Michael Krauthammer, Yong Kong, Byung Hak Ha, Perry Evans, Antonella Bacchiocchi, James P McCusker, Elaine Cheng, Matthew J Davis, Gerald Goh, Murim Choi, [......], Miguel A Materin, Roger S Lo, Shrikant Mane, Shuangge Ma, Kenneth K Kidd, Nicholas K Hayward, Richard P Lifton, Joseph Schlessinger, Titus J Boggon, Ruth Halaban[show abstract] [hide abstract]
ABSTRACT: We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.Nature Genetics 07/2012; 44(9):1006-14. · 35.53 Impact Factor
Article: Ocular neoplastic disease.[show abstract] [hide abstract]
ABSTRACT: Ocular neoplasms, both primary and metastatic, may present with visual disturbance or vision loss and often are asymptomatic. Clinical ophthalmologic examination may demonstrate leukocoria, abnormal pupillary light reflex, or a mass lesion with or without retinal detachment or hemorrhage. Retinoblastoma in children and uveal melanoma and ocular metastases in adults are the most important ocular malignant neoplasms referred for imaging to aid with diagnosis and staging. Familiarity with their common imaging appearances, the common patterns of spread, and the diagnostic findings of greatest concern to the ocular oncologist will enhance accuracy of imaging interpretation. Clinical ophthalmologic examination and imaging using B-scan ultrasound, A-scan ultrasound, fluorescein angiography, computed tomography and magnetic resonance imaging have complementary roles in ocular tumor staging and treatment assessment.Seminars in Ultrasound CT and MRI 02/2011; 32(1):28-37. · 1.24 Impact Factor
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ABSTRACT: PURPOSE: To report a patient with small juxtapapillary choroidal melanoma with chromosome 3 monosomy treated with I(125) plaque and transpupillary thermotherapy (TTT). A 64-year-old Caucasian male presented with painless blurred vision of the left eye. Ocular examination disclosed a small juxtapapillary choroidal melanocytic tumor with overlying subretinal fluid and orange pigment. Ultrasound showed an elevated choroidal mass of 2 mm thickness with low reflectivity on A-scan and hollowness on B scan, consistent with a small choroidal melanoma. The patient was treated with plaque I(125) radiotherapy combined with one session of TTT. Genetic testing of the tumor cells obtained by fine needle aspiration biopsy showed chromosome 3 monosomy. At 1 year after treatment, the tumor was regressed with resolution of subretinal fluid and 20/40 visual acuity. A small choroidal melanoma can manifest monosomy of chromosome 3, a known predictive factor for the development of systemic metastasis.Middle East African journal of ophthalmology 07/2010; 17(3):268-9.
Article: Fundus autofluorescence and optical coherence tomography findings in choroidal melanocytic lesions.[show abstract] [hide abstract]
ABSTRACT: To establish the characteristics of secondary retinal and retinal pigment epithelial (RPE) changes associated with the presence of choroidal melanoma and choroidal nevus as documented by optical coherence tomography (OCT) and fundus autofluorescence (FAF). PubMed review of major English publications examining the correlation between clinical characteristics of choroidal melanoma and nevus with OCT and FAF findings. The intrinsic properties of choroidal melanoma, as well as overlying RPE changes, drusen, and lipofuscin are best characterized by FAF, while OCT is more sensitive for the identification of subretinal and intraretinal fluid as well as atrophy, degeneration, and photoreceptor loss in the neurosensory retina. Secondary retinal changes associated with choroidal melanocytic lesions can be documented by OCT and FAF. OCT-evident changes are observed more often with choroidal melanoma than choroidal nevus. OCT is better suited to identify the overlying retinal detachment and edema, even before these findings are clinically apparent. FAF is most useful in documenting the presence of lipofuscin, a finding that represents one of the important criteria in differentiating small choroidal melanoma from benign choroidal nevus.Middle East African journal of ophthalmology 07/2010; 17(3):201-6.
Article: Periocular triamcinolone for prevention of macular edema after plaque radiotherapy of uveal melanoma: a randomized controlled trial.Noel Horgan, Carol L Shields, Arman Mashayekhi, Pedro F Salazar, Miguel A Materin, Myra O'Regan, Jerry A Shields[show abstract] [hide abstract]
ABSTRACT: To determine the efficacy and safety of periocular triamcinolone acetonide (40 mg) for the prevention of macular edema in patients undergoing plaque radiotherapy for uveal melanoma. Prospective, randomized, controlled clinical trial. One-hundred sixty-three patients with newly diagnosed uveal melanoma undergoing iodine 125 plaque radiotherapy were entered into the study. Fifty-five patients were randomized to the control group and 108 to the triamcinolone group. Eighteen-month data were available for 143 (88%) of the 163 patients. Periocular injection of triamcinolone acetonide (40 mg in 1 ml) at the time of plaque radiotherapy and 4 months and 8 months later. Optical coherence tomography was performed at each patient evaluation. Optical coherence tomography-evident macular edema, moderate vision loss, and poor final visual acuity. Optical coherence tomography-evident macular edema occurred significantly less often in the triamcinolone group compared with the control group up to 18 months after plaque radiotherapy (hazard estimate, 0.45; 95% confidence interval, 0.19-0.70; P = 0.001). At the 18-month follow-up, moderate vision loss (loss of 3 lines or more of best-corrected visual acuity [BCVA]) and severe vision loss (BCVA <5/200 Snellen) occurred significantly less frequently in the triamcinolone group than in the control group (31% vs. 48% [P = 0.039] and 5% vs. 15% [P = 0.048], respectively). Rates of elevated intraocular pressure and cataract progression were similar in both groups. Periocular triamcinolone is beneficial in reducing the risk of macular edema up to 18 months after plaque radiotherapy for uveal melanoma and significantly reduces the risk of moderate vision loss and poor visual acuity in these patients.Ophthalmology 05/2009; 116(7):1383-90. · 5.45 Impact Factor