To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III ...non-small-cell lung cancer (NSCLC) and SCLC.
ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.
The literature search identified 14 relevant studies to inform the evidence base for this guideline.
Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.
Ligand-gated channels, in which a substrate transport pathway is formed as a result of the binding of a small-molecule chemical messenger, constitute a diverse class of membrane proteins with ...important functions in prokaryotic and eukaryotic organisms. Despite their widespread nature, no ligand-gated channels have yet been found within the outer membrane (OM) of Gram-negative bacteria. Here we show, using in vivo transport assays, intrinsic tryptophan fluorescence and X-ray crystallography, that high-affinity (submicromolar) substrate binding to the OM long-chain fatty acid transporter FadL from Escherichia coli causes conformational changes in the N terminus that open up a channel for substrate diffusion. The OM long-chain fatty acid transporter FadL from E. coli is a unique paradigm for OM diffusion-driven transport, in which ligand gating within a β-barrel membrane protein is a prerequisite for channel formation.
Membrane proteins that transport hydrophobic compounds have important roles in multi-drug resistance and can cause a number of diseases, underscoring the importance of protein-mediated transport of ...hydrophobic compounds. Hydrophobic compounds readily partition into regular membrane lipid bilayers, and their transport through an aqueous protein channel is energetically unfavourable. Alternative transport models involving acquisition from the lipid bilayer by lateral diffusion have been proposed for hydrophobic substrates. So far, all transport proteins for which a lateral diffusion mechanism has been proposed function as efflux pumps. Here we present the first example of a lateral diffusion mechanism for the uptake of hydrophobic substrates by the Escherichia coli outer membrane long-chain fatty acid transporter FadL. A FadL mutant in which a lateral opening in the barrel wall is constricted, but which is otherwise structurally identical to wild-type FadL, does not transport substrates. A crystal structure of FadL from Pseudomonas aeruginosa shows that the opening in the wall of the beta-barrel is conserved and delineates a long, hydrophobic tunnel that could mediate substrate passage from the extracellular environment, through the polar lipopolysaccharide layer and, by means of the lateral opening in the barrel wall, into the lipid bilayer from where the substrate can diffuse into the periplasm. Because FadL homologues are found in pathogenic and biodegrading bacteria, our results have implications for combating bacterial infections and bioremediating xenobiotics in the environment.
The current literature provides compelling evidence suggesting that an eddy-resolving (as opposed to eddy-permitting or eddy-parameterized) ocean component model will significantly impact the ...simulation of the large-scale climate, although this has not been fully tested to date in multi-decadal global coupled climate simulations. The purpose of this paper is to examine how resolved ocean fronts and eddies impact the simulation of large-scale climate. The model used for this study is the NCAR Community Climate System Model version 3.5 (CCSM3.5)—the forerunner to CCSM4. Two experiments are reported here. The control experiment is a 155-year present-day climate simulation using a 0.5° atmosphere component (zonal resolution 0.625 meridional resolution 0.5°; land surface component at the same resolution) coupled to ocean and sea-ice components with zonal resolution of 1.2° and meridional resolution varying from 0.27° at the equator to 0.54° in the mid-latitudes. The second simulation uses the same atmospheric and land-surface models coupled to eddy-resolving 0.1° ocean and sea-ice component models. The simulations are compared in terms of how the representation of smaller scale features in the time mean ocean circulation and ocean eddies impact the mean and variable climate. In terms of the global mean surface temperature, the enhanced ocean resolution leads to a ubiquitous surface warming with a global mean surface temperature increase of about 0.2 °C relative to the control. The warming is largest in the Arctic and regions of strong ocean fronts and ocean eddy activity (i.e., Southern Ocean, western boundary currents). The Arctic warming is associated with significant losses of sea-ice in the high-resolution simulation. The sea surface temperature gradients in the North Atlantic, in particular, are better resolved in the high-resolution model leading to significantly sharper temperature gradients and associated large-scale shifts in the rainfall. In the extra-tropics, the interannual temperature variability is increased with the resolved eddies, and a notable increases in the amplitude of the El Niño and the Southern Oscillation is also detected. Changes in global temperature anomaly teleconnections and local air-sea feedbacks are also documented and show large changes in ocean–atmosphere coupling. In particular, local air-sea feedbacks are significantly modified by the increased ocean resolution. In the high-resolution simulation in the extra-tropics there is compelling evidence of stronger forcing of the atmosphere by SST variability arising from ocean dynamics. This coupling is very weak or absent in the low-resolution model.
Accurate mass determination of clusters of galaxies is crucial if they are to be used as cosmological probes. However, there are some discrepancies between cluster masses determined based on ...gravitational lensing and X-ray observations assuming strict hydrostatic equilibrium (i.e., the equilibrium gas pressure is provided entirely by thermal pressure). Cosmological simulations suggest that turbulent gas motions remaining from hierarchical structure formation may provide a significant contribution to the equilibrium pressure in clusters. We analyze a sample of massive clusters of galaxies drawn from high-resolution cosmological simulations and find a significant contribution (20%-45%) from non-thermal pressure near the center of relaxed clusters, and, in accord with previous studies, a minimum contribution at about 0.1 R vir, growing to about 30%-45% at the virial radius, R vir. Our results strongly suggest that relaxed clusters should have significant non-thermal support in their core region. As an example, we test the validity of strict hydrostatic equilibrium in the well-studied massive galaxy cluster A1689 using the latest high-resolution gravitational lensing and X-ray observations. We find a contribution of about 40% from non-thermal pressure within the core region of A1689, suggesting an alternate explanation for the mass discrepancy: the strict hydrostatic equilibrium is not valid in this region.
Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined ...with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer.
Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response.
From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study.
HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.
Cold dark matter (CDM) hierarchical structure formation models predict the existence of large-scale accretion shocks between the virial and turnaround radii of clusters of galaxies. Kocsis et al. ...suggest that the Sunyaev-Zel'dovich signal associated with such shocks might be observable with the next generation radio interferometer, ALMA (Atacama Large Millimeter Array). We study the three-dimensional distribution of accretion shocks around individual clusters of galaxies drawn from adaptive mesh refinement (AMR) and smoothed particle hydrodynamics simulations of CDM (dark energy dominated CDM) models. In relaxed clusters, we find two distinct sets of shocks. One set ('virial shocks'), with Mach numbers of 2.5-4, is located at radii 0.9-1.3 R vir, where R vir is the spherical infall estimate of the virial radius, covering about 40%-50% of the total surface area around clusters at these radii. Another set of stronger shocks ('external shocks') is located farther out, at about 3 R vir, with large Mach numbers (100), covering about 40%-60% of the surface area. We simulate SZ surface brightness maps of relaxed massive galaxy clusters drawn from high-resolution AMR runs, and conclude that ALMA should be capable of detecting the virial shocks in massive clusters of galaxies. More simulations are needed to improve estimates of astrophysical noise and to determine optimal observational strategies.
The recent increase in reports of drug-facilitated sexual assaults has caused alarm in the general public and prompted forensic toxicologists from across North America to address the toxicological ...issues surrounding this matter. The authors have developed recommendations and guidelines to inform law enforcement, medical, and scientific personnel of the requirements for performing successful toxicological examinations in cases of drug-facilitated rape.
Cold dark matter (CDM) hierarchical structure formation models predict the existence of large-scale accretion shocks between the virial and turnaround radii of clusters of galaxies. Kocsis et al. ...suggest that the Sunyaev-Zel'dovich signal associated with such shocks might be observable with the next generation radio interferometer, ALMA (Atacama Large Millimeter Array). We study the three-dimensional distribution of accretion shocks around individual clusters of galaxies drawn from adaptive mesh refinement (AMR) and smoothed particle hydrodynamics simulations of {lambda}CDM (dark energy dominated CDM) models. In relaxed clusters, we find two distinct sets of shocks. One set ('virial shocks'), with Mach numbers of 2.5-4, is located at radii 0.9-1.3 R {sub vir}, where R {sub vir} is the spherical infall estimate of the virial radius, covering about 40%-50% of the total surface area around clusters at these radii. Another set of stronger shocks ({sup e}xternal shocks{sup )} is located farther out, at about 3 R {sub vir}, with large Mach numbers ({approx}100), covering about 40%-60% of the surface area. We simulate SZ surface brightness maps of relaxed massive galaxy clusters drawn from high-resolution AMR runs, and conclude that ALMA should be capable of detecting the virial shocks in massive clusters of galaxies. More simulations are needed to improve estimates of astrophysical noise and to determine optimal observational strategies.
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