15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSE: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS: 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Randomized Trial of Treat-and-Extend Intravitreal Aflibercept for Radiation Retinopathy: 1-Year Outcomes.

Purpose: Radiation retinopathy (RR)-related macular edema commonly causes poor visual acuity outcomes in patients previously treated with ocular radiation therapy. Current treatments are not US Food and Drug Administration (FDA)-approved and prior studies have variable outcomes. We performed a multicenter, prospective, randomized clinical trial to assess the safety and efficacy of 2 mg intravitreal aflibercept injections (IAIs) for the treatment of RR. Methods: Thirty-nine eyes in 39 patients with RR-related macular edema causing vision loss were assigned randomly to cohorts (1:1 ratio) in which patients either did or did not receive a loading dose of 3 IAIs followed by a treat-and-extend regimen. The primary outcome measure was the mean Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA) change from baseline. Results: Of the 39 randomized patients, 30 (76.9%) completed the year 1 follow-up visit. The overall mean BCVA change from baseline was 4.3 letters (P = 0.087), with 1.57 letters and 6.69 letters gained in cohorts 1 and 2, respectively (P = 0.31). There was a significant difference in central retinal thickness (CRT) from baseline to week 52 overall (484.4 µm to 326.5 µm) and within cohorts 1 (441.2 µm to 311.1 µm) and 2 (522.3 µm to 339.9 µm), respectively (P < 0.001). A total of 96.7% of the patients had visual acuity of 20/200 or better, and 30.0% improved 10 or more letters. Conclusions: Aflibercept may improve CRT and may prevent vision loss in patients with RR using a treat-and-extend regimen through 52 weeks of therapy. Larger, multicenter studies are needed to confirm these findings.

Intraocular Lens and Lens Capsule Spread of Iridociliary Melanoma: Clinical and Histopathologic Features of 2 Cases.

Purpose: The aim of this study was to describe 2 patients with intraocular lens (IOL) and lens capsule spread of iridociliary melanoma. Methods: Two pseudophakic patients with iridociliary body melanoma that spread onto the surface of their IOL and remaining lens capsule were included. Their eyes were enucleated and the histopathologic features were evaluated. Results: Case 1 was an 82-year-old woman with diffuse primary iridociliary melanoma affecting the iris, lens capsule, IOL surface, and ciliary body. Case 2 was a 68-year-old female who developed melanoma recurrence in the anterior segment after plaque brachytherapy for iridociliary melanoma. The melanoma in both cases grew as a pigmented membrane onto the surface of the IOL. Conclusions: IOL and lens capsule spread of iridociliary melanoma can occur primarily or develop secondarily after plaque brachytherapy of a pseudophakic eye. Since the extent of the melanoma may be uncertain and there is a high likelihood of glaucoma, enucleation is a reasonable option.

Prepapillary vascular loop-a new classification.

BACKGROUND/OBJECTIVES: To analyze the ophthalmic characteristics of congenital prepapillary vascular loop (PVL) and to propose a new morphologic classification dividing the loops into six types. SUBJECTS/METHODS: Collaborative multinational multicentre retrospective study of PVL cases. RESULTS: There was a total of 49 cases (61 eyes), 37 unilateral (75.5%) and 12 bilateral (24.5%), 32 arterial type (65.3%) and 18 venous type (36.7%) (one patient had either kind in each eye). The mean number of loops per eye was 2.7 (range, 1-7). The loops were asymptomatic in 42 cases (85.7%). Other findings included: the presence of cilioretinal artery (14 cases), retinal vascular tortuosity (26 cases), amaurosis fugax (1 case), branch retinal artery occlusion (1 case) and vitreous haemorrhage (3 cases). Six morphologic loop types could be discerned based on elevation (flat vs. elevated), shape (figure of 8 or corkscrew with hyaline sheath), number (multiple or single), location (central or peripheral), lumen size (arterial vs. arteriolar) and presence of vascular tortuosity or vitreous traction. CONCLUSIONS: PVL are usually asymptomatic and can be divided into six morphologic types with different pathogenesis during early embryogenesis.

Gene Expression Profiling in Uveal Melanoma: Five-Year Prospective Outcomes and Meta-Analysis.

INTRODUCTION: The prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) predicts metastatic risk based on primary tumor biology. Here we report outcomes from a prospective registry of 15-GEP-tested patients, and a meta-analysis with published cohorts. OBJECTIVES: Management and 5-year clinical outcomes following 15-GEP testing were evaluated. METHODS: Eighty-nine patients with 15-GEP results were prospectively enrolled at four centers. Physician-recommended management plans were collected, and clinical outcomes tracked every 6 months. RESULTS: Eighty percent of Class 1 (low-risk) patients underwent low-intensity management; all Class 2 (high-risk) patients underwent high-intensity management (p < 0.0001). Median follow-up for event-free patients was 4.9 years. Five Class 1 (10%) and 23 Class 2 (58%) tumors metastasized (p < 0.0001). Five-year Class 1 and 2 metastasis-free survival rates were 90% (81-100%) and 41% (27-62%; p < 0.0001), and melanoma-specific survival rates were 94% (87-100%) and 63% (49-82%; p = 0.0007). Class 2 was the only independent predictor of metastasis and was associated with increased risk for metastasis and mortality by meta-analysis. CONCLUSIONS: UM patient management is guided by 15-GEP testing. Class 2 patients were managed more intensely, in accordance with an observed metastatic rate of >50%; Class 1 patients were safely spared intensive surveillance, resulting in appropriate utilization of healthcare resources.

Unilateral Multiple Extramedullary Plasmacytoma of the Choroid and Conjunctiva: A Case Report.

Purpose: We report a case of multiple extramedullary plasmacytoma (EMP) of the choroid and conjunctiva as a sign of multiple myeloma (MM) relapse. Methods: An observational case report with clinicopathologic correlation is presented. Results: A 45-year-old man with a 2.5-year history of MM presented with left eye pain. Examination revealed a conjunctival nodule and choroidal infiltrate in the left eye. Excisional biopsy demonstrated plasmacytoma of the conjunctiva and choroid. Despite radiotherapy and chemotherapy, multiple EMP recurred and the patient died 8 months after initial presentation. Conclusions: Multiple EMP of the choroid and conjunctiva has a poor prognosis and can present as a sign of MM relapse. Our imaging demonstrates the clinical manifestations of this tumor and can aid future diagnoses. Our radiation dose (20 Gy) was inadequate, which is an important reportable factor for future patients.

Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma.

For the treatment of choroidal melanoma, palladium-103 (Pd) and ruthenium-106 (Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between Pd and Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. Pd patients (n=124) and Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but Ru had lower grades of retinopathy (P=0.006). Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01-14.31, P=0.048). Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02-0.38; P<0.001). Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.

Visual acuity, oncologic, and toxicity outcomes with 103Pd vs. 125I plaque treatment for choroidal melanoma.

PURPOSE: To evaluate outcomes of choroidal melanoma patients treated with 125I or 103Pd plaque brachytherapy. METHODS AND MATERIALS: From 1993 to 2012, our institution treated 160 patients with 103Pd (56.1%) and 125 patients with 125I (43.9%) plaque brachytherapy. Tumor outcomes, visual acuity (VA), and toxicity were compared. Multivariate analyses (MVAs) and propensity score analysis were used to help address differences in baseline characteristics. RESULTS: Median followup was longer for 125I patients, 52.7 vs. 43.5 months (p < 0.01). At baseline, 103Pd patients had lower rates of VA worse than 20/200 (4.4% vs. 16%, p = 0.002), T3-T4 tumors (17.5% vs. 32.8%, p = 0.03), and transpupillary thermotherapy use (3.1% vs. 9.6%, p = 0.001). Both 103Pd and 125I provided >90% 3-year overall survival and >93% 5-year secondary enucleation-free survival. On MVA, radionuclide was not predictive for tumor outcomes. A higher percentage maintained vision better than 20/40 with 103Pd (63% vs. 35%, p = 0.007) at 3 years. MVA demonstrated 103Pd radionuclide (odds ratio [OR]: 2.12, p = 0.028) and tumor height ≤5 mm (OR: 2.78, p = 0.017) were associated with VA better than 20/40. Propensity score analysis matched 23 125I with 107 103Pd patients. 103Pd continued to predict better VA at 3 years (OR: 8.10, p = 0.014). On MVA for the development of VA worse than 20/200 or degree of vision loss, radionuclide was not significant. Lower rates of radiation retinopathy were seen with 103Pd than 125I (3 years: 47.3% vs. 63.9%, p = 0.016), with radionuclide significant in MVA. CONCLUSIONS: Both 125I and 103Pd achieve excellent tumor control. An increased probability of long-term VA better than 20/40 and reduced risk of radiation retinopathy is associated with 103Pd.

PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS.

PURPOSE: To describe the development of uveitis and retinal vasculitis in association with pembrolizumab treatment for metastatic uveal melanoma. METHODS: A case report and a brief review of the literature are presented. Information collected and reported include the patient's clinical course, physical examination findings, fluorescein angiogram images, retinal photographs, and her response to treatment. RESULTS: A 54-year-old woman was diagnosed with a large choroidal malignant melanoma and had the affected eye enucleated. Pathology confirmed a mixed cell choroidal melanoma, and gene expression profiling was Class 2. Seventeen months after enucleation, the patient was diagnosed with metastatic uveal melanoma to the liver. Disease progression was observed during ipilimumab treatment. Pembrolizumab treatment was initiated, and after four infusions, she presented to clinic complaining of floaters and blurred vision. Examination revealed a nongranulomatous panuveitis characterized by perivascular retinal pigment epithelium pigmentary changes, retinal venous sheathing, 1+ anterior chamber and vitreous cellular reaction, 2+ vitreous haze, and optic disk edema. A dexamethasone sustained-release implant was administered and the uveitis regressed. A relapse in symptoms occurred but quickly subsided with a repeat injection. CONCLUSION: Pembrolizumab may induce a uveitic reaction. There is mounting evidence that patients using prembrolizumab should be educated and monitored for signs of uveitis.

Clinical Performance and Management Outcomes with the DecisionDx-UM Gene Expression Profile Test in a Prospective Multicenter Study.

Uveal melanoma management is challenging due to its metastatic propensity. DecisionDx-UM is a prospectively validated molecular test that interrogates primary tumor biology to provide objective information about metastatic potential that can be used in determining appropriate patient care. To evaluate the continued clinical validity and utility of DecisionDx-UM, beginning March 2010, 70 patients were enrolled in a prospective, multicenter, IRB-approved study to document patient management differences and clinical outcomes associated with low-risk Class 1 and high-risk Class 2 results indicated by DecisionDx-UM testing. Thirty-seven patients in the prospective study were Class 1 and 33 were Class 2. Class 1 patients had 100% 3-year metastasis-free survival compared to 63% for Class 2 (log rank test p = 0.003) with 27.3 median follow-up months in this interim analysis. Class 2 patients received significantly higher-intensity monitoring and more oncology/clinical trial referrals compared to Class 1 patients (Fisher's exact test p = 2.1 × 10(-13) and p = 0.04, resp.). The results of this study provide additional, prospective evidence in an independent cohort of patients that Class 1 and Class 2 patients are managed according to the differential metastatic risk indicated by DecisionDx-UM. The trial is registered with Clinical Application of DecisionDx-UM Gene Expression Assay Results (NCT02376920).

Stellate nonhereditary idiopathic foveomacular retinoschisis.

PURPOSE: To describe a new classification of stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR). DESIGN: Retrospective case series and literature review. PARTICIPANTS: A total of 17 patients from 5 institutions. METHODS: Detailed case history, multimodal imaging, and genetic testing were reviewed for patients with macular schisis without a known predisposing condition. Patients with a stellate appearance centered on the fovea with correlating confirmed expansion of the outer plexiform layer (OPL) by optical coherence tomography (OCT) were included. Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or advanced glaucomatous optic nerve changes. MAIN OUTCOME MEASURES: Clinical features, anatomic characteristics, and visual acuity. RESULTS: A total of 22 eyes from 16 female patients and 1 male patient with foveomacular schisis were reviewed from 5 institutions. Initial visual acuity was ≥ 20/50 in all eyes (mean, 20/27), but visual acuity in a single eye decreased from 20/20 to 20/200 after the development of subfoveal fluid. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to >5 years. CONCLUSIONS: In this largest known series of patients with SNIFR, all patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (≥ 20/40) except in a single patient in whom subretinal fluid developed under the fovea.

Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses.

OBJECTIVE: Assess current clinical practices for uveal melanoma (UM) and the impact of molecular prognostic testing on treatment decisions. DESIGN: Cross-sectional survey and sequential medical records review. PARTICIPANTS: Ophthalmologists who treat UM. METHODS: (A) Medical records review of all Medicare beneficiaries tested by UM gene expression profile in 2012, conducted under an institutional review board-approved protocol. (B) 109 ophthalmologists specializing in the treatment of UM were invited to participate in 24-question survey in 2012; 72 were invited to participate in a 23-question survey in 2014. MAIN OUTCOME MEASURES: Responses analyzed by descriptive statistics, frequency analyses (percentages, Tukey, histograms), and Fisher's exact test. Descriptive presentation of essay answers. RESULTS: The review of Medicare medical records included 191 evaluable patients, 88 (46%) with documented medical treatment actions or institutional policies related to surveillance plans. Of these 88, all gene expression profiling (GEP) Class 1 UM patients were treated with low-intensity surveillance. All GEP Class 2 UM patients were treated with high-intensity surveillance (P<0.0001 versus Class 1). There were 36 (19%) with information concerning referrals after initial diagnosis. Of these 36, all 23 Class 2 patients were referred to medical oncology; however, none of the 13 Class 1 patients were referred (P<0.0001 versus Class 1). Only Class 2 patients were recommended for adjunctive treatment regimens. 2012 survey: 50 respondents with an annual median of 35 new UM patients. The majority of respondents (82%) performed molecular analysis of UM tumors after fine needle biopsy (FNAB); median: 15 FNAB per year; 2014 survey: 35 respondents with an annual median of 30 new UM patients. The majority offered molecular analyses of UM tumor samples to most patients. Patients with low metastatic risk (disomy 3 or GEP Class 1) were generally assigned to less frequent (every 6 or 12 months) and less intensive clinical visits. Patients with high metastatic risk (monosomy 3 or GEP Class 2) were assigned to more frequent surveillance with hepatic imaging and liver function testing every 3-6 months. High-risk patients were considered more suitable for adjuvant treatment protocols. CONCLUSION: The majority of ophthalmologists treating UM have adopted molecular diagnostic tests for the purpose of designing risk-appropriate treatment strategies.

Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease.

PURPOSE: StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. METHODS: Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. RESULTS: Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. CONCLUSIONS: In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.

Vitreomacular traction as a consequence of posterior hyaloidal contraction after transpupillary thermotherapy.

PURPOSE: To describe the pathogenesis, clinical characteristics, management, and outcomes of patients in whom vitreomacular traction evolved pursuant to treatment of choroidal melanoma with transpupillary thermotherapy. DESIGN: Retrospective, uncontrolled, observational, interventional case series. METHODS: Vitreomacular traction with macular distortion, macular edema, and vision loss developed in 6 eyes of 6 patients after successful transpupillary thermotherapy for choroidal melanoma. Clinical examination, fluorescein angiography, fundus photography, and spectral-domain optical coherence tomography were performed. Symptomatic patients underwent pars plana vitrectomy (PPV). Primary outcome measures include visual acuity and resolution of macular distortion by clinical examination, spectral-domain optical coherence tomography, or both. RESULTS: In all 6 patients, the malignant lesions were treated successfully. The posterior hyaloid was attached in all eyes before transpupillary thermotherapy. All eyes demonstrated focal hyaloidal contraction and vitreomacular traction between the transpupillary thermotherapy scar and the macula. Mean time from transpupillary thermotherapy to PPV for treatment of vitreomacular traction was 23 ± 18 months. Mean length of follow-up was 11 months. Mean logarithm of the minimal angle of resolution visual acuity before transpupillary thermotherapy was 0.23 ± 0.38. Mean visual acuity after transpupillary thermotherapy was 0.53 ± 0.42. Mean visual acuity before membrane peel was 0.65 ± 0.34. Mean visual acuity after membrane peel was 0.44 ± 0.21. All patients undergoing PPV showed visual improvement. CONCLUSIONS: Hyaloidal contraction can occur after transpupillary thermotherapy and is a reversible cause of vision loss. The mechanism of vision loss resulting from hyaloidal contraction is flat vitreomacular traction. PPV and membrane peeling are effective in improving macular anatomic features and visual function.

Bilateral choroidal tumors consistent with metastatic malignant paraganglioma.

PURPOSE: To report a patient with bilateral choroidal metastasis from a malignant paraganglioma. METHODS: Clinicopathologic case report and literature review. RESULTS: A 68-year-old woman presented with bilateral amelanotic focal choroidal lesions. A thorough systemic work-up for a primary cancer revealed a paraganglioma (extraadrenal pheochromocytoma) and a pheochromocytoma of the left adrenal gland. Fine-needle aspiration biopsy of the choroidal lesion was consistent with metastatic paraganglioma. CONCLUSION: Metastatic paraganglioma, although rare, has the ability to metastasize to the choroid.

Conjunctival angiolymphoid hyperplasia with eosinophilia in a child.

Angiolymphoid hyperplasia with eosinophilia is a rare benign vascular proliferation with lymphocytic and eosinophilic infiltrate. Angiolymphoid hyperplasia with eosinophilia presents as single or multiple dome-shaped papules or plaques involving the dermis and subcutaneous tissues of the head and neck region. Conjunctival angiolymphoid hyperplasia with eosinophilia is rare, with only two previous case reports.

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN: Prospective, multicenter study. PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis. RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Ophthalmic and systemic findings in interstitial deletions of chromosome 14q: a case report and literature review.

We report a patient with clinical anophthalmia, partial eyelid fusion and a hypoplastic socket on the right. The left eye has microphthalmia involving the anterior and posterior segments, microcornea, iris coloboma, chorioretinal dysgenesis, macular dysplasia, absence of retinal vessels, and optic nerve aplasia. Systemic abnormalities include microcephaly, bilateral hearing loss, and duodenal atresia. Electrophysiologic testing showed no response from either eye. Cytogenetic testing revealed a de novo interstitial deletion of chromosome 14q22.3q23.1. The literature of similar interstitial deletions and ongoing candidate gene studies are reviewed.