carboplatin injections. Ten eyes received a total dose EBRT of only 3000 rad. Eight eyes received subconjuctival injections of only an isotonic sodium chloride solution. Ten eyes served as untreated controls. MAIN OUTCOME MEASURES: Eyes were enucleated at 20 weeks to assess the presence of tumor on histopathological examination. RESULTS: Salvage therapy using low-dose EBRT was able to reestablish tumor control in a dose-dependent manner. Increasing the EBRT dose to 3000 rad resulted in 100% tumor control. The dose-dependent curves were significantly different between the treatment groups-EBRT alone vs salvage EBRT after receiving subconjunctival carboplatin injections (P<.001). CONCLUSION: Low-dose hyperfractionated salvage EBRT following failed primary subconjunctival carboplatin chemotherapy is efficacious in the treatment of retinoblastoma in this animal model. Clinical Relevance Salvage EBRT using a reduced total radiation dose could be associated with a radiation-related treatment enhancement in pediatric retinoblastoma.

Animals↗
PubMed2004

Practical approach to management of retinoblastoma.

OBJECTIVE: To present a simplified approach to management of retinoblastoma using basic clinical features. DESIGN: In a prospective, nonrandomized, single-center clinical trial, 158 eyes of 103 patients with retinoblastoma were managed with 6 cycles of chemoreduction (vincristine sulfate, etoposide, and carboplatin). The eyes were classified according to the Reese-Ellsworth classification and were also grouped on the basis of clinical features as follows: group 1, tumor only; group 2, tumor plus subretinal fluid; group 3, tumor plus focal seeds (3a, focal subretinal seeds; 3b, focal vitreous seeds); group 4, tumor plus diffuse seeds (4a, diffuse subretinal seeds; 4b, diffuse vitreous seeds); and group 5, neovascular glaucoma or invasive retinoblastoma. MAIN OUTCOME MEASURE: Treatment success (avoidance of enucleation and external beam radiotherapy). RESULTS: According to the Reese-Ellsworth classification, chemoreduction was successful in 100% of group Ia, 100% of group Ib, 86% of group IIa, 100% of group IIb, 91% of group IIIa, 100% of group IIIb, 50% of group IVa, 77% of group IVb, 50% of group Va, and 27% of group Vb. There was erratic correlation of the Reese-Ellsworth classification with treatment success. In contrast, the simplified grouping system displayed a smooth, nonerratic correlation for treatment success, with 100% success for group 1, 91% for group 2, 59% for group 3, and 12% for group 4 (group 5 always managed by primary enucleation). When all 6 subcategory groups were analyzed, there was consistent correlation for treatment success of 100% for group 1, 91% for group 2, 68% for group 3a, 54% for group 3b, 17% for group 4a, and 11% for group 4b. CONCLUSION: This practical approach to retinoblastoma using basic clinical features is predictive of treatment success for eyes in which modern conservative therapy for retinoblastoma is used.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Visual fields in retinoblastoma survivors.

OBJECTIVE: To describe the visual field defects in retinoblastoma survivors and relate those defects to characteristics such as tumor size, tumor location, and treatment modality. METHODS: Thirty-one patients treated for retinoblastoma were included in this study. Humphrey visual fields were determined in 33 eyes. RESULTS: Twenty-seven patients (29 eyes, 68 tumors) had sufficient diagnosis and treatment data available for further analysis. Twenty-six of the 27 patients had both absolute and relative visual field defects. Four types of visual field defects were observed and correlated with location of the tumor and therapy to the individual tumors: (1) no residual defect, (2) absolute scotoma, (3) arcuate and sector scotoma, and (4) "pseudo"-visual field defects caused by relative enophthalmos resulting from radiation. CONCLUSIONS: Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment for their intraocular disease. Characteristics that determine the size and type of defects are tumor size, tumor location, and treatment method.

Antineoplastic Agents, Alkylating↗
PubMed2004

Effectiveness of vitamin D analogues in treating large tumors and during prolonged use in murine retinoblastoma models.

OBJECTIVE: To investigate the effectiveness of the vitamin D analogues 1,25-(OH)(2)-16-ene-23-yne vitamin D(3) (16,23-D(3)) and 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model. METHODS: For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm(3). Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed. RESULTS: In the large-tumor study, tumor volume ratios for the 1alpha-OH-D(2) and 16,23-D(3) groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1alpha-OH-D(2) and 16,23-D(3) groups (P =.15). In the long-term study, the 1alpha-OH-D(2) group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D(3) group and its control. Some toxic effects related to hypercalcemia were seen in both studies. CONCLUSIONS: In athymic mice in the large-tumor study, both 1alpha-OH-D(2) and 16,23-D(3) were effective in inhibiting tumor growth compared with controls. In the long-term study, 1alpha-OH-D(2) inhibited tumor growth but 16,23-D(3) did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality. Clinical Relevance Use of 1alpha-OH-D(2) inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.

Animals↗
PubMed2005

Long-term visual outcome following chemoreduction for retinoblastoma.

OBJECTIVE: To evaluate long-term visual outcome following chemoreduction. DESIGN: Interventional case series evaluating 54 eyes of 40 children with retinoblastoma successfully treated with chemoreduction, consisting of a combination of intravenous carboplatin, etoposide phosphate, and vincristine sulfate plus focal therapy without external beam radiotherapy or enucleation. All patients were followed up for at least 5 years. Patient and tumor data were analyzed for their effect on the main outcome measures (final visual acuities of 20/40 or better and of 20/200 or better) using univariate and multivariate regression models. Patients who failed chemoreduction were excluded. RESULTS: There were 4 eyes in Reese-Ellsworth group I, 7 in group II, 3 in group III, 15 in group IV, and 25 in group V. The mean distance from the posterior tumor margin to the optic disc was 2 mm, and from the tumor margin to the foveola it was 3 mm. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. Of 33 eyes with macular tumor, only 8 (24%) had a final visual acuity of 20/40 or better, and 15 (45%) had a final visual acuity of 20/200 or better. Of 21 eyes with extramacular tumor, 19 (90%) had a final visual acuity of 20/40 or better, and all (100%) had a final visual acuity of 20/200 or better. CONCLUSION: The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma.

OBJECTIVES: Fibroblast growth factors (FGFs) represent potent effectors and play essential roles in both normal development and many pathological processes. Little is known about their possible implication in retinoblastoma growth. We sought to examine FGF high- and low-affinity receptor (FGFR) expression, activation of FGFR1 by acidic FGF (FGF-1), and proliferative effects on Y79 cells. METHODS: Expression of FGFR1 to FGFR4 was screened in Y79 cells by means of immunochemical and reverse transcriptase polymerase chain reaction techniques. Tyrosine phosphorylation of FGFR1 induced by FGF was examined by immunoprecipitation after stimulation with FGF-1 in the presence or absence of heparin. Retinoblastoma proliferation was monitored by radiolabeled thymidine incorporation or a vital dye-based assay, after addition of FGF-1 with or without inclusion of a specific FGFR1 neutralizing antibody or FGFR1 antisense oligonucleotides. Low-affinity heparan sulfate proteoglycan coreceptors were blocked through sodium chlorate or heparinase treatment of Y79 cells. RESULTS: Y79 retinoblastoma expressed all 4 FGFRs, at both the protein and messenger RNA levels. The FGFR1 was differentially phosphorylated in a time- and heparin-dependent manner by FGF-1. Proliferation of Y79 cells induced by FGF-1 was entirely mediated by FGFR1, since inclusion of specific neutralizing antibodies or antisense oligonucleotides completely prevented tumor cell multiplication. Finally, FGF-1-induced proliferation was dependent on the presence and sulfation of heparan sulfate proteoglycan. CONCLUSIONS: Y79 retinoblastoma expresses all 4 FGFRs, but FGFR1 activation entirely accounts for FGF-1-driven cell proliferation. CLINICAL RELEVANCE: These studies demonstrate a role for the FGF-1/FGFR1 pathway in retinoblastoma proliferation, and may contribute to developing therapeutic strategies to limit retinoblastoma growth.

Blotting, Western↗
PubMed2006

Small molecule inhibition of HDM2 leads to p53-mediated cell death in retinoblastoma cells.

PURPOSE: To determine the efficacy of inducing p53-mediated cell death in retinoblastoma cells by Nutlin 3A, a small molecule HDM2 inhibitor. METHODS: Retinoblastoma cell lines WERI-RB-1 and Y79 were treated with Nutlin 3A. Cell viability assays, Western blot analyses, confocal microscopy, and flow cytometry were performed to measure cell survival, p53 protein levels, activation of downstream targets, and apoptosis. To determine whether the effects of Nutlin 3A were p53-dependent, cell viability assays were performed on Y79 cells expressing short interfering RNA (siRNA) against p53. RESULTS: Nutlin 3A induced cell death in Y79 and WERI-RB-1 in the 5- to 10-microM dose range. Treated cells demonstrated increased protein levels of p53 and the p53 targets p21 and HDM2. Phosphorylation of p53-serine-15, a marker for activation of p53 via genotoxic mechanisms, was absent. Y79 cells expressing siRNA against p53 demonstrated resistance to Nutlin 3A. CONCLUSIONS: Nutlin 3A induced p53-mediated apoptosis in a dose-dependent, nongenotoxic fashion in 2 retinoblastoma cell lines. CLINICAL RELEVANCE: Nutlin 3A is effective against retinoblastoma cells in a nongenotoxic manner. Because the mutagenic effects of radiation and chemotherapy may increase risks of secondary tumor formation, targeted p53 activation may be a safer alternative treatment for retinoblastoma in the future.

Annexin A5↗