Ruixue Wang

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.

We surveyed the genetic diversity among avian influenza virus (AIV) in wild birds, comprising 167 complete viral genomes from 14 bird species sampled in four locations across the United States. These isolates represented 29 type A influenza virus hemagglutinin (HA) and neuraminidase (NA) subtype combinations, with up to 26% of isolates showing evidence of mixed subtype infection. Through a phylogenetic analysis of the largest data set of AIV genomes compiled to date, we were able to document a remarkably high rate of genome reassortment, with no clear pattern of gene segment association and occasional inter-hemisphere gene segment migration and reassortment. From this, we propose that AIV in wild birds forms transient "genome constellations," continually reshuffled by reassortment, in contrast to the spread of a limited number of stable genome constellations that characterizes the evolution of mammalian-adapted influenza A viruses.

2 Background: Patients with advanced esophageal cancer after first-line chemotherapy (chemo) have a poor prognosis and limited treatment options. We present results of the phase 3 KEYNOTE-181 study of pembrolizumab vs investigator’s choice chemo as second-line therapy for patients (pts) with advanced/metastatic squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ (NCT02564263). Methods: Eligible pts were randomized 1:1 to pembrolizumab 200 mg Q3W for up to 2 years or investigator’s choice chemo of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (SCC vs adenocarcinoma) and region (Asia vs rest of world). Primary end points were OS in the SCC, PD-L1 combined positive score (CPS) ≥10, and ITT populations. Results: 628 pts were randomized including 401 with SCC, and 222 with CPS ≥10. As of October 15, 2018, the median follow-up was 7.1 mo (pembrolizumab) vs 6.9 mo (chemo). Pembrolizumab was superior to chemo for OS in CPS ≥10 (N=222; median 9.3 vs 6.7 mo; HR 0.69; 95% CI 0.52-0.93; P=0.0074). The 12-mo OS rate in pts with CPS ≥10 was 43% vs 20%. There was clinically meaningful improvement in OS with pembrolizumab vs chemo in pts with SCC, but this was not statistically significant per prespecified boundaries (N=401; 8.2 mo vs 7.1 mo; HR 0.78; 95% CI 0.63-0.96; P=0.0095). In the ITT population, while directionally favorable, the difference in OS was not statistically significant (N=628; 7.1 mo vs 7.1 mo; HR 0.89; 95% CI 0.75-1.05; P=0.0560). Fewer pts had any-grade (64% vs 86%) or grade 3-5 (18% vs 41%) drug-related AEs with pembrolizumab vs chemo. Conclusion: Pembrolizumab significantly improved OS compared with chemo as second-line therapy for advanced esophageal cancer with PD-L1 CPS ≥10, with a more favorable safety profile. These data support pembrolizumab as a new second-line standard of care for esophageal cancer with PD-L1 CPS ≥10. The phase 3 KEYNOTE-590 study of pembrolizumab plus chemo as first-line therapy for advanced esophageal cancer is ongoing (NCT03189719). Clinical trial information: NCT02564263.

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10(7)pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation.