Melanomas are notoriously difficult to classify because of a lack of discrete clinical and pathological stages. Here, we show that primary uveal melanomas surprisingly cluster into two distinct molecular classes based on gene expression profile. Genes that discriminate class 1 (low-grade) from class 2 (high-grade) include highly significant clusters of downregulated genes on chromosome 3 and up-regulated genes on chromosome 8q, which is consistent with previous cytogenetic studies. A three-gene signature allows biopsy-size tumor samples to be assigned accurately to tumor classes using either array or PCR platforms. Most importantly, this molecular classification strongly predicts metastatic death and outperforms other clinical and pathological prognostic indicators. These studies offer new insights into melanoma pathogenesis, and they provide a practical foundation for effective clinical predictive testing.

Purpose To evaluate the feasibility, safety, and utility of intraoperative optical coherence tomography (OCT) for use during ophthalmic surgery. Design Prospective, consecutive, case series Methods A prospective, single-center, consecutive, case series was initiated to assess intraoperative OCT in ophthalmic surgery. Intraoperative scanning was performed with a microscope mounted spectral domain OCT system. Disease specific or procedure-specific imaging protocols (e.g., scan type, pattern, size, orientation, density) were utilized for anterior and posterior segment applications. A surgeon feedback form was recorded as part of the study protocol to answer specific questions regarding intraoperative OCT utility immediately after the surgical procedure was completed. Results During the first 24 months of the PIONEER study, 531 eyes were enrolled (275 anterior segment cases and 256 posterior segment surgical cases). Intraoperative OCT imaging was obtained in 518 of 531 eyes (98%). Surgeon feedback indicated that intraoperative OCT informed surgical decision-making and altered surgeon understanding of underlying tissue configurations in 69/144 (48%) lamellar keratoplasty cases and 63/146 (43%) membrane peeling procedures. The most common anterior segment surgical procedure was descemet stripping automated endothelial keratoplasty (DSAEK, n = 135). Vitrectomy with membrane peeling was the most common procedure for posterior segment surgery (n = 154). The median time that surgery was paused to perform intraoperative OCT was 4.9 minutes per scan session. No adverse events were specifically attributed to intraoperative OCT scanning during the procedure. Conclusions Intraoperative OCT is feasible for numerous anterior and posterior segment ophthalmic surgical procedures. A microscope mounted intraoperative OCT system provided efficient imaging during operative procedures. The information gained from intraoperative OCT may impact surgical decision-making in a high frequency of both anterior and posterior segment cases.

IMPORTANCE Optical coherence tomography (OCT) has transformed the clinical management of a myriad of ophthalmic conditions. Applying OCT to ophthalmic surgery may have implications for surgical decision making and patient outcomes.OBJECTIVE To assess the feasibility and effect on surgical decision making of a microscope-integrated intraoperative OCT (iOCT) system. DESIGN, SETTING, AND PARTICIPANTSReport highlighting the 1-year results (March 2014-February 2015 of the RESCAN 700 portion of the DISCOVER (Determination of Feasibility of Intraoperative Spectral Domain Microscope Combined/Integrated OCT Visualization During En Face Retinal and Ophthalmic Surgery) study, a single-site, multisurgeon, prospective consecutive case series regarding this investigational device. Participants included patients undergoing ophthalmic surgery. Data on clinical characteristics were collected, and iOCT was performed during surgical milestones, as directed by the operating surgeon. A surgeon questionnaire was issued to each surgeon and was completed after each case to evaluate the role of iOCT during surgery and its particular role in select surgical procedures. MAIN OUTCOMES AND MEASURESPercentage of cases with successful acquisition of iOCT (ie, feasibility). Percentage of cases in which iOCT altered surgical decision making (ie, utility). RESULTSDuring year 1 of the DISCOVER study, a total of 227 eyes (91 anterior segment cases and 136 posterior segment cases) underwent imaging with the RESCAN 700 system. Successful imaging (eg, the ability to acquire an OCT image of the tissue of interest) was obtained for 224 of 227 eyes (99% [95% CI, 98%-100%]). During lamellar keratoplasty, the iOCT data provided information that altered the surgeon's decision making in 38% of the cases (eg, complete graft apposition when the surgeon believed there was interface fluid). In membrane peeling procedures, iOCT information was discordant with the surgeon's impression of membrane peel completeness in 19% of cases (eg, lack of residual membrane or presence of occult membrane), thus affecting additional surgical maneuvers. CONCLUSIONS AND RELEVANCEThe DISCOVER study demonstrates the feasibility of real-time iOCT with a microscope-integrated iOCT system for ophthalmic surgery. The information gained from iOCT appears to allow surgeons to assess subtle details in a unique perspective from standard en face visualization, which can affect surgical decision making some of the time, although the effect of these changes in decision making on outcomes remains unknown. A prospective randomized masked trial is needed to confirm these results.

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Polymerase chain reaction testing of ocular fluid is useful in supporting a clinical diagnosis of ARN, but treatment should not be delayed while awaiting PCR results. Initial oral or intravenous antiviral therapy is effective in treating ARN. The adjunctive use of intravitreal foscarnet may be more effective than systemic therapy alone. The role of prophylactic laser retinopexy or early PPV is unknown at this time.

Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metastatic death. Class 1 tumors have a low risk and class 2 tumors a high risk for metastatic death. Here, we used genes that discriminate these tumor classes to identify biological correlates of the aggressive class 2 signature. A search for Gene Ontology categories enriched in our classdiscriminating gene list revealed a global down-regulation of neural crest and melanocyte-specific genes and an upregulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up-regulation of the epithelial adhesion molecule E-cadherin, colocalization of E-cadherin and B-catenin to the plasma membrane, and formation of cell-cell adhesions and acinar structures. One of our top class-discriminating genes was the helix-loop-helix inhibitor ID2, which was strongly down-regulated in class 2 tumors. The class 2 phenotype could be recapitulated by eliminating Id2 in cultured class 1 human uveal melanoma cells and in a mouse ocular melanoma model. Id2 seemed to suppress the epithelial-like class 2 phenotype by inhibiting an activator of the E-cadherin promoter. Consequently, Id2 loss triggered up-regulation of E-cadherin, which in turn promoted anchorage-independent cell growth, a likely antecedent to metastasis. These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention.

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High-quality retinal imaging is feasible with an MMOCT system. Intraoperative imaging with model eyes provides high-resolution depth information including visualization of the instrument and intraoperative tissue manipulation. This study demonstrates a key component of an interactive platform that could provide enhanced information for the vitreoretinal surgeon.