The absence of a universally accepted definition of radiocontrast nephropathy (RCN) has hampered efforts to characterize effectively the incidence and the clinical significance of this condition. The objective of this study was to identify a clinically relevant definition of RCN by assessment of the relationships between increases in serum creatinine (Scr) of varying magnitude after coronary angiography and clinical outcomes. An electronic medical database was used to identify all patients who underwent coronary angiography at the University of Pittsburgh Medical Center during a 12-yr period and abstract Scr levels before and after angiography, as well as demographic characteristics and comorbid conditions. Changes in Scr after angiography were categorized into mutually exclusive categories on the basis of absolute and relative changes from baseline levels, with a separate category denoting "unknown" change. Discrete proportional odds models were used to examine the association between increases in Scr and 30-d in-hospital mortality and length of stay. A total of 27,608 patients who underwent coronary angiography were evaluated. Small absolute (0.25 to 0.5 mg/dl) and relative (25 to 50%) increases in Scr were associated with risk-adjusted odds ratios for in-hospital mortality of 1.83 and 1.39, respectively. Larger increases in Scr generally were associated with greater risks for these clinical outcomes. Small increases in Scr after the administration of intravascular radiocontrast are associated with adverse patient outcomes. This observation will help guide the postprocedure care of patients who undergo coronary angiography and has important implications for future studies that investigate RCN.

On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no differencein OSbetween treatmentarmsatthe interimanalysis. The most common adverse drug reactions (.25%) in crizotinibtreated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy. The Oncologist 2014;19:e5-e11Implications for Practice: Prior to identification of activating genetic alternations and their targeted therapies in non-small cell lung cancer (NSCLC), patients with metastatic disease were treated with platinum-doublet chemotherapy and cytotoxic monotherapy regimens in the first-and second-line settings, respectively. However, with the identification of EGFR-mutation-targeted therapies and now ALK-alteration-targeted therapies, standard treatment in patients with NSCLC containing specific genetic alterations is evolving toward more efficacious and less toxic therapies. As more molecular targets are identified and their respective drugs developed, the management of metastatic NSCLC will move away from traditional cytotoxic chemotherapy regimens.

On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine-and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDAapproved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, openlabel, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ≥1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (≥20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. The Oncologist 2018;23:1-7Implications for Practice: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

None.

BackgroundThe diamondback moth Plutella xyllostella has developed a high level of resistance to the latest insecticide chlorantraniliprole. A better understanding of P. xylostella’s resistance mechanism to chlorantraniliprole is needed to develop effective approaches for insecticide resistance management.Principal FindingsTo provide a comprehensive insight into the resistance mechanisms of P. xylostella to chlorantraniliprole, transcriptome assembly and tag-based digital gene expression (DGE) system were performed using Illumina HiSeq™ 2000. The transcriptome analysis of the susceptible strain (SS) provided 45,231 unigenes (with the size ranging from 200 bp to 13,799 bp), which would be efficient for analyzing the differences in different chlorantraniliprole-resistant P. xylostella stains. DGE analysis indicated that a total of 1215 genes (189 up-regulated and 1026 down-regulated) were gradient differentially expressed among the susceptible strain (SS) and different chlorantraniliprole-resistant P. xylostella strains, including low-level resistance (GXA), moderate resistance (LZA) and high resistance strains (HZA). A detailed analysis of gradient differentially expressed genes elucidated the existence of a phase-dependent divergence of biological investment at the molecular level. The genes related to insecticide resistance, such as P450, GST, the ryanodine receptor, and connectin, had different expression profiles in the different chlorantraniliprole-resistant DGE libraries, suggesting that the genes related to insecticide resistance are involved in P. xylostella resistance development against chlorantraniliprole. To confirm the results from the DGE, the expressional profiles of 4 genes related to insecticide resistance were further validated by qRT-PCR analysis.ConclusionsThe obtained transcriptome information provides large gene resources available for further studying the resistance development of P. xylostella to pesticides. The DGE data provide comprehensive insights into the gene expression profiles of the different chlorantraniliprole-resistant stains. These genes are specifically related to insecticide resistance, with different expressional profiles facilitating the study of the role of each gene in chlorantraniliprole resistance development.

No abstract

The FDA approved ramucirumab (CYRAMZA; Eli Lilly and Company) for previously treated patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma initially as monotherapy (April 21, 2014) and subsequently as combination therapy with paclitaxel (November 5, 2014). In the monotherapy trial, 355 patients in the indicated population were randomly allocated (2:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks. In the combination trial, 665 patients were randomly allocated (1:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks, in combination with paclitaxel, 80 mg/m 2 on days 1, 8, and 15 of 28-day cycles. Overall survival (OS) was increased in patients who received ramucirumab in both the monotherapy [HR, 0.78; 95% confidence interval (CI), 0.60-0.998; log rank P ¼ 0.047] and combination trials (HR, 0.81; 95% CI, 0.68-0.96; P ¼ 0.017). The most common adverse reactions were hypertension and diarrhea in the monotherapy trial and fatigue, neutropenia, diarrhea, and epistaxis in the combination trial. Because of concerns about the robustness of the monotherapy trial results, FDA approved the original application after receiving the results of the combination trial confirming the OS effect. Based on exploratory exposure-response analyses, there is residual uncertainty regarding the optimal dose of ramucirumab. Clin Cancer Res; 21(15); 3372-6. Ó2015 AACR.

X-ray detectors with high performance, durability, and flexibility detectors are required for a wide range of applications in several fields, such as medical treatment (imaging, diagnostic radiology, etc.), nondestructive testing (radioscopic inspections, radiography testing, etc.), security and defense (luggage/body scanning systems, paper mail, etc.), nuclear and radiation industries (nuclear power plants, research reactors, users of nuclear gauges, etc.), and scientific research and development. [1]-[9] Thereof, indirect X-ray detectors are widely used for ordinary flat panel X-ray detection, among which scintillator is the most important factor affecting the detection performance. [10][11][12][13][14] Currently, the ideal scintillator should meet the following basic conditions: (i) good stopping power and excellent radiation absorption, [15]-[18] (ii) high photoluminescence (PL) with large Stokes shift and radioluminescence (RL) intensity, (iii) nontoxicity with environmentally stable, [19] (iv) easily manufactured and extendable to large-area flexible applications. [20,21] Among all, inorganic copper (I)-based metal halide semiconductors meeting all the above requirements are considered as promising candidates. In particular, zero-dimensional (0D) cesium copper chloride, Cs 3 Cu 2 Cl 5 , shows excellent photoelectric performance in ultraviolet photodetectors. [22] With isolated [Cu 2 Cl 5 ] 3dimers and Cs + ions, Cs 3 Cu 2 Cl 5 is expected to exhibit intriguing optical properties mainly derived from self-trapped excitons (STEs). Different from the narrow and rapid emission of free excitons and inter-band recombination, the emission of STEs is featured with broad spectra and large Stokes shifts. Generally, the STEs emission that occurs in Cs 3 Cu 2 Cl 5 originates from structural deformation of [Cu 2 Cl 5 ] 3− dimers. [23] At the time of photoexcitation, the Cu-Cl bonds elongate (shrink) on the equatorial plane but shrink (elongate) in the axial direction, which in turn causes the local structure change from a high symmetry to a low symmetry configuration.To further improve its photophysical characteristics, the diversified structural optimization in Cs 3 Cu 2 Cl 5 could offer deeper insights and more controlling knobs on STEs emission. Zero-dimensionalCs 3 Cu 2 Cl 5 exhibits intriguing optical properties, which can meet the basic requirements of ideal scintillator application. Here, green emitter Cs 3 Cu 2 Cl 5 nanosheets are successfully synthesized, and by doping with 2% potassium (K + ), their photoluminescence quantum yield (70.23% to 81.39%), radioluminescence intensity, and stability are improved. Further experimental and theoretical studies point out that: (1) K + brings the neighboring [Cu 2 Cl 5 ] 3− dimers groups closer, leading to lattice shrinkage and lower lattice constants; (2) such compact crystal structure results in stronger exciton-photon coupling and reduced phonon-electron coupling strength, which is beneficial to form self-trapped excitons and enhanced luminescence; (3) lower lattice ...