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Retinoblastoma which developed in microphthalmia.

We report a rare case of retinoblastoma which developed in unilateral microphthalmia. A 4-year-old girl presented with a large, intraocular mass in microphthalmia without a family history of retinoblastoma. The eyeball was enucleated due to rapid growth of the intraocular tumor. Microscopically it proved to be a retinoblastoma with some Flexner-Wintersteiner rosettes. This unusual case shows that retinoblastoma should not be excluded just because the eye is small, particularly if the family history is not available or is incomplete.

Child, Preschool↗

Transgenic mouse models for tumors of melanocytes and retinal pigment epithelium.

Cutaneous and ocular melanomas are due to malignant transformation of neural crest-derived melanocytes. The rising incidence of this tumor in humans has stimulated experiments to devise suitable mouse models. In the past years, transgenic mouse lines have been generated using different oncogenes - Ha-ras, SV40 T antigen (Tag), ret - which develop benign lesions of melanocytes, melanoma, and/or eye tumors. Pigment cell tumors in humans, although rather rare, can also develop from the retinal pigment epithelium (RPE), a cell layer of neuroectodermal origin. We, therefore, established transgenic models for this ocular tumor. Regulated by the promoter of tyrosinase-related protein-1 (TRP-1), two oncogenes, ret and SV40 Tag, were targeted to the developing RPE in transgenic mice. The TRP-1/ret transgenic mice displayed microphthalmia and benign tumors of the RPE. Expression of SV40 T antigen (TRP-1/Tag) led to malignant tumors, which were invasive and metastasized to inguinal lymph node and spleen.

Animals↗

Pterin-dependent tyrosine hydroxylase mRNA is not expressed in human melanocytes or melanoma cells.

Pterin-dependent tyrosine hydroxylase has been described to occur occasionally in melanocytes. It is therefore important to quantify the mRNA of this enzyme in pigment cells to understand whether this enzyme can take an active part in pigment formation. A real-time reverse transcription-polymerase chain reaction method was used to quantify tyrosine hydroxylase mRNA in melanocytes and melanoma cells. The calibrator was obtained by amplification of a segment of cDNA from tyrosine hydroxylase mRNA, which included the target thus allowing enumeration of the number of transcripts per cell. In melanocytes (n = 3), tyrosine hydroxylase mRNA ranged from non-detectable to 0.000492 transcripts/cell and in melanoma cells from non-detectable to 0.005340 transcripts/cell. In neuroblastoma cells, the median tyrosine hydroxylase mRNA number was 0.4 transcripts/cell (range 0.02-25 transcripts/cell). The amount of tyrosine hydroxylase mRNA in the pigment cells was far less than the mRNA concentrations of four melanocyte-specific proteins measured in the same melanocytes and melanoma cells. We conclude that on the average less than 1 of 1000 melanocytes and melanoma cells contains at least one tyrosine hydroxylase mRNA molecule. Consequently, in 999 of 1000 cells translation into the corresponding enzyme protein cannot occur because of the lack of an mRNA template. Thus, in these cells there is no pterin-dependent tyrosine hydroxylase that can contribute to pigment formation by producing priming amounts of l-dopa for proper function of tyrosinase.

Base Sequence↗

Direct test of potential roles of EIIIA and EIIIB alternatively spliced segments of fibronectin in physiological and tumor angiogenesis.

Fibronectin splice variants containing the EIIIA and/or EIIIB exons are prominently expressed in the vasculature of a variety of human tumors but not in normal adult tissues. To understand the functions of these splice variants in physiological and tumor angiogenesis, we used EIIIB-null and EIIIA-null strains of mice to examine neovascularization of mouse retinas, pancreatic tumors in Rip-Tag transgenic mice, and transplanted melanomas. Contrary to expectations, physiological and tumor angiogenesis was not significantly affected by the absence of either EIIIA or EIIIB splice variants. Tumor growth was also not affected. In addition, the expression levels of smooth muscle alpha actin, believed to be modulated by EIIIA-containing fibronectins, were not affected either. Our experiments show that despite their tight regulation during angiogenesis, the presence of EIIIA or EIIIB splice variants individually is not essential for neovascularization.

Alternative Splicing↗

A survey of paediatricians' practice and training in routine infant eye examination.

A survey of a sample of UK paediatricians was carried out to identify the practices and determine the training of those involved in routine surveillance examinations to detect ophthalmic disorders in infants. The findings indicate important variation in current practices and raise concerns about both undergraduate and postgraduate training in ophthalmic assessment of infants.

Eye Abnormalities↗

Late diagnosis of retinoblastoma in a developing country.

OBJECTIVES: To assess the diagnostic process of retinoblastoma in a developing country. STUDY DESIGN: Prospective survey of 95 consecutive parents of patients with retinoblastoma. RESULTS: Fifty six parents consulted initially with a paediatrician. Their children tended to be younger, with a significantly higher frequency of advanced disease. Only half of the patients who consulted with a paediatrician were appropriately referred to an ophthalmologist; the paediatrician underestimated the complaints in the remainder. Children taken to an ophthalmologist were older and had less advanced disease. In about three quarters of these children, a diagnosis of retinoblastoma was suspected by the ophthalmologist on the first visit. Parents of patients with more advanced disease consulted significantly later. Poor parental education correlated significantly with late consultation. Lack of health insurance and living outside Buenos Aires City correlated significantly with an increased risk of extraocular disease. CONCLUSIONS: Paediatricians are the first health professional seen by most children with retinoblastoma. However, the diagnosis is not readily established. There is also a delay in consultation by parents, which is significantly longer in cases with advanced extraocular disease. Socioeconomic factors and access to health care might play a role in delayed diagnosis.

Argentina↗

Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma.

BACKGROUND/AIM: Celecoxib, a cyclooxygenase-2 inhibitor and antiangiogenic agent, has demonstrated potent anticancer effects in preclinical studies and in human clinical trials. To evaluate the potential utility of this agent in the treatment of retinoblastoma, the authors investigated the effects of celecoxib in retinoblastoma cell lines and in a murine model of this disease. METHODS: Growth inhibitory effects of celecoxib were evaluated in Y79 and Weri-RB1 human retinoblastoma cell lines by WST-1 cell proliferation assay. For animal study, two groups of 24, 8 week old LHbeta-TAg transgenic mice were treated with celecoxib (250 mg/kg, orally once a day) or vehicle control, 5 days/week for 6 weeks. Mice were sacrificed on day 43. Enucleated eyes were serially sectioned and ocular tumour burden was quantified by histopathological analysis. RESULTS: Celecoxib did not inhibit proliferation of Y79 or Weri-RB1 cells, even at concentrations far exceeding clinically achievable levels. No significant difference in ocular tumour burden between celecoxib treated and control mice (p=0.73) was found. CONCLUSION: Celecoxib was ineffective at inhibiting proliferation of retinoblastoma cells in vitro and was ineffective at controlling retinoblastoma tumour growth in a murine model of this disease. On the basis of these findings, oral celecoxib therapy is unlikely to have clinical utility in the treatment of retinoblastoma.

Angiogenesis Inhibitors↗

Systemic carboplatin for retinoblastoma: change in tumour size over time.

BACKGROUND/AIM: Chemotherapy for intraocular retinoblastoma is used to shrink individual retinal tumours to a size amenable to focal treatments. Quantitative data regarding retinal tumour response following treatment with primary systemic carboplatin are reported. METHODS: Changes in area and largest basal diameter of tumours that were exposed to carboplatin, had no concomitant focal treatment, and had digital funduscopic photography performed before and after treatment, were measured. Response was evaluated. RESULTS: 36 tumours were measured following one treatment: 34/36 (94.4%) responded, with a 37.1% mean decrease in area (median = 37.0%; range 4.0%-76.7%). Mean reduction in basal diameter was 21.3% (med = 21.0%; -7.9%-52.5%). 20 tumours were treated with a second cycle: 15/20 (75.0%) responded. Mean decrease in area was 17.8% (med = 15.3%; -7.0%-49.7%). The mean cumulative decrease in area after two treatments was 55.1% (med = 56.2%; 33.0%-74.5%). Mean cumulative reduction in basal diameter was 33.6% (med = 33.6%; 10.9%-53.2%). 12 tumours were treated with a third cycle: 3/12 (25.0%) responded, 8/12 were stable, and one progressed. Mean decrease in area was 5.4% (med = 7.2%; -17.7%-20.6%). Cumulative decrease in area after three treatments was 58.1% (med = 57.3%; 34.8%-77.2%). Mean cumulative reduction in basal diameter was 38.8% (med = 38.2%; 19.1%-54.1%). CONCLUSIONS: Carboplatin caused measurable shrinkage of retinoblastoma tumours. Response was greatest following the initial treatment and decreased with subsequent treatments.

Antineoplastic Agents↗