Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Drupal 7 module development: create your own Drupal 7 modules from scratch

Create your own Drupal 7 modules from scratc

Ideological Challenges to Changing Strategic Orientation in Commodity Agriculture

Why do some firms not change their strategic orientation despite economic incentives to do so? Most current literature on changing strategic orientations has focused on an antecedents and outcomes approach to business orientations. Intimated, but rarely addressed, are the notions that (1) strategic orientations may be thought of as ideologies and (2) such ideologies are likely to contend with each other. Taking such a perspective may be helpful in discussing why it is challenging to transition to more sustainable strategic orientations even in the presence of financial incentives to do so. In assessing the transition to organic production and marketing in a commodity agriculture context, the authors find that contending ideologies restrict its adoption. In addition, they suggest that strategic orientations are not adopted or contested solely within firms but also among them. The authors find that ideological contestation among firms in this context takes the form of a marketplace drama between a chemical, productionist orientation and an organic orientation in which protagonists mobilize several forms of legitimacy

Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

© 2018 American Academy of Ophthalmology Purpose: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. Design: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. Participants: Participants with available plasma samples (N = 436). Methods: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. Main Outcome Measures: Changes in the natural log (ln) of plasma VEGF levels. Results: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61 pg/ml, −0.31±0.54 pg/ml, and −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were −0.01 (−0.12 to +0.10; P = 0.89), −0.31 (−0.44 to −0.18; P \u3c 0.001), and −0.30 (−0.43 to −0.18; P \u3c 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (−0.23 [−0.38 to −0.09]; P \u3c 0.001); the difference between aflibercept and ranibizumab was −0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. Conclusions: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay\u27s ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted