Summary Background Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of ...pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. Methods We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0·00825 (one-sided) for the analysis of overall survival and a threshold of p<0·001 for progression-free survival. This trial is registered at ClinicalTrials.gov , number NCT01905657. Findings Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10·4 months with pembrolizumab 2 mg/kg, 12·7 months with pembrolizumab 10 mg/kg, and 8·5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio HR 0·71, 95% CI 0·58–0·88; p=0·0008) and for pembrolizumab 10 mg/kg versus docetaxel (0·61, 0·49–0·75; p<0·0001). Median progression-free survival was 3·9 months with pembrolizumab 2 mg/kg, 4·0 months with pembrolizumab 10 mg/kg, and 4·0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0·88, 0·74–1·05; p=0·07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0·79, 95% CI 0·66–0·94; p=0·004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14·9 months vs 8·2 months; HR 0·54, 95% CI 0·38–0·77; p=0·0002) and with pembrolizumab 10 mg/kg than with docetaxel (17·3 months vs 8·2 months; 0·50, 0·36–0·70; p<0·0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5·0 months vs 4·1 months; HR 0·59, 95% CI 0·44–0·78; p=0·0001) and with pembrolizumab 10 mg/kg than with docetaxel (5·2 months vs 4·1 months; 0·59, 0·45–0·78; p<0·0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 13% of 339 patients given 2 mg/kg, 55 16% of 343 given 10 mg/kg, and 109 35% of 309 given docetaxel). Interpretation Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. Funding Merck & Co.
Rapid extraction of photogenerated charge carriers is essential to achieve high efficiencies with perovskite solar cells (PSCs). Here, a new mesoscopic architecture as electron‐selective contact for ...PSCs featuring 40 nm sized TiO2 beads endowed with mesopores of a few nanometer diameters is introduced. The bimodal pore distribution inherent to these films produces a very large contact area of 200 m2 g−1 whose access by the perovskite light absorber is facilitated by the interstitial voids between the particles. Modification of the TiO2 surface by CsBr further strengthens its interaction with the perovskite. As a result, photogenerated electrons are extracted rapidly producing a very high fill factor of close to 80% a VOC of 1.14 V and a PCE up to 21% with negligible hysteresis.
Cesium modification of bimodal mesoporous TiO2 surface for perovskite solar cells enhances electron transfer and reduces recombination at the interface between perovskite and elective‐selective layers. As a result, photogenerated electrons are extracted rapidly producing a very high fill factor of close to 80% a VOC of 1.14 V and a power conversion efficiency of 21% with negligible hysteresis.
One of the most prominent hole‐transporting material (HTM) for hybrid perovskite solar cells has been 2,2″,7,7″‐tetrakisN,N‐di(4‐methoxyphenyl)amino‐9,9′‐spirobifluorene (spiro‐OMeTAD), which is ...commonly doped with metal bis(trifluoromethylsulfonyl)imide (M(TFSI)n) salts that contribute to generating the active radical cation HTM species. The underlying role of the metal cation, however, remains elusive. Here, the effect of metal cations (M = Li, Zn, Ca, Cu, and Sc) on doping spiro‐OMeTAD is analyzed by a combination of techniques, including electron paramagnetic resonance spectroscopy and cyclic voltammetry, which is complemented by photovoltaic device and hole mobility analysis. As a result, the authors reveal the superiority of Zn(TFSI)2 salts in device performances as compared to the others, including redox‐active Cu(TFSI)2. This analysis thereby unravels new design principles for dopant engineering in HTMs for hybrid perovskite photovoltaics.
Dopant engineering for spiro‐OMeTAD hole‐transporting materials towards efficient perovskite solar cells. The presence of M(TFSI)n salts as p‐type dopants are required to improve the hole transfer of spiro‐OMeTAD, critical for photovoltaic performance. This study assesses the role of metal cations in the process, revealing the superiority of Zn‐based dopants as compared to redox‐active Cu‐based ones and others as producing a very high fill factor of close to 80% a VOC of 1.15 V and a power conversion efficiency of 21.9%.
Research summary: This article uses Exponential Random Graph Models (ERGMs) to advance strategic management research, focusing on an application to board interlock network tie formation. Networks ...form as the result of actor attributes as well as through the influence of existing ties. Conventional regression models require assumptions of independence between observations, and fail to incorporate endogenous structural effects of the observed network. ERGMs represent a methodological innovation for network formation research given their ability to model actor attributes along with endogenous structural processes. We illustrate these advantages by modeling board interlock formation among Fortune 100 firms. We also demonstrate how ERGMs offer significant opportunities to extend existing strategy research and open new pathways in multiparty alliances, microfoundations of interorganizational network formation, and multiplexity of ties among actors. Managerial summary: Social networks are increasingly important in the business world, not only between individuals but also between organizations. Firms can obtain information, resources, and status through their external network connections, and understanding how these outside ties form is an important goal of strategy research. Our paper helps advance this effort by introducing a new tool for social network analysis, Exponential Random Graph Models (ERGMs) to the management and strategy fields. We provide an example of this method, demonstrating how social network ties form between companies when they hire common directors to their boards. Executives can benefit from this research through a greater understanding of how corporate relationships are built with allies as well as among competitors.
Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety ...data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study.
In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466.
Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39–56) patients in part B and 23 (64%; 46–79) in part D.
The combination of osimertinib and savolitinib has acceptable risk–benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs.
AstraZeneca.
Li-TFSI is the most common p-dopant for the hole conductor spiro-MeOTAD in the normal structure (n–i–p) of perovskite solar cells (PSCs), which consistently yield the highest power conversion ...efficiency (PCE) albeit at the risk of lower long-term operational stability. Here we successfully replace conventional Li-TFSI with Zn-TFSI 2 , which not only acts as a highly effective p-dopant but also enhances considerably both the photovoltaic performance and long-term stability. The incorporation of Zn-TFSI 2 as a dopant for spiro-MeOTAD leads to an increase by one order in the hole mobility compared to Li-TFSI from 3.78 × 10 −3 cm 2 V −1 s −1 to 3.83 × 10 −2 cm 2 V −1 s −1 . Furthermore, the device with Zn-TFSI 2 showed an 80 mV higher built-in voltage and a bigger recombination resistance than the one with Li-TFSI, which were responsible for the striking increase in both the open-circuit voltage and fill factor, leading to a stabilized PCE of 22.0% for the best cells. Remarkably, the device employing Zn-TFSI 2 demonstrated superb photo-stability, showing even a 2% increase in the PCE after 600 h light soaking at the maximum power point (mpp) under full sun, while the PCE of the device with Li-TFSI decreased by 20% under the same conditions. Similarly, the device with Zn-TFSI 2 showed better operational stability at 50 °C resulting in a 21% decrease in the PCE after 100 h aging at the mpp under full sun while the Li-TFSI based one showed a 55% decrease. Moreover, the Zn-TFSI 2 based device was capable of effectively resisting humidity compared to the one based on Li-TFSI from shelf stability monitoring (R.H. ≥ 40%) in the dark.
The physiological importance of GSK3-like kinases in plants emerged when the functional role of plant GSK3-like kinases represented by BIN2 was first elucidated in the brassinosteroid （BR）-regulated ...signal transduction pathway. While early studies focused more on understanding how GSK3-like kinases regulate BR signaling, recent studies have implicated many novel substrates of GSK3-like kinases that are involved in a variety of cellular processes as well as BR signaling. Plant GSK3-like kinases play diverse roles in physiological and developmental processes such as cell growth, root and stomatal cell development, flower development, xylem differentiation, light response, and stress responses. Here, we review the progress made in recent years in understanding the versatile functions of plant GSK3-like kinases. Based on the relationship between GSK3-like kinases and their newly identified substrates, we discuss the physiological and biochemical relevance of various cellular signaling mediated by GSK3-like kinases in plants.
Septoturbinoplasty is a surgical procedure that can improve nasal congestion symptoms in patients with nasal septal deviation and inferior turbinate hypertrophy. However, it is unclear which physical ...domains of nasal airflow after septoturbinoplasty are related to symptomatic improvement. This work employs computational fluid dynamics modeling to identify the physical variables and domains associated with symptomatic improvement. Sixteen numerical models were generated using eight patients' pre- and postoperative computed tomography scans. Changes in unilateral nasal resistance, surface heat flux, relative humidity, and air temperature and their correlations with improvement in the Nasal Obstruction Symptom Evaluation (NOSE) score were analyzed. The NOSE score significantly improved after septoturbinoplasty, from 14.4 ± 3.6 to 4.0 ± 4.2 (p < 0.001). The surgery not only increased the airflow partition on the more obstructed side (MOS) from 31.6 ± 9.6 to 41.9 ± 4.7% (p = 0.043), but also reduced the unilateral nasal resistance in the MOS from 0.200 ± 0.095 to 0.066 ± 0.055 Pa/(mL·s) (p = 0.004). Improvement in the NOSE score correlated significantly with the reduction in unilateral nasal resistance in the preoperative MOS (r = 0.81). Also, improvement in the NOSE score correlated better with the increase in surface heat flux in the preoperative MOS region from the nasal valve to the choanae (r = 0.87) than in the vestibule area (r = 0.63). Therefore, unilateral nasal resistance and mucous cooling in the preoperative MOS can explain the perceived improvement in symptoms after septoturbinoplasty. Moreover, the physical domain between the nasal valve and the choanae might be more relevant to patient-reported patency than the vestibule area.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M‐positive advanced ...non–small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum‐pemetrexed according to the plasma T790M status.
Methods
Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next‐generation sequencing (NGS; Guardant360, Guardant Health).
Results
With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M‐positive vs 39 mm for T790M‐negative; P < .0001) and the presence of extrathoracic disease (58% for M1b‐positive vs 39% for M0‐1a‐positive; P = .002). Progression‐free survival (PFS) was prolonged in randomized patients (tissue T790M‐positive) with a T790M‐negative cobas plasma result in comparison with those with a T790M‐positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum‐pemetrexed groups (median, 5.6 vs 4.2 months).
Conclusions
PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M‐positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
This exploratory analysis of the AURA3 study demonstrates that plasma‐based platforms (cobas EGFR Mutation Test v2, next‐generation sequencing, and droplet digital polymerase chain reaction) are suitable for epidermal growth factor receptor mutation detection in routine clinical practice. In patients with tissue T790M‐positive non–small cell lung cancer, the absence of detectable plasma T790M is associated with longer progression‐free survival, which may be attributed to a lower disease burden.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in ...advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events).
Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected.
Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio HR, 0.49 95% CI, 0.35 to 0.68; log-rank
< .0001; median, 24.0
11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4
9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 95% CI, 0.49 to 1.00; log-rank
= .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 95% CI, 0.98 to 1.031;
= .69).
Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
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