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Circulating tumor DNA (ctDNA) detection has multiple promising applications in oncology, but the road toward implementation in clinical practice is unclear. We aimed to support the implementation process by exploring potential future pathways of ctDNA testing. To do so, we studied four ctDNA‐testing applications in two cancer types and elicited opinions from 30 ctDNA experts in the Netherlands. Our results showed that the current available evidence differed per application and cancer type. Tumor profiling and monitoring treatment response were found most likely to be implemented in non‐small cell lung cancer (NSCLC) within 5 years. For colorectal cancer, applications of ctDNA testing were found to be at an early stage in the implementation process. Demonstrating clinical utility was found a key aspect for successful implementation, but there was no consensus regarding the evidence requirements. The next step toward implementation is to define how clinical utility of biomarkers should be evaluated. Finally, these data indicate that specific challenges for each clinical application and tumor type should be appropriately addressed in a deliberative process involving all stakeholders to ensure implementation of ctDNA testing and timely access for patients. [ABSTRACT FROM AUTHOR]

Monitoring the changes in porewater pressure associated with the construction of earthworks can yield information on the stiffness and permeability of the ground, as well as how the natural groundwater regime might be impacted. This paper presents 3 years of porewater pressure measurements in weathered Lias Group mudstone, obtained from a trial cutting and a trial embankment constructed for the UK's High Speed Two (HS2) railway. The immediate changes in porewater pressure were small in relation to the changes in total stress imposed. This can be explained by the consolidation or swelling during the period of construction, combined with the sensitivity of very stiff clays and mudstones to a very small (0.5%) reduction in the degree of saturation. In the longer term, porewater pressures reduced across the site owing to the reduction in ground level at the trial cutting. Rates of porewater pressure change were accelerated by more permeable limestone within the ground profile reducing drainage path lengths. It was concluded that construction-induced porewater pressure changes may be smaller, and their rate of dissipation more rapid, in weathered clays and mudstones such as those of the Lias Group than in younger, more compressible clay deposits. [ABSTRACT FROM AUTHOR]

Deep foundations may be used in a range of soil types where significant foundation resistance is required, but their installation is often associated with disturbance due to noise and vibration. Greater restrictions on use in urban and offshore environments is now commonplace. Screw piles and rotary-jacked straight-shafted piles are two potential methods of silent piling that could be used as alternative foundation solutions, but the effects of certain geometric and installation properties such as installation pitch, i.e., the ratio between vertical displacement and rotation, on the required installation torque and force in sand are not well understood. In this paper, the effects of installation pitch and base geometry on the installation requirements of a straight-shafted pile are simulated in three dimensions using the discrete element method (DEM). The installation requirements of straight-shafted piles into sand have been validated against centrifuge testing in three different relative densities. The DEM shows reductions in installation force can be achieved by increasing the installation pitch or including a conical tip. An existing cone penetration test (CPT)-based prediction method for installation requirements has been improved to include the effects of installation pitch and base geometry for rotary-installed piles in sand. Key words: discrete element method (DEM), rotary installation, silent piling, installation requirements, cone penetration test (CPT). Il existe plusieurs types de sols pour lesquels des fondations profondes sont necessaries, mais leur installation est souvent associee a des perturbations dues au bruit et aux vibrations. Les restrictions d'utilisation plus importantes dans les environnements urbains et offshore sont desormais monnaie courante. Parmi les methodes de pieux silencieux, les pieux visses et les pieux droits a verin rotatif representent deux solutions possibles, mais les effets de certaines proprietes geometriques et d'installation telles que le pas d'installation, c'est-a-dire le rapport entre le deplacement vertical et la rotation, sur le couple et la force d'installation requis dans le sable ne sont pas bien compris. Le present document simule en trois dimensions les effets du pas d'installation et de la geometrie de la base sur les exigences d'installation d'un pieu droit en utilisant la methode des elements discrets (MED). Les exigences d'installation des pieux droits dans le sable ont ete validees par des essais en centrifugeuse, dans trois densites relatives differentes. La methode des elements discrets montre qu'il est possible de reduire la force d'installation en augmentant le pas d'installation ou en incluant une base conique. Une methode de prevision des besoins d'installation basee sur un essai de penetration au cone (CPT) a ete amelioree pour inclure les effets du pas d'installation et de la geometrie de la base pour les pieux rotatifs installes dans le sable. [Traduit par la Redaction] Mots-cles: methode des elements discrets (MED), installation rotative, pieux silencieux, prescriptions d'installation, essai de penetration au cone (CPT)., 1. Introduction Deep foundations may be used in a range of soil types where significant foundation resistance is required but, depending on the pile type, their installation may be associated [...]

Background: The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab. Methods: Pretreatment samples from 135 patients receiving nivolumab were used to evaluate the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1T TILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were randomly assigned to a training (n = 55) and validation cohort (n = 80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m). Results: In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) compared to individual biomarkers PD-1T TILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Additionally, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) demonstrated inferior predictive performance compared to PD-1T TILs and TIS alone. PD-1T TILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1T TILs could more accurately discriminate patients with no long-term benefit, as specificity was substantially higher compared to TIS (74% versus 39%). Conclusion: Composite biomarkers did not show improved predictive performance compared to PD-1T TILs and TIS alone for both the 6- and 12-month endpoints. PD-1T TILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1T TILs. [ABSTRACT FROM AUTHOR]

Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges, including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures. Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice, very useful profiles can be obtained with ∼0.1× genome coverage. We improve on previous methods by first implementing a combined correction for sequence mappability and GC content, and second, by applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions was previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1000 samples, most of which were obtained from the fixed tissue archives of more than 25 institutions. We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches and better copy number data than high-resolution microarrays at a substantially lower cost.

Background Post-colonoscopy colorectal cancers (PCCRCs) decrease the effect of colorectal cancer (CRC) screening programs. To enable PCCRC incidence reduction in the long-term, we classified PCCRCs diagnosed after colonoscopies performed in a fecal immunochemical test (FIT)-based screening program. Methods PCCRCs diagnosed after colonoscopies performed between 2014–2016 for a positive FIT in the Dutch CRC screening program were included. PCCRCs were categorized according to the World Endoscopy Organization consensus statement into (a) interval PCCRC (diagnosed before the recommended surveillance); (b) non-interval type A (diagnosed at the recommended surveillance interval); (c) non-interval type B (diagnosed after the recommended surveillance interval); or (d) non-interval type C (diagnosed after the intended recommended surveillance interval, with surveillance not implemented owing to co-morbidity). The most probable etiology was determined by root-cause analysis. Tumor stage distributions were compared between categories. Results 116362 colonoscopies were performed after a positive FIT with 9978 screen-detected CRCs. During follow-up, 432 PCCRCs were diagnosed. The 3-year PCCRC rate was 2.7%. PCCRCs were categorized as interval (53.5%), non-interval type A (14.6%), non-interval type B (30.6%), and non-interval type C (1.4%). The most common etiology for interval PCCRCs was possible missed lesion with adequate examination (73.6%); they were more often diagnosed at an advanced stage (stage III/IV; 53.2%) compared with non-interval type A (15.9%; P <0.001) and non-interval type B (40.9%; P =0.03) PCCRCs. Conclusions The 3-year PCCRC rate was low in this FIT-based CRC screening program. Approximately half of PCCRCs were interval PCCRCs. These were mostly caused by missed lesions and were diagnosed at a more advanced stage. This emphasizes the importance of high quality colonoscopy with optimal polyp detection. [ABSTRACT FROM AUTHOR]