The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 ...that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Context.
Heavily obscured active galactic nuclei (AGNs) are known to show deep silicate absorption features in the mid-infrared (mid-IR) wavelength range of 10–20 μm. The detailed profiles of the ...features reflect the properties of silicate dust, which are likely to include information on AGN activities obscured by large amounts of dust.
Aims.
We reveal AGN activities obscured by large amounts of dust through the silicate dust properties obtained from the mid-IR spectral bands.
Methods.
We selected 115 mid-IR spectra of heavily obscured AGNs observed by
Spitzer
/IRS and systematically analyzed the composition of silicate dust by spectral fitting using the 10 μm amorphous and 23 μm crystalline bands.
Results.
We find that the main component of the silicate dust obscuring AGNs is amorphous olivine, the median mass column density of which is one order of magnitude higher than those of the minor components of amorphous pyroxene and crystalline forsterite. The median mass fraction of the amorphous pyroxene, ∼2%, is significantly lower than that of the diffuse interstellar medium (ISM) dust in our Galaxy, while the median mass fraction of the crystalline forsterite, ∼6%, is higher than that of the diffuse ISM dust. We also find that the mass fractions of the amorphous pyroxene and the crystalline forsterite positively correlate with each other.
Conclusions.
The low mass fraction of the amorphous pyroxene suggests that the obscuring silicate dust is newly formed, originating from starburst activities. The relatively high mass fraction of crystalline forsterite implies that the silicate dust is processed in the high temperature environment close to the nucleus and transported to outer cooler regions by molecular outflows. The positive correlation between the mass fractions can be naturally explained considering that amorphous pyroxene is transformed from crystalline forsterite by ion bombardments. We also find that spectra with high ratios of the H
2
O ice absorption to silicate mass column density tend to indicate low mass fractions of amorphous pyroxene and crystalline forsterite, which is consistent with the scenario of the thermal dust processing close to the nucleus.
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Abstract
Mid-infrared silicate dust bands observed in heavily obscured active galactic nuclei (AGNs) include information on the mineralogical properties of silicate dust. We aim to investigate the ...mineralogical picture of the circumnuclear region of heavily obscured AGNs to reveal obscured AGN activities through the picture. In our previous study, we investigated the properties of silicate dust in heavily obscured AGNs, focusing on the mineralogical composition and the crystallinity with Spitzer/IRS 5.3–12
μ
m spectra. In this study, we model the full-range Spitzer/IRS 5–30
μ
m spectra of 98 heavily obscured AGNs using a one-dimensional radiative transfer calculation with four dust species in order to evaluate wider ranges of the properties of silicate dust more reliably. Comparing fitting results between four dust models with different sizes and porosities, 95 out of the 98 galaxies prefer a porous silicate dust model without micron-sized large grains. The pyroxene mass fraction and the crystallinity are overall consistent with—but significantly different from—the previous results for the individual galaxies. The pyroxene-poor composition, small dust size, and high porosity are similar to newly formed dust around mass-loss stars as seen in our Galaxy, which presumably originates from the recent circumnuclear starburst activity. The high crystallinity on average suggests dust processing induced by AGN activities.
The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have ...now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer.
We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS).
Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027).
Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments.
The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We present photometric and spectroscopic observations of SN 2020bio, a double-peaked Type IIb supernova (SN) discovered within a day of explosion, primarily obtained by Las Cumbres ...Observatory and Swift. SN 2020bio displays a rapid and long-lasting initial decline throughout the first week of its light curve, similarly to other well-studied Type IIb SNe. This early-time emission is thought to originate from the cooling of the extended outer hydrogen-rich (H-rich) envelope of the progenitor star that is shock heated by the SN explosion. We compare SN 2020bio to a sample of other double-peaked Type IIb SNe in order to investigate its progenitor properties. Analytical model fits to the early-time emission give progenitor radius (≈100–1500
R
⊙
) and H-rich envelope mass (≈0.01–0.5
M
⊙
) estimates that are consistent with other Type IIb SNe. However, SN 2020bio displays several peculiarities, including (1) weak H spectral features indicating a greater amount of mass loss than other Type IIb progenitors; (2) an underluminous secondary light-curve peak that implies a small amount of synthesized
56
Ni (
M
Ni
≈0.02
M
⊙
); and (3) low-luminosity nebular O
i
and interaction-powered nebular features. These observations are more consistent with a lower-mass progenitor (
M
ZAMS
≈ 12
M
⊙
) that was stripped of most of its H-rich envelope before exploding. This study adds to the growing diversity in the observed properties of Type IIb SNe and their progenitors.
Purpose
Unlike other laparoscopic techniques, the peritoneum is not incised in laparoscopic totally extraperitoneal inguinal hernia repair (TEP), and the preperitoneal space is developed as the ...surgical field by blunt dissection and CO
2
insufflation. While many studies have investigated the effect of neuromuscular blockade (NMB) on the surgical conditions and postoperative pain of laparoscopic intraperitoneal surgery, few studies have investigated those of TEP. In the present study, we investigated the effect of NMB on the surgical conditions and postoperative pain of TEP.
Methods
Forty-two adult patients scheduled for unilateral TEP under general anesthesia with remifentanil and desflurane were randomly assigned to paralyzed or non-paralyzed groups. In the paralyzed group, rocuronium doses were administered to maintain post-tetanic count at ≤ 5 during surgery. Non-paralyzed subjects were not given any rocuronium. Postoperatively, surgeon-evaluated surgical conditions, assessed using a 100-mm visual analogue scale ranging from 0 mm (not acceptable) to 100 mm (excellent), were compared between the two groups. For evaluation of postoperative pain, the time from the end of anesthesia to the initial requirement of postoperative analgesia was compared by the log-rank test.
Results
Median interquartile range score of surgical condition in the paralyzed and non-paralyzed groups were 84 75–90 and 84 78–87, respectively (
P
= 0.46). Significant differences in postoperative analgesic requirements between the two groups were not confirmed (
P
= 0.74).
Conclusion
NMB did not improve the surgical conditions nor reduce postoperative pain. NMB is not routinely needed for TEP just because it is a laparoscopic procedure.
Clinical trial registration
The trial was registered in the UMIN clinical trials registry (UMIN000029683, October 24, 2017; Principal investigator: Masafumi Fujimoto,
https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000033920
) prior to patient enrolment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Context. The environmental conditions for asympotic giant branch (AGB) stars to reach the carbon-rich (C-rich) phase are important to understand the evolutionary process of AGB stars. The difference ...between the spatial distributions of C-rich and oxygen-rich (O-rich) AGB stars is essential for the study of the Galactic structure and the chemical evolution of the interstellar medium. Aims. We quantitatively investigate the spatial distributions of C-rich and O-rich AGB stars in our Galaxy. We discuss the difference between them and its origin. Methods. We classify a large number of AGB stars newly detected by the AKARI mid-infrared all-sky survey. In the color–color diagrams, we define their occupation zones based on the locations of known objects. We then obtain the spatial distributions of C-rich and O-rich AGB stars, assuming that they have the same luminosity for a given mass-loss rate. Results. We find that O-rich AGB stars are concentrated toward the Galactic center and that the density decreases with Galactocentric distance, whereas C-rich AGB stars show a relatively uniform distribution within about 8 kpc of Sun. Conclusions. Our result confirms the trends reported in previous studies and extends them to a Galactic scale. We discuss the relations between our result, the Galactic metallicity gradient, and the chemical evolution of the ISM in our Galaxy.
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Aims. We investigate the properties of hydrocarbon grains in the galactic superwind of M 82. Methods. With AKARI, we performed near-infrared (2.5–4.5 μm) spectroscopic observations of 34 regions in ...M 82 including its northern and southern halos. Results. Many of the spectra show strong emission at 3.3 μm caused by polycyclic aromatic hydrocarbons (PAHs) and relatively weak features at 3.4–3.6 μm caused by aliphatic hydrocarbons. In particular, we clearly detect the PAH 3.3 μm emission and the 3.4–3.6 μm features in halo regions, which are located at a distance of 2 kpc away from the galactic center. We find that the ratios of the 3.4–3.6 μm features to the 3.3 μm feature intensity significantly increase with distance from the galactic center, while the ratios of the 3.3 μm feature to the AKARI 7 μm band intensity do not. Conclusions. Our results clearly confirm the presence of small PAHs even in the harsh environment of the halo of M 82. The results also reveal that the aliphatic hydrocarbons emitting the 3.4–3.6 μm features are unusually abundant in the halo, suggesting that small carbonaceous grains are produced by shattering of larger grains in the galactic superwind.
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Background
Reducing near‐fatal asthma exacerbations is a critical problem in asthma management.
Objectives
To determine patterns of factors preceding asthma exacerbations in a real‐world setting.
...Methods
In a nationwide prospective study of 190 patients who had experienced near‐fatal asthma exacerbation, cluster analysis was performed using asthma symptoms over the 2‐week period before admission.
Results
Three distinct clusters of symptoms were defined employing the self‐reporting of a visual analogue scale. Cluster A (42.1%): rapid worsening within 7.4 hours from moderate attack to admission, young to middle‐aged patients with low Body mass index and tendency to depression who had stopped anti‐asthma medications, smoked, and hypersensitive to environmental triggers and furred pets. Cluster B (40.0%): fairly rapid worsening within 48 hours, mostly middle‐aged and older, relatively good inhaled corticosteroid (ICS) or ICS/long‐acting beta‐agonist (LABA) compliance, and low perception of dyspnea. Cluster C (17.9%): slow worsening over 10 days before admission, high perception of dyspnea, smokers, and chronic daily mild‐moderate symptoms. There were no differences in overuse of short‐acting beta‐agonists, baseline asthma severity, or outcomes after admission for patients in these 3 clusters.
Conclusion
To reduce severe or life‐threatening asthma exacerbation, personalized asthma management plans should be considered for each cluster. Improvement of ICS and ICS/LABA compliance and cessation of smoking are important in cluster A. To compensate for low perception of dyspnea, asthma monitoring of peak expiratory flow rate and/or exhaled nitric oxide would be useful for patients in cluster B. Avoidance of environmental triggers, increase usual therapy, or new anti‐type 2 response‐targeted therapies should be considered for cluster C.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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