Joan M. O’Brien

Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.

BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown. Here we report frequent somatic mutations in the heterotrimeric G protein α-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the uvea (46%). The mutations occur exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene. Our results demonstrate an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.

Ocular manifestations of leukemia: leukemic infiltration versus infectious process

OBJECTIVE To determine whether specific guidelines can be developed to distinguish whether retinal infiltration in leukemia patients represents infection or neoplasia. DESIGN Retrospective noncomparative interventional case series. PARTICIPANTS Six patients recently seen at University of California San Francisco with retinal infiltrates in a setting of leukemia, for which adequate written and photographic information of disease course was available. INTERVENTION Observation consisted of retrospective review of clinic charts, hospital medical records, and fundus photographs. MAIN OUTCOME MEASURES Determination of whether retinal infiltrates represented neoplasia or infection was made by review of medical records. RESULTS In this series, neoplastic retinal infiltrates were found in patients who had newly diagnosed leukemia and those who were in blast crisis. In contrast, the two patients who were in complete remission, but had undergone bone marrow transplantation, had retinal infiltrates attributable to infection. CONCLUSIONS Every patient with retinal infiltrates in the setting of newly or previously diagnosed leukemia requires a systemic and central nervous system workup before the initiation of ophthalmologic treatment. The systemic status of the patient is highly informative in determining whether infection or neoplasia is responsible for the infiltration.

Spontaneous regression of orbital Langerhans cell granulomatosis in a three-year-old girl.

PURPOSE To report a case of spontaneous regression of orbital Langerhans cell granulomatosis. METHOD Case report. A 3-year-old girl was initially examined with a 5-week history of slowly progressive blepharoptosis and periorbital swelling of the left eye. RESULTS Computed tomographic scan showed a mass in the left orbit eroding into the left frontal bone; fine-needle aspiration confirmed diagnosis of Langerhans cell granulomatosis. After initial biopsy, the patient was treated by close observation alone. Six months after initial examination, the monostotic lesion had completely resolved. CONCLUSIONS In some cases of monostotic Langerhans cell granulomatosis, initial biopsy followed by observation alone may allow for the spontaneous regression of the lesion. This conservative approach to treatment is an important therapeutic option that may spare the patient the adverse effects of surgical resection, radiation, or chemotherapy.

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 LHβ-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.

Siblings of retinoblastoma patients: are we underestimating their risk?

PURPOSE To describe the clinical presentation of probable germ-line mosaicism in four retinoblastoma kindreds. METHODS Review of 255 retinoblastoma patients and their family records in a University of California, San Francisco-Bascom Palmer database to identify those with potential germ-line mosaicism. Parents and siblings of retinoblastoma patients were given comprehensive ophthalmologic examinations. RESULTS Four kindreds were identified, wherein retinoblastoma was diagnosed in two siblings and both parents demonstrated no evidence of retinoblastoma or retinocytoma. CONCLUSION Clinical appearance of germ-line mosaicism is demonstrated in our retinoblastoma patient populations. We recommend routine clinical screening of all parents and siblings of retinoblastoma patients to provide more accurate genetic counseling and to allow earlier examination and treatment of children at presymptomatic disease stages. Germ-line mosaicism must be considered as a genetic transmission pattern in these patients, and genetic counseling should specifically recognize this possibility. If a parent is germ-line mosaic, the possibility of bearing a second child with retinoblastoma is clearly higher than conventionally believed.

Poliosis as a manifestation of conjunctival melanoma.

appear to bind copper in these disease states but are not known to do so in vitro. In at least 1 case, the coppercarrying protein was sequenced in an attempt to determine whether it shared the N-terminal Asp-Ala-His amino acid sequence known to bind copper in albumin, but no such sequence was found. Sequences as simple as Gly-His are capable of binding copper under certain circumstances, especially if they are repeated, rendering it difficult to determine the location of a potential binding site based on sequence alone. Myeloma protein is known to accumulate in the eye as an amyloid, and although individual myeloma proteins do not appear to bind copper, closely packed myeloma proteins may be able to do so.