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.

Two-year results for ranibizumab for radiation retinopathy (RRR): a randomized, prospective trial.

PURPOSE: To assess the efficacy of a treat-and-extend strategy with intravitreal ranibizumab for radiation-related macular edema. METHODS: Forty eyes with radiation-induced macular edema and decreased visual acuity were enrolled in the phase IIb, prospective clinical trial and randomized into 3 cohorts: (A) monthly ranibizumab, (B) monthly ranibizumab with targeted retinal photocoagulation (TRP), or (C) as-needed ranibizumab and TRP. In year 2, all subjects entered a treat-and-extend protocol for ranibizumab. The primary outcome measure was mean change in early treatment diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) from baseline. RESULTS: Through year 1, the mean change in ETDRS BCVA was significantly different between the three cohorts (p < 0.001); cohort A saw the largest gain with + 4.0 letters. Significant anatomic improvements were also seen in all cohorts. Comparatively, through year 2, cohorts A, B, and C had a mean change in ETDRS BCVA of - 1.9, - 3.9, and + 1.3 letters, respectively; additionally, no significant differences were found in absolute ETDRS BCVA across time (ANOVA, p = 0.123). Overall, 90% of eyes maintained VA 20/200 or better and 33.3% of subjects gained at least one line of vision. There were no significant differences in mean central macular thickness for any cohort compared to baseline (p = 0.09). The presence of retinal hemorrhage and intraretinal exudates stayed consistent from year 1 to year 2 for all cohorts. CONCLUSIONS: Among eyes with radiation-related macular edema, a treat-and-extend regimen with ranibizumab may not result in as many visual and anatomic improvements as monthly injections. However, treat-and-extend still may prevent serious visual complications compared to historical controls. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02222610.

Agility: What It Is, How to Measure It, and How to Use It.

A positive and expected by-product of a well-programmed instructional sequence is an escalation of learning, where skills are acquired more quickly as teaching goes on. Despite the importance of this effect in behavior analysis and education, techniques for detecting and analyzing it are rarely observed in practice settings. A behavioral approach to this phenomenon is rooted in the term agility, which has persisted in the precision-teaching community as a description of desirable acquisition patterns. Precision teachers have long carried forward a loose definition of agility as "celerating celerations." Although this definition might succeed in generally orienting practitioners toward the goal of helping people acquire new skills more quickly, its lack of technical specificity has hindered efforts to fully integrate such analyses into practice. In this article, the authors define agility and distinguish it from other concepts common to education and behavior analysis. Further, a tutorial for quantifying and analyzing agility using frequency, celeration, and bounce multipliers is presented in detail. Finally, the practical implications afforded by analyses of agility are delineated.

Randomized Trial of Monthly Versus As-Needed Intravitreal Ranibizumab for Radiation Retinopathy-Related Macular Edema: 1-Year Outcomes.

PURPOSE: To assess efficacy of intravitreal ranibizumab injections and targeted panretinal photocoagulation (TRP) for radiation retinopathy-related macular edema. DESIGN: Phase IIb, prospective, randomized clinical trial. METHODS: Setting: Multicenter. SUBJECTS: Forty eyes in 40 treatment-naïve patients with radiation-induced macular edema and a resulting decrease in visual acuity ranging between 20/25 and 20/400 (Snellen equivalent). INTERVENTION: Patients either received intravitreal 0.5 mg ranibizumab monthly, monthly ranibizumab with TRP, or 3 monthly ranibizumab (loading doses) followed by as-needed (PRN) injections and TRP. After week 52, all subjects entered a treat-and-extend protocol for ranibizumab. MainOutcomeMeasures: Mean Early Treatment Diabetic Maculopathy Study (ETDRS) BCVA change from baseline. RESULTS: Mean patient age was 57 years (range, 22-80 years), ETDRS BCVA was 56.7 letters (20/74 Snellen equivalent), and central macular thickness (CMT) was 423 µm (range, 183-826 µm). Thirty-seven patients completed the month 12 visit (92.5%), at which time the change in mean BCVA was +4.0 letters, -1.9 letters, and +0.9 letters in the monthly, monthly plus laser, and PRN plus laser cohorts, respectively. There was a significant difference in mean BCVA at 1 year among all 3 cohorts (P < .001), as well as between cohorts in pairwise comparisons, with the most significant gains in the monthly group. A total of 82.5% of the patients retained visual acuity of 20/200 or better, and 20.0% improved 10 or more ETDRS letters. CONCLUSIONS: Ranibizumab may improve vision and anatomy in patients with radiation retinopathy-related macular edema and prevent vision loss through 48 weeks of therapy. Monthly injections were more effective than as-needed approach, and the addition of TRP yielded no therapeutic benefits.

Integrating Phase Change Lines and Labels into Graphs in Microsoft Excel®.

Creating phase change lines and their corresponding labels in Microsoft Excel® remains a difficulty for many behavior analysts who want these display features to be integrated into the graph itself. Previous methods designed to address this issue have had limited utility across the types of data sets commonly analyzed by behavior analysts. The purpose of this article is to provide a fully functional method for integrating phase change lines and labels into Microsoft Excel® line graphs. This method is a combination of previous recommendations and allows for easy integration of new data and exportation of graphical displays to other software programs (e.g., Microsoft Word® and PowerPoint®).

Analysis of the complete plastomes of three species of Membranoptera (Ceramiales, Rhodophyta) from Pacific North America.

Next generation sequence data were generated and used to assemble the complete plastomes of the holotype of Membranoptera weeksiae, the neotype (designated here) of M. tenuis, and a specimen examined by Kylin in making the new combination M. platyphylla. The three plastomes were similar in gene content and length and showed high gene synteny to Calliarthron, Grateloupia, Sporolithon, and Vertebrata. Sequence variation in the plastome coding regions were 0.89% between M. weeksiae and M. tenuis, 5.14% between M. weeksiae and M. platyphylla, and 5.18% between M. tenuis and M. platyphylla. We were unable to decipher the complete mitogenomes of the three species due to low coverage and structural problems; however, we assembled and analyzed, the cytochrome oxidase I, II, and III loci and found that M. weeksiae and M. tenuis differed in sequence by 1.3%, M. weeksiae and M. platyphylla by 8.4%, and M. tenuis and M. platyphylla by 8.1%. Evaluation of standard marker genes indicated that sequences from the rbcL, RuBisCO spacer, and CO1 genes closely approximated the pair-wise genetic distances observed between the plastomes of the three species of Membranoptera. A phylogenetic tree based on rbcL sequences showed that M. tenuis and M. weeksiae were sister taxa. Short rbcL sequences were obtained from type specimens of M. dimorpha, M. multiramosa, and M. edentata and confirmed their conspecificity with M. platyphylla. The data support the recognition of three species of Membranoptera occurring south of Alaska: M. platyphylla, M. tenuis, and M. weeksiae.

Initial Experiences with Endovascular Management of Submassive Pulmonary Embolism: Is It Safe?

BACKGROUND: Interventional strategies for massive and submassive pulmonary embolism (smPE) have historically included either systematic intravenous thrombolytic alteplase or surgical embolectomy, both of which are associated with significant morbidity and mortality. However, with the advent of endovascular techniques, recent studies have suggested that an endovascular approach to the treatment of acute smPE may be both safe and effective with excellent outcomes. The purpose of this study was to evaluate the outcomes of patients who have undergone catheter-directed thrombolysis (CDT) for smPE at our institution in an effort to determine the safety of the procedure. METHODS: A retrospective review was conducted from December 2012 to June 2015 to identify patients whom underwent CDT in the treatment of a smPE at our institution. Primary measure was safety of the procedure. Outcome variables were classified as serious or minor adverse events. Serious events included death, stroke, myocardial infarction, and bleeding complications requiring surgical intervention or transfusion. Minor events included groin hematoma, development of arteriovenous fistula, and bleeding requiring interruption or cessation of CDT. In addition, a secondary measure included effectiveness of CDT based on preinterventional and postinterventional clinical examination and radiographic findings. RESULTS: A total of 27 patients undergoing CDT for smPE at our institution were evaluated. The standard procedure included access via bilateral femoral veins and placement of bilateral EKOS catheters for ultrasound-assisted thrombolysis (USAT), with Activase (alteplase) at 1 mg per hour in each catheter for a total of 12 hr. There were no serious adverse events and only 4 patients (14.8%) had minor events, of which only 1 patient required premature termination of therapy due to bleeding resulting in a 3.7% clinically relevant bleeding rate. In addition, a reduction in a right-to-left ventricular end-diastolic diameter ratio (RV/LV ratio) on follow-up imaging was observed in each of the 18 patients where preinterventional and postinterventional imaging was available. Likewise, via chart review, all patients reported significant cessation of shortness-of-breath and resolution of chest pain with associated decrease in supplemental oxygen requirement. CONCLUSIONS: Current evidence, the majority of which has been industry funded, suggests that CDT should be considered as the first-line therapy for smPE. Our experience, in this single-institution retrospective review, demonstrates that CDT with USAT in the treatment of smPE is safe, while providing immediate resolution of both RV strain and clinical symptoms such as shortness-of-breath and chest pain. We hope that these data will allow other institutions to consider CDT as a plausible option in the treatment of smPE.

Retinal Astrocytic Hamartoma Arises in Nerve Fiber Layer and Shows "Moth-Eaten" Optically Empty Spaces on Optical Coherence Tomography.

PURPOSE: To evaluate the specific spectral-domain (SD) optical coherence tomography (OCT) features of retinal astrocytic hamartoma (RAH) and the relationship of these features with tumor size and location. DESIGN: Retrospective case series. PARTICIPANTS: Forty-seven eyes of 42 patients with RAH. METHODS: All patients with clinically confirmed RAH were imaged with fundus photography and SD OCT. MAIN OUTCOME MEASURES: Precise OCT location of RAH features and the relationship of patient age, visual acuity, tumor size, and tumor location to the presence and size of intralesional optically empty spaces (OESs), appearing as so-called moth-eaten spaces. RESULTS: Of 42 patients with RAH, 36 (86%) had unilateral disease and 6 (14%) had bilateral disease. Systemic tuberous sclerosis complex was present in 8 patients (19%). The largest tumor (per eye) demonstrated a mean basal diameter of 3.0 mm (median, 2.0 mm) and a mean thickness of 1.9 mm (median, 1.8 mm). The mean tumor proximity to the foveola was 3.0 mm and that to the optic disc was 1.8 mm. Related features included subretinal fluid (n = 9; 19%), cystoid retinal edema (n = 6; 13%), retinal traction (n = 11; 23%), intralesional cavities (n = 28; 60%), and intralesional calcification (n = 29; 62%). On SD OCT, the tumor epicenter was in the nerve fiber layer (n = 47; 100%), with all other retinal layers appearing thinned or compressed. The tumor showed OESs (n = 43; 91%), representing intralesional calcification or cavitation, and each OES showed a mean diameter of 327 µm (median, 200 µm). When comparing the number of OESs per SD OCT cut through the mass, we found no relationship with patient age, tumor diameter and thickness, distance to the foveola or optic disc, tumor calcification, central macular thickness, or logarithm of the minimum angle of resolution (logMAR) visual acuity. However, a correlation of OES number with OES size (P = 0.01) and macular tumor location (P = 0.03) was found. Further analysis demonstrated OES size correlated with tumor basal diameter (P < 0.01), tumor thickness (P < 0.01), tumor calcification (P = 0.01), and logMAR visual acuity (P = 0.02). CONCLUSIONS: Retinal astrocytic hamartomas arose in the nerve fiber layer in every case and demonstrated moth-eaten OES, related to intrinsic calcification or cavitation, in 91% of cases. Macular tumors have a greater number of OESs, whereas larger calcified tumors have larger OES diameter.

NONINFECTIOUS VITRITIS AFTER INTRAVITREAL INJECTION OF ANTI-VEGF AGENTS: Variations in Rates and Presentation by Medication.

PURPOSE: The purpose of this study was to describe and compare the rates and characteristics of noninfectious vitritis after intravitreal injection of bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY). METHODS: A retrospective case series evaluated intravitreal injections from 2006 to 2013. Cases of inflammatory response were separated into culture-positive endophthalmitis, noninfectious vitritis (not treated with intravitreal antibiotics), and indeterminate. Noninfectious cases were analyzed for rate, presentation, and clinical course. RESULTS: A total of 66,356 bevacizumab, 26,161 ranibizumab, and 8071 aflibercept injections were screened. The rates of noninfectious vitritis were 0.10% (67 cases) for bevacizumab, 0.02% (6 cases) for ranibizumab, and 0.16% (13 cases) for aflibercept. The differences were statistically significant based on Chi-square analysis (P < 0.001). Mean differences in visual decline were not significant by Kruskal-Wallis analysis (P = 0.12), but the percentage of patients with any visual decline did vary by medication according to Fisher exact test (P < 0.05). The percentage of patients with complaints of pain, blurred vision, and subjective floaters was not significantly different by medication based on Fisher exact testing (P = 0.2, P = 0.18, P = 0.16, respectively). Bevacizumab and aflibercept cases tended to present in separate chronological clusters. CONCLUSION: The results suggest a difference in rates of noninfectious vitritis for antivascular endothelial growth factor medications. Many cases tended to cluster instead of occurring at a consistent rate each year.

Optimal number of angle images for calculating anterior angle volume and iris volume measurements.

PURPOSE: We determined the optimal number of angle images required to obtain reliable measurements of trabecular-iris circumferential volume (TICV) and iris volume (IV) using swept-source Fourier domain anterior segment optical coherence tomography (SSFD-ASOCT) scans in narrow angle eyes. METHODS: Scleral spur landmarks (SSL) were manually identified on ASOCT angle images from 128 meridians from each of 24 eyes with chronic primary angle closure (PAC) spectrum of disease. The anterior and posterior corneal curves, and the anterior and posterior iris surfaces were identified automatically by the anterior chamber analysis and interpretation (ACAI) software, then manually examined and edited by the reader if required. Trabecular-iris circumferential volume at 750 µm from SSL (TICV750) and IV were subsequently calculated using varying numbers of angle images. Threshold error was determined to be less than the lower 95% confidence limit of mean absolute percent error (MAPE) of the change in TICV or IV resulting from laser peripheral iridotomy, which would be 17% for TICV and 5% for IV, based on previous studies. The optimal number of angle images was the smallest number of images where MAPE was less than this threshold for TICV and IV. RESULTS: A total of 32 equally-spaced angle images (16 meridians) was required to estimate TICV750 and 16 angle images (8 meridians) to estimate IV. Both were within 4.6% and 1.6% of MAPE, respectively. CONCLUSIONS: It is possible to determine TICV and IV parameters reliably in narrow angles without evaluating all 128 meridians obtained with SSFD-ASOCT.

Fine mapping of V(D)J recombinase mediated rearrangements in human lymphoid malignancies.

BACKGROUND: Lymphocytes achieve diversity in antigen recognition in part by rearranging genomic DNA at loci encoding antibodies and cell surface receptors. The process, termed V(D)J recombination, juxtaposes modular coding sequences for antigen binding. Erroneous recombination events causing chromosomal translocations are recognized causes of lymphoid malignancies. Here we show a hybridization based method for sequence enrichment can be used to efficiently and selectively capture genomic DNA adjacent to V(D)J recombination breakpoints for massively parallel sequencing. The approach obviates the need for PCR amplification of recombined sequences. RESULTS: Using tailored informatics analyses to resolve alignment and assembly issues in these repetitive regions, we were able to detect numerous recombination events across a panel of cancer cell lines and primary lymphoid tumors, and an EBV transformed lymphoblast line. With reassembly, breakpoints could be defined to single base pair resolution. The observed events consist of canonical V(D)J or V-J rearrangements, non-canonical rearrangements, and putatively oncogenic reciprocal chromosome translocations. We validated non-canonical and chromosome translocation junctions by PCR and Sanger sequencing. The translocations involved the MYC and BCL-2 loci, and activation of these was consistent with histopathologic features of the respective B-cell tumors. We also show an impressive prevalence of novel erroneous V-V recombination events at sites not incorporated with other downstream coding segments. CONCLUSIONS: Our results demonstrate the ability of next generation sequencing to describe human V(D)J recombinase activity and provide a scalable means to chronicle off-target, unexpressed, and non-amplifiable recombinations occurring in the development of lymphoid cancers.

Stimulus specificity and dishabituation of operant responding in humans.

Habituation has recently been addressed within the operant conditioning paradigm. While the literature on this topic is growing, the examination of dishabituation, a fundamental characteristic of habituation, remains limited. This study expanded research on habituation of operant responding in non-human animals to research involving humans. Specifically, dishabituation and stimulus specificity were examined under a variety of conditions involving changes in the reinforcer type, reinforcement schedule, reinforcer amount, and selected properties of the antecedent stimuli for a computerized task with 46 undergraduate students. An additional 3 participants were exposed to a control condition. Evaluation of within session patterns of responding indicates that the introduction of stimulus changes into the operant context reliably produced dishabituation of operant responding in humans.