Summary Background Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. ...The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. Methods In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov , number NCT02039674. Findings Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% 95% CI 9–42%; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 39% of 59 patients in the pembrolizumab plus chemotherapy group and 16 26% of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven 12% of 59) and decreased neutrophil count (three 5%); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine 15% of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two 3% each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Interpretation Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Funding Merck & Co.
Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype ...transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chemical specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small molecule conformational propensities, solvation, and protein–ligand binding.
The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ...ANC, ALC, AMC and NLR, both before and after treatment with nivolumab, are indicative markers of overall survival (OS) and evaluated change in NLR as a predictive marker of response in non -small cell lung cancer (NSCLC) patients treated with nivolumab.
A total of 109 patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio were examined with Kaplan-Meier curves and proportional hazard model.
Post-treatment NLR ≥5 after two cycles of nivolumab was associated with poor OS (median OS in NLR = <5 vs NLR = ≥5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2) months respectively, p<0.001). In addition NLR increased in non-responders after two cycles of nivolumab by 6.6±21.8 as compared to responders (p = 0.027).
Post-treatment ANC, ALC and NLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response in NSCLC patients treated with nivolumab.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New estimates of the impacts of germplasm improvement in the major staple crops between 1965 and 2004 on global land-cover change are presented, based on simulations carried out using a global ...economic model (Global Trade Analysis Project Agro-Ecological Zone), a multicommodity, multiregional computable general equilibrium model linked to a global spatially explicit database on land use. We estimate the impact of removing the gains in cereal productivity attributed to the widespread adoption of improved varieties in developing countries. Here, several different effects—higher yields, lower prices, higher land rents, and trade effects—have been incorporated in a single model of the impact of Green Revolution research (and subsequent advances in yields from crop germplasm improvement) on land-cover change. Our results generally support the Borlaug hypothesis that increases in cereal yields as a result of widespread adoption of improved crop germplasm have saved natural ecosystems from being converted to agriculture. However, this relationship is complex, and the net effect is of a much smaller magnitude than Borlaug proposed. We estimate that the total crop area in 2004 would have been between 17.9 and 26.7 million hectares larger in a world that had not benefited from crop germplasm improvement since 1965. Of these hectares, 12.0-17.7 million would have been in developing countries, displacing pastures and resulting in an estimated 2 million hectares of additional deforestation. However, the negative impacts of higher food prices on poverty and hunger under this scenario would likely have dwarfed the welfare effects of agricultural expansion.
An eviction, the legalized removal of a tenant from their home, is a particular node in a complex web of legal, economic, and other social arrangements. It is a process that contains a few key ...ingredients, including a property, a tenant, a landlord, a court, and a corpus of governing statutes and case law. However, absent an eviction's legal framework and justification, expelling a tenant from their home might more closely resemble ouster, theft, trespassing, or kidnapping; the law is what creates, defines, and empowers the eviction process as legitimate and unique according to its own logic and that of its legislators, courts, and the police they mobilize. Put differently, an eviction is made possible by laws and legal gaps, and underneath this legal tapestry is a thought world, a mix of different, interacting assumptions that think and feel it into existence. Deeper than concerns about practicality, efficiency, and abstract notions of fairness, these assumptions are derived from and effectuate principles that attend to existential priorities - to the essence of personhood, its fundamental interests, what governs and defines it, and what is necessary to protect it (and those interests).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, PRFLJ, SAZU, UILJ, UKNU, UL, UM, UPUK
The gas-phase decomposition kinetics and thermochemistry of bis(dimethylamino)silane (BDMAS), a potential precursor in the chemical vapor deposition of silicon nitride and silicon carbonitride thin ...films, were systematically studied using ab initio calculations at the CCSD(T)/6-311 + G(2d,p)//B3LYP/6-311 + + G(d,p) level of theory. The reaction routes were mapped out, exploring both the concerted and stepwise reactions in three different zones with the initial cleavage of Si–N, N–Me (Me = CH3), and Si–H, respectively. It was found that the energy needed to break N–Me at 80.6 kcal·mol–1 is lower than the ones for Si–N and Si–H, both at 87.4 kcal·mol–1. When compared with tris(dimethylamino)silane (TrDMAS), it has been shown that the three bonds of N–Me, Si–N, and Si–H in BDMAS can be ruptured more easily, suggesting that BDMAS could be a more efficient precursor gas than TrDMAS. Upon decomposition, BDMAS tends to form methyleneimine and silanimine species, where four methyleneimine species and three silanimine species were produced. From the investigation of the effect of temperature on the kinetic and thermodynamic competition of different decomposition pathways, it has been demonstrated that the concerted formation of N-dimethylaminosilyl methyleneimine (H2CN–SiH2NMe2) by the elimination of CH4 from BDMAS is the most kinetically and thermodynamically favored pathway in the whole temperature range from 0 K (ΔH 0 ‡ = 62.7 kcal·mol–1 and ΔH 0 = 7.7 kcal·mol–1) up to 2673 K. In addition, lower temperatures favor the production of N-methyl methyleneimime (H2CNMe), whereas high temperatures promote the formation of N-methylsilanimine (H2Si = NMe) and 1-dimethylamino-N-methylsilanimine (Me2NSi = NMe).
Background
VSL#3 is a patented probiotic for which several clinical trials suggest benefits on motor function, bloating, and symptoms of irritable bowel syndrome (IBS).
Objectives
To quantify effects ...of VSL#3 on abdominal pain, stool consistency, overall response, abdominal bloating, and quality of life (QOL) in IBS through meta‐analysis.
Methods
MEDLINE (OvidSP and PubMed), EMBASE, Web of Science, and Scopus were searched up to May 2017. Using a fixed effects model, we pooled data from intention‐to‐treat analyses of randomized trials (RCTs) comparing VSL#3 to placebo in IBS. Data were reported as relative risk (RR), overall mean difference (MD), or standardized MD (SMD) with 95% confidence intervals (CI). Quality of evidence was rated using the GRADE approach.
Key Results
Among 236 citations, 5 RCTs (243 patients) were included. No significant differences were observed for abdominal pain (SMD = −0.03; 95% CI −0.29 to 0.22), bloating (SMD = −0.15; 95% CI −0.40 to 0.11), proportion of bowel movements with normal consistency (overall MD = 0; 95% CI −0.09 to 0.08), or IBS‐QOL (SMD = 0.08; 95% CI −0.22 to 0.39). VSL#3 was associated with a nearly statistically significant increase in overall response (RR = 1.39; 95% CI 0.99‐1.98).
Conclusions & Inferences
In this systematic review and meta‐analysis, there was a trend toward improvement in overall response with VSL#3, but no clear evidence effectiveness for IBS. However, the number and sample sizes of the trials are small and the overall quality of evidence for 3 of the 5 outcomes was low. Larger trials evaluating validated endpoints in well‐defined IBS patients are warranted.
VSL#3 is a patented probiotic for which several clinical trials suggest benefits on symptoms of irritable bowel syndrome (IBS). In the current systematic review and meta‐analysis, we were unable to demonstrate clear evidence for benefit with VSL#3 in IBS, although a strong trend toward improvement in overall response was observed. Further study of VSL#3 in well‐defined IBS patients using validated clinical endpoints is required.
•KEYNOTE-021 A-C evaluated pembrolizumab + platinum chemotherapy in advanced NSCLC.•No dose-limiting toxicity occurred in any cohort at pembrolizumab 2 or 10 mg/kg.•Evidence of antitumor activity in ...all 3 cohorts at both pembrolizumab doses.•Pembrolizumab + platinum chemotherapy is a feasible front-line treatment strategy.
Platinum-based chemotherapy for advanced non–small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti–programmed death 1 monocloncal antibody pembrolizumab.
Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review.
Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively.
Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy.
In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy ...alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study.
Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m2 plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1.
After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy.
First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.