Активность

In the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data.

Patients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 11 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m

every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay).

Of 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumaversus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%).

The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.

We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1).

Of 2689 patients with NSCLC, 20.6% (N= 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 1 versus 1.8 mo, HR= 0.57 [95% CI 0.38-0.84], p= 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR= 0.56 [95% CI 0.36-0.86], p= 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N= 17), with a lower ORR (22% versus 0%, p= 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR= 0.25 [95% CI 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR= 0.29 [95% CI 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs.

Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.

Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.Modern data analysis tools and statistical modeling techniques are increasingly used in clinical research to improve diagnosis, estimate disease progression and predict treatment outcomes. What seems less emphasized is the importance of the study design, which can have a serious impact on the study cost, time and statistical efficiency. This paper provides an overview of different types of adaptive designs in clinical trials and their applications to cardiovascular trials. We highlight recent proliferation of work on adaptive designs over the past two decades, including some recent regulatory guidelines on complex trial designs and master protocols. We also describe the increasing role of machine learning and use of metaheuristics to construct increasingly complex adaptive designs or to identify interesting features for improved predictions and classifications.Heading date is a critical trait that determines the regional adaptability and grain productivity of many crops. PYR41 Although rice is a facultative short-day plant, its domestication led to the Ghd7-Ehd1-Hd3a/RFT1 pathway for adaptation to long-day conditions (LDs). The formation of the “florigen activation complex” (FAC) containing florigen Hd3a has been characterized. However, the molecular composition of the FAC that contains RFT1 for long-day flowering is unclear. We show here that RFT1 forms a ternary FAC with 14-3-3 proteins and OsFD1 to promote flowering under LDs. We identified a calcineurin B-like-interacting protein kinase, OsCIPK3, which directly interacts with and phosphorylates OsFD1, thereby facilitating the localization of the FAC to the nucleus. Mutation in OsCIPK3 results in a late heading date under LDs but a normal heading date under short-day conditions. Collectively, our results suggest that OsCIPK3 phosphorylates OsFD1 to promote RFT1-containing FAC formation and consequently induce flowering in rice under LDs.

There is limited evidence about the transmission and prevalence of oropharyngeal gonorrhoea in heterosexuals. From August 2017, Melbourne Sexual Health Centre (MSHC) began testing for oropharyngeal gonorrhoea among heterosexuals with untreated urogenital gonorrhoea. This study aims to determine the positivity of oropharyngeal gonorrhoea among heterosexuals diagnosed with urogenital gonorrhoea at MSHC between August 2017 and May 2020.

We included individuals who had oropharyngeal gonorrhoea testing within 30days of initial testing. We reported the number and proportion of oropharyngeal gonorrhoea positivity, stratified by gender and contact of gonorrhoea. The χ

test was performed to compare the oropharyngeal gonorrhoea positivity between groups.

Of 617 individuals with untreated urogenital gonorrhoea, 424 (68.7%) were tested for oropharyngeal gonorrhoea. Oropharyngeal gonorrhoea positivity was 38.9% (95%CI 34.2-43.7%, 165/424), and was higher in women than in men (115/252, 45.6% versus 50/172, 29.1%, p = 0.