•Circulating tumor DNA panels are currently underutilised for immunotherapy efficacy prediction.•A 2x improvement in efficacy prediction compared to traditional “molecular response”.•Our approach is ...broadly applicable across liquid biopsy platforms.
Predicting the outcome of immunotherapy-treated non-small cell lung cancer (NSCLC) patients is challenging. Measuring circulating tumor DNA (ctDNA) in plasma is promising, but its application for outcome delineation needs further refinement. Since most information from the next-generation sequencing (NGS) panel is typically left unused, we aim to integrate more information.
Patient and ctDNA data were compiled from five published studies involving advanced NSCLC. Plasma samples collected prior (t0) and early during (t1) immunotherapy were selected, tracking the changes of the highest t0 variant per gene. Durable benefit (DB, defined as progression free survival ≥ ½ year) was predicted. Performance was quantified using the integrated receiver operating characteristic curve (ROC AUC) and compared with the traditional molecular response (MR).
A total of 365 patients were pooled. Seven recurrently mutated genes were selected which optimally predicted DB (ROC AUC: 0.77-0.11+0.10), outperforming the MR predictor (with a ROC AUC: 0.64-0.11+0.11). Inclusion of patient characteristics led to a slight further improvement (ROC AUC: 0.80-0.10+0.09). The model performed satisfactory across all ctDNA platforms despite differences in panel size and content.
Relative to a non-informative classifier (ROC AUC: 0.5), a twofold improvement in predictive value was achieved compared to MR by an integration of changes across seven selected genes in immunotherapy-treated NSCLC patients, whilst being broadly applicable across ctDNA NGS panels.
Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill ...defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.
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•Increase in blood neutrophil molecular states in early-stage COPD•Progenitor reprogramming is linked to altered blood neutrophil states•Neutrophil state abundance correlates with lung function decline
Kapellos et al. show that systemic molecular changes in neutrophils in early-stage COPD are associated with increased granulopoiesis and demonstrate that neutrophil transcriptomic states correlate with lung function decline.
Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic ...procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15–20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40–50%.
Immune checkpoint inhibitors (ICIs) are increasingly being used in non-small-cell lung cancer (NSCLC), yet biomarkers predicting their benefit are lacking. We evaluated if on-treatment changes of ...circulating tumor DNA (ctDNA) from ICI start (t
) to after two cycles (t
) assessed with a commercial panel could identify patients with NSCLC who would benefit from ICI.
The molecular ctDNA response was evaluated as a predictor of radiographic tumor response and long-term survival benefit of ICI. To maximize the yield of ctDNA detection, de novo mutation calling was performed. Furthermore, the impact of clonal hematopoiesis (CH)-related variants as a source of biologic noise was investigated.
After correction for CH-related variants, which were detected in 75 patients (44.9%), ctDNA was detected in 152 of 167 (91.0%) patients. We observed only a fair agreement of the molecular and radiographic response, which was even more impaired by the inclusion of CH-related variants. After exclusion of those, a ≥ 50% molecular response improved progression-free survival (10
2 months; hazard ratio HR, 0.55; 95% CI, 0.39 to 0.77;
.0011) and overall survival (18.4
5.9 months; HR, 0.44; 95% CI, 0.31 to 0.62;
< .0001) compared with patients not achieving this end point. After adjusting for clinical variables, ctDNA response and
/
mutations (HR, 2.08; 95% CI, 1.4 to 3.0;
< .001) remained independent predictors for overall survival, irrespective of programmed death ligand-1 expression. A landmark survival analysis at 2 months (n = 129) provided similar results.
On-treatment changes of ctDNA in plasma reveal predictive information for long-term clinical benefit in ICI-treated patients with NSCLC. A broader NSCLC patient coverage through de novo mutation calling and the use of a variant call set excluding CH-related variants improved the classification of molecular responders, but had no significant impact on survival.
It is shown that the Pauli equation and the concept of spin naturally emerge from logical inference applied to experiments on a charged particle under the conditions that (i) space is homogeneous ...(ii) the observed events are logically independent, and (iii) the observed frequency distributions are robust with respect to small changes in the conditions under which the experiment is carried out. The derivation does not take recourse to concepts of quantum theory and is based on the same principles which have already been shown to lead to e.g. the Schrödinger equation and the probability distributions of pairs of particles in the singlet or triplet state. Application to Stern–Gerlach experiments with chargeless, magnetic particles, provides additional support for the thesis that quantum theory follows from logical inference applied to a well-defined class of experiments.
•The Pauli equation is obtained through logical inference applied to robust experiments on a charged particle.•The concept of spin appears as an inference resulting from the treatment of two-valued data.•The same reasoning yields the quantum theoretical description of neutral magnetic particles.•Logical inference provides a framework to establish a bridge between objective knowledge gathered through experiments and their description in terms of concepts.
The quantum delayed-choice experiment of Tang et al. (2012) is simulated on the level of individual events without making reference to concepts of quantum theory or without solving a wave equation. ...The simulation results are in excellent agreement with the quantum theoretical predictions of this experiment. The implication of the work presented in the present paper is that the experiment of Tang et al. can be explained in terms of cause-and-effect processes in an event-by-event manner.
The interplay between the singlet ground state of the antiferromagnetic Heisenberg model and the experimentally measured Neel state of antiferromagnets is studied. To verify the hypothesis M. I. ...Katsnelson et al., Phys. Rev. B 63, 212404 (2001) that the latter can be considered to be a result of local measurements destroying the entanglement of the quantum ground state, we have performed systematic simulations of the effects of von Neumann measurements for the case of a one-dimensional antiferromagnetic spin-1/2 system for various types and degrees of magnetic anisotropies. It is found that in the ground state, a magnetization measurement can create decoherence waves M. I. Katsnelson et al., Phys. Rev. A 62, 022118 (2000) in the magnetic sublattices, and that a symmetry breaking anisotropy does not lead to alignment of the spins in a particular direction. However, for an easy-axis anisotropy of the same order magnitude as the exchange constant, a measurement on the singlet ground state can create Neel ordering in finite systems of experimentally accessible size.
We study the decoherence process of a four spin-1/2 antiferromagnet
that is coupled to an environment of spin-1/2 particles. The preferred
basis of the antiferromagnet is discussed in two limiting ...cases and we
identify two
exact
pointer states. Decoherence near the
two limits is examined whereby entropy is used to quantify the
robustness
of states against environmental coupling. We
find that close to the quantum measurement limit, the self-Hamiltonian
of the system of interest can become dynamically relevant on macroscopic
timescales. We illustrate this point by explicitly constructing a state
that is more robust than (generic) states diagonal in the
system-environment interaction Hamiltonian.
Survival analysis concerns the study of timeline data where the event of interest may remain unobserved (i.e., censored). Studies commonly record more than one type of event, but conventional ...survival techniques focus on a single event type. We set out to integrate both multiple independently censored time-to-event variables as well as missing observations. An energy-based approach is taken with a bi-partite structure between latent and visible states, known as harmoniums (or restricted Boltzmann machines). The present harmonium is shown, both theoretically and experimentally, to capture non-linearly separable patterns between distinct time recordings. We illustrate on real world data that, for a single time-to-event variable, our model is on par with established methods. In addition, we demonstrate that discriminative predictions improve by leveraging an extra time-to-event variable. In conclusion, multiple time-to-event variables can be successfully captured within the harmonium paradigm.
The quantum delayed-choice experiment of Tang et al. Nature Photonics 6 (2012) 600 is simulated on the level of individual events without making reference to concepts of quantum theory or without ...solving a wave equation. The simulation results are in excellent agreement with the quantum theoretical predictions of this experiment. The implication of the work presented in the present paper is that the experiment of Tang et al. can be explained in terms of cause-and-effect processes in an event-by-event manner.
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