Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type ...patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%.
We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation–positive, advanced NSCLC and PD-L1–positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab.
Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern.
Pembrolizumab’s lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.
A central tenet of close-contact or respiratory infection epidemiology is that infection patterns within human populations are related to underlying patterns of social interaction. Until recently, ...few researchers had attempted to quantify potentially infectious encounters made between people. Now, however, several studies have quantified social mixing behaviour, using a variety of methods. Here, we review the methodologies employed, suggest other appropriate methods and technologies, and outline future research challenges for this rapidly advancing field of research.
Obliterative bronchiolitis (OB) is the key impediment to the long‐term survival of lung transplant recipients and the lack of a robust preclinical model precludes examining OB immunopathogenesis. In ...the current study, lungs from C57BL/10 H‐2b mice that are MHC compatible, but minor histocompatability antigen incompatible, were transplanted into C57BL/6 mice. Histological features and cytokine profiles of OB were assessed. Moderate rejection (grade A3) developed by day 14, with evidence of OB at that time point. At 21 days, OB was present in 55% of grafts and moderate to severe rejection (grade A3‐A4) was present in all mice. At 28 days, OB was present in 44% of mice and severe rejection (grade A4) was present in all. IL‐17A, but not IL‐17F, splenic mRNA transcripts and serum protein levels were increased only in mice that developed OB, whereas IL‐10 transcripts and protein were increased only in non‐OB mice. Neutralizing IL‐17 prevented OB, down regulated acute rejection, and upregulated systemic IL‐10. Collectively, these data show that transplantation of minor histoincompatible lungs from C57BL/10 mice into C57BL/6 mice results in a highly reproducible preclinical model of OB. In addition, these data indicate that neutralizing IL‐17A or augmenting IL‐10 could be therapeutic interventions to prevent OB.
This article reports on an orthotopic mouse lung transplant that develops obliterative bronchiolitis, and shows that neutralizing IL‐17A prevents this lesion. See editorial by Kreisel et al on page 882.
Isoprene surface ocean concentrations and vertical distribution, atmospheric mixing ratios, and calculated sea‐to‐air fluxes spanning approximately 125° of latitude (80°N–45°S) over the Arctic and ...Atlantic Oceans are reported. Oceanic isoprene concentrations were associated with a number of concurrently monitored biological variables including chlorophyll a (Chl a), photoprotective pigments, integrated primary production (intPP), and cyanobacterial cell counts, with higher isoprene concentrations relative to all respective variables found at sea surface temperatures greater than 20°C. The correlation between isoprene and the sum of photoprotective carotenoids, which is reported here for the first time, was the most consistent across all cruises. Parameterizations based on linear regression analyses of these relationships perform well for Arctic and Atlantic data, producing a better fit to observations than an existing Chl a‐based parameterization. Global extrapolation of isoprene surface water concentrations using satellite‐derived Chl a and intPP reproduced general trends in the in situ data and absolute values within a factor of 2 between 60% and 85%, depending on the data set and algorithm used.
Key Points
Isoprene water concentrations correlated well with Chl a, primary production, photoprotective pigments, and cyanobacterial cell counts
Higher isoprene concentrations relative to all respective variables were found at sea surface temperatures greater than 20°C
Predicted isoprene water concentrations based on satellite Chl a compared well with observations
The prompt optical emission that arrives with the γ-rays from a cosmic γ-ray burst (GRB) is a signature of the engine powering the burst, the properties of the ultra-relativistic ejecta of the ...explosion, and the ejecta's interactions with the surroundings. Until now, only GRB 990123 had been detected at optical wavelengths during the burst phase. Its prompt optical emission was variable and uncorrelated with the prompt γ-ray emission, suggesting that the optical emission was generated by a reverse shock arising from the ejecta's collision with surrounding material. Here we report prompt optical emission from GRB 041219a. It is variable and correlated with the prompt γ-rays, indicating a common origin for the optical light and the γ-rays. Within the context of the standard fireball model of GRBs, we attribute this new optical component to internal shocks driven into the burst ejecta by variations of the inner engine. The correlated optical emission is a direct probe of the jet isolated from the medium. The timing of the uncorrelated optical emission is strongly dependent on the nature of the medium.
This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at ...Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.
We report abundances of elements from 26Fe to 34Se in the cosmic radiation measured during fifty days of exposure of the Trans-Iron Galactic Element Recorder (TIGER) balloon-borne instrument. These ...observations add support to the concept that the bulk of cosmic ray acceleration takes place in OB associations, and they further support cosmic ray acceleration models in which elements present in interstellar grains are accelerated preferentially compared with those found in interstellar gas.
This work reports a precise measurement of the reactor antineutrino flux using 2.2 million inverse beta decay (IBD) events collected with the Daya Bay near detectors in 1230 days. The dominant ...uncertainty on the neutron detection efficiency is reduced by 56% with respect to the previous measurement through a comprehensive neutron calibration and detailed data and simulation analysis. The new average IBD yield is determined to be (5.91±0.09)×10−43 cm2/fission with total uncertainty improved by 29%. The corresponding mean fission fractions from the four main fission isotopes U235, U238, Pu239, and Pu241 are 0.564, 0.076, 0.304, and 0.056, respectively. The ratio of measured to predicted antineutrino yield is found to be 0.952±0.014±0.023 (1.001±0.015±0.027) for the Huber-Mueller (ILL-Vogel) model, where the first and second uncertainty are experimental and theoretical model uncertainty, respectively. This measurement confirms the discrepancy between the world average of reactor antineutrino flux and the Huber-Mueller model.
Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be ...defined.
To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia.
Positron emission tomography (PET) studies of (18)Ffluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000.
Regional distribution of (18)Ffluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses.
Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001).
In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.
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