IMPORTANCE Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. OBJECTIVE To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. DESIGN, SETTING, AND PARTICIPANTS This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. EXPOSURES Absence or presence of specific autoimmune markers and antibodies before treatment. MAIN OUTCOMES AND MEASURES Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. RESULTS Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). CONCLUSIONS AND RELEVANCE The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic b...

Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

In order to propose a ferromagnet exhibiting highly spin-polarized transport, we theoretically analyzed the spin polarization ratio of the conductivity of the bulk Fe4N with a perovskite type structure, in which N is located at the body center position of fcc-Fe. The spin polarization ratio is defined by P = (σ ↑ − σ ↓ )/(σ ↑ + σ ↓ ), with σ ↑(↓) being the conductivity at zero temperature of the up spin (down spin). The conductivity is obtained by using the Kubo formula and the Slater-Koster tight binding model, where parameters are determined from the least-square fitting of the dispersion curves by the tight binding model to those by the first principles calculation. In the vicinity of the Fermi energy, |P | takes almost 1.0, indicating perfectly spin-polarized transport. In addition, by comparing Fe4N to fcc-Fe (Fe4N0) in the ferromagnetic state with the equilibrium lattice constant of Fe4N, it is shown that the non-magnetic atom N plays an important role in increasing |P |. PACS numbers: 72.25.BaRecently, highly efficient spin-electronics devices operating at room temperature have been extensively developed for applications to the magnetic memory and the magnetic sensor. A typical device has ferromagnetic tunnel junctions consisting of a ferromagnetic electrode (FME)/insulator/FME, which exhibits a large magnetoresistance (MR) effect. 1,2,3,4,5,6,7 The efficiency of the MR effect is often defined by the MR ratio = (R AP − R P )/R AP , with R P and R AP being the resistance of the parallel and anti-parallel magnetization configurations of FMEs, respectively. Experimentally, regarding junctions with an electrode of a half-metallic ferromagnet, Co 2 Cr 0.6 Fe 0.4 Al/Al-O/CoFe/NiFe/IrMn/Ta junctions exhibited an MR ratio of 16 % at room temperature, 1 and Co 2 MnSi/Al-O/Co 75 Fe 25 had an MR ratio of 70 % at room temperature. 2 Regarding junctions of electrodes with usual ferromagnets, single-crystal Fe(001)/MgO(001)/Fe(001) junctions exhibited MR ratios of 88 % 3 and 180 % 4 at room temperature. Furthermore, CoFeB/MgO/CoFeB junctions achieved MR ratios of 260 % 5 and 355 % 6 (the world's highest value) at room temperature, although the crystal structure of CoFeB and the role of the light element B on the spinpolarized transport have not been clarified yet. Generally, the MR ratio becomes large with increasing the spin polarization of the conduction electron in the FME. In the future, an FME with more highly spin-polarized electrons, which would result in larger MR ratios, will be strongly desired from the viewpoint of the development of highly efficient MR devices.Towards proposal of such an FME, we extracted an idea to obtain electrodes exhibiting the highly spinpolarized transport at room temperature. We found that ferromagnets consisting of magnetic elements and * Electronic mail:tskokad@ipc.shizuoka.ac.jp light elements, such as CoFeB, might be very useful as the electrodes.We consider Fe as a representative magnetic element in this idea. We define the spin polarization (SP) ratio about the density of states...

Background-A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. Methods and Results-KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-␤ 1 ; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. Conclusions-These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation. (Circulation. 2005;111:222-229.)

Engineering using liquids confined in channels 10-1000 nm in dimension, or "extended-nanofluidics," is the next target of microfluidic science. Liquid properties at this scale were unrevealed until recently because of the lack of fundamental technologies for investigating these ultrasmall spaces. In this article, the fundamental technologies are reviewed, and the emerging science and technology in the extended-nanospace are discussed.