PURPOSE 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 (t0) to after two cycles (t1) assessed with a commercial panel could identify patients with NSCLC who would benefit from ICI. PATIENTS AND METHODS 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. RESULTS 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 v 2 months; hazard ratio [HR], 0.55; 95% CI, 0.39 to 0.77; P = .0011) and overall survival (18.4 v 5.9 months; HR, 0.44; 95% CI, 0.31 to 0.62; P < .0001) compared with patients not achieving this end point. After adjusting for clinical variables, ctDNA response and STK11/ KEAP1 mutations (HR, 2.08; 95% CI, 1.4 to 3.0; P < .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. CONCLUSION 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.
We propose and develop the thesis that the quantum theoretical description of experiments emerges from the desire to organize experimental data such that the description of the system under scrutiny and the one used to acquire the data are separated as much as possible. Application to the Stern-Gerlach and Einstein-Podolsky-Rosen-Bohm experiments are shown to support this thesis. General principles of logical inference which have been shown to lead to the Schrödinger and Pauli equation and the probabilistic descriptions of the Stern-Gerlach and Einstein-Podolsky-Rosen-Bohm experiments, are used to demonstrate that the condition for the separation procedure to yield the quantum theoretical description is intimately related to the assumptions that the observed events are independent and that the data generated by these experiments is robust with respect to small changes of the conditions under which the experiment is carried out.
The interplay between the singlet ground state of the antiferromagnetic Heisenberg model and the experimentally measured Néel 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 Néel ordering in finite systems of experimentally accessible size.
The logical inference approach to quantum theory, proposed earlier [Ann. Phys. 347 (2014) 45-73], is considered in a relativistic setting. It is shown that the Klein-Gordon equation for a massive, charged, and spinless particle derives from the combination of the requirements that the space-time data collected by probing the particle is obtained from the most robust experiment and that on average, the classical relativistic equation of motion of a particle holds.
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