Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial

SummaryBackgroundThe diagnosis and staging of lung cancer is an important process that identifies treatment options and guides disease prognosis. We aimed to assess endobronchial ultrasound-guided transbronchial needle aspiration as an initial investigation technique for patients with suspected lung cancer.MethodsIn this open-label, multicentre, pragmatic, randomised controlled trial, we recruited patients who had undergone a CT scan and had suspected stage I to IIIA lung cancer, from six UK centres and randomly assigned them to either endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or conventional diagnosis and staging (CDS), for further investigation and staging. If a target node could not be accessed by EBUS-TBNA, then endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was allowed as an alternative procedure. Randomisation was stratified according to the presence of mediastinal lymph nodes measuring 1 cm or more in the short axis and by recruiting centre. We used a telephone randomisation method with permuted blocks of four generated by a computer. Because of the nature of the intervention, masking of participants and consenting investigators was not possible. The primary endpoint was the time-to-treatment decision after completion of the diagnostic and staging investigations and analysis was by intention-to-diagnose. This trial is registered with ClinicalTrials.gov, number NCT00652769.FindingsBetween June 10, 2008, and July 4, 2011, we randomly allocated 133 patients to treatment: 66 to EBUS-TBNA and 67 to CDS (one later withdrew consent). Two patients from the EBUS-TBNA group underwent EUS-FNA. The median time to treatment decision was shorter with EBUS-TBNA (14 days; 95% CI 14–15) than with CDS (29 days; 23–35) resulting in a hazard ratio of 1·98, (1·39–2·82, p<0·0001). One patient in each group had a pneumothorax from a CT-guided biopsy sample; the patient from the CDS group needed intercostal drainage and was admitted to hospital.InterpretationTransbronchial needle aspiration guided by endobronchial ultrasound should be considered as the initial investigation for patients with suspected lung cancer, because it reduces the time to treatment decision compared with conventional diagnosis and staging techniques.FundingUK Medical Research Council

Fractional quantum Hall state at \nu=1/4 in a wide quantum well

We investigate, with the help of Monte-Carlo and exact-diagonalization calculations in the spherical geometry, several compressible and incompressible candidate wave functions for the recently observed quantum Hall state at the filling factor $\nu=1/4$ in a wide quantum well. The quantum well is modeled as a two-component system by retaining its two lowest subbands. We make a direct connection with the phenomenological effective-bilayer model, which is commonly used in the description of a wide quantum well, and we compare our findings with the established results at $\nu=1/2$ in the lowest Landau level. At $\nu=1/4$, the overlap calculations for the Halperin (5,5,3) and (7,7,1) states, the generalized Haldane-Rezayi state and the Moore-Read Pfaffian, suggest that the incompressible state is likely to be realized in the interplay between the Halperin (5,5,3) state and the Moore-Read Pfaffian. Our numerics shows the latter to be very susceptible to changes in the interaction coefficients, thus indicating that the observed state is of multicomponent nature.Comment: 14 pages, 8 figures; minor changes, accepted for publication in Phys. Rev.

Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening

Risk stratification for covert invasive cancer among patients referred for colonic endoscopic mucosal resection: a large multicenter cohort

Background & Aims Among patients with large colorectal sessile polyps or laterally spreading lesions, it is important to identify those at risk for submucosal invasive cancer (SMIC). Lesions with overt endoscopic evidence of SMIC are referred for surgery, although those without these features might still contain SMIC that is not visible on endoscopic inspection (covert SMIC). Lesions with a high covert SMIC risk might be better suited for endoscopic submucosal dissection than for endoscopic mucosal resection (EMR). We analyzed a group of patients with large colon lesions to identify factors associated with SMIC, and examined lesions without overt endoscopic high-risk signs to determine factors associated with covert SMIC. Methods We performed a prospective cohort study of consecutive patients referred for EMR of large sessile or flat colorectal polyps or laterally spreading lesions (≥20 mm) at academic hospitals in Australia from September 2008 through September 2016. We collected data on patient and lesion characteristics, outcomes of procedures, and histology findings. We excluded serrated lesions from the analysis of covert SMIC due to their distinct phenotype and biologic features. Results We analyzed 2277 lesions (mean size, 36.9 mm) from 2106 patients (mean age, 67.7 years; 53.2% male). SMIC was evident in 171 lesions (7.6%). Factors associated with SMIC included Kudo pit pattern V, a depressed component (0–IIc), rectosigmoid location, 0–Is or 0–IIa+Is Paris classification, non-granular surface morphology, and increasing size. After exclusion of lesions that were obviously SMIC or serrated, factors associated with covert SMIC were rectosigmoid location (odds ratio, 1.87; P =.01), combined Paris classification, surface morphology (odds ratios, 3.96−22.5), and increasing size (odds ratio, 1.16/10 mm; P =.012). Conclusions In a prospective study of 2106 patients who underwent EMR for large sessile or flat colorectal polyps or laterally spreading lesions, we associated rectosigmoid location, combined Paris classification and surface morphology, and increasing size with increased risk for covert malignancy. Rectosigmoid 0–Is and 0–IIa+Is non-granular lesions have a high risk for malignancy, whereas proximally located 0–Is or 0–IIa granular lesions have a low risk. These findings can be used to inform decisions on which patients should undergo endoscopic submucosal dissection, EMR, or surgery. ClinicalTrials.gov, Number: NCT02000141

A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

BACKGROUND: Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. METHODOLOGY: We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. CONCLUSIONS: This article proposes a network-based multi-target computational estimation method for anticoagulant activities of compounds by combining network efficiency analysis with scoring function from molecular docking

Recommendations for accelerating open preprint peer review to improve the culture of science

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts