Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

PURPOSE: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). METHODS: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. RESULTS: Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. CONCLUSIONS: Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients

Ocular injuries from paintball pellets

Objective: To evaluate the ocular effects of blunt trauma due to injury from a paintball pellet. Design: Noncomparative case series. Participants: Thirteen patients who suffered ocular injury from paintballs are described. The patients presented to six different civilian and military emergency departments in tertiary care medical centers. Intervention: Patients were treated for the ocular injury. Main Outcome Measures: Patients were evaluated for initial and final visual acuity. The reason for persistent loss of vision was delineated. Results: There were 12 males and I female with an average age of 21 years (range, 12-33 years). Eleven of the 13 had no ocular protection at the time of the ocular injury. On initial examination, nine patients had a hyphema, nine had a vitreous hemorrhage, six had a retinal tear or detachment, three had corneal or corneal-scleral ruptures, and one had traumatic optic neuropathy. The final visual acuity was 20/40 or better in two patients, 20/50 to 20/150 in three patients, and 20/200 or worse in eight patients. Conclusion: Injuries due to paintball pellets can result in severe ocular damage and significant loss of vision. Eyecare professionals should be aware of the risks of this sport and must strongly advise participants to wear adequate protection when involved in this activity

Integrative radiogenomic profiling of squamous cell lung cancer

Radiation therapy is one of the mainstays of anti-cancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is not well defined. Here we report the development of a high-throughput platform for measuring radiation survival in vitro and its validation by comparison to conventional clonogenic radiation survival analysis. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiation therapy, to identify parameters that predict radiation sensitivity. We confirmed that activation of NFE2L2, a frequent event in lung squamous cancers, correlates with radiation resistance. NFE2L2 knockdown conferred both growth arrest and radiation sensitivity in a cell line with NFE2L2 mutation but not in a wild type cell line. An expression-based, in silico screen nominated inhibitors of PI3K as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1 mutant cells to radiation. To assess determinants of radiation sensitivity further, we combined results from this high-throughput assay with single-sample gene set enrichment analysis (ssGSEA) of gene expression data. The resulting analysis identified pathways implicated in cell survival, genotoxic stress, detoxification, and innate and adaptive immunity as key correlates of radiation sensitivity. The integrative, high-throughput approach shown here for large-scale profiling of radiation survival and genomic features of solid-tumor derived cell lines should facilitate tumor radiogenomics and the discovery of radiation sensitizers and protective agents

Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).

PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants