Immunogenicity of influenza vaccination in patients with cancer receiving immune checkpoint inhibitors

Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs.

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of fibroblast growth factor receptor 2 (FGFR2) was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose‐dependent manner and selectively in FGFR2‐amplified cells. Regorafenib induced G1 arrest (SNU‐16, KATO‐III) and apoptosis (NCI‐H716); however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU‐16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2‐amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR2‐amplified gastric and colorectal cancers

Discontinuation risk from adverse events: immunotherapy alone vs. combined with chemotherapy: a systematic review and network meta-analysis

Abstract Background While immunotherapy combined with chemotherapy (Chemo-IO) is generally recognized for providing superior outcomes compared to monotherapy (mono-IO), it is associated with a higher incidence of treatment-related adverse events (TRAEs), which may lead to treatment discontinuation. In this study, we compared the rates of treatment discontinuation between mono-IO and Chemo-IO as first-line treatments for various solid tumors. Methods We systematically reviewed clinical trials from databases (PubMed, Embase, Cochrane Library, and an additional source) published from January 1, 2018, to July 10, 2023. We included phase III randomized controlled trials (RCTs) that utilized immunotherapy agents in at least one arm as first-line treatments for a variety of solid tumors. Data extraction followed the Preferred Reporting Items for Systematic Reviews (PRISMA) extension statement for network meta-analysis. A random effects model was used for the network meta-analysis, with the risk of bias assessed using the Cochrane risk-of-bias tool II. The primary outcomes encompassed treatment discontinuation rates due to TRAEs among patients who underwent immunotherapy, either alone or combined with chemotherapy, for various solid tumors. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated to compare between treatment groups. Results From 29 RCTs, a total of 21,677 patients and 5 types of treatment were analyzed. Compared to mono-IO, Chemo-IO showed a significantly higher rate of discontinuation due to TRAEs (RR 2.68, 95% CI 1.98–3.63). Subgroup analysis for non-small cell lung cancer (NSCLC) patients also exhibited a greater risk of discontinuation due to TRAEs with Chemo-IO compared to mono-IO (RR 2.93, 95% CI 1.67–5.14). Additional analyses evaluating discontinuation rates due to either treatment emergent adverse events (TEAEs) or AEs regardless of causality (any AEs) consistently revealed an elevated risk associated with Chemo-IO. Conclusions Chemo-IO was associated with an elevated risk of treatment discontinuation not only due to TRAEs but also any AEs or TEAEs. Given that the treatment duration can impact clinical outcomes, a subset of patients might benefit more from mono-IO than combination therapy. Further research is imperative to identify and characterize this subset

Macrophage migration inhibitory factor promotes resistance to MEK blockade in KRAS mutant colorectal cancer cells

Although MEK blockade has been highlighted as a promising antitumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single‐MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK. MIF knockdown by siRNA restored sensitivity to refametinib in KRAS mutant cells. In addition, combination with refametinib and 4‐IPP, a MIF inhibitor, effectively reduced the activity of STAT3 and MAPK, more than single‐agent treatment. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against refametinib‐resistant cells by inhibition of MIF activation. These results reveal that MIF‐induced STAT3 and MAPK activation evoked an intrinsic resistance to refametinib. Our results provide the basis for a rational combination strategy against KRAS mutant colorectal cancers, predicated on the understanding of cross talk between the MEK and MIF pathways

Suppression of Interfacial Current Fluctuation in MoTe2 Transistors with Different Dielectrics

For transition metal dichalcogenides, the fluctuation of the channel current due to charged impurities is attributed to a large surface area and a thickness of a few nanometers. To investigate current variance at the interface of transistors, we obtain the low-frequency (LF) noise features of MoTe2 multilayer field-effect transistors with different dielectric environments. The LF noise properties are analyzed using the combined carrier mobility and carrier number fluctuation model which is additionally parametrized with an interfacial Coulomb-scattering parameter (α) that varies as a function of the accumulated carrier density (Nacc) and the location of the active channel layer of MoTe2. Our model shows good agreement with the current power spectral density (PSD) of MoTe2 devices from a low to high current range and indicates that the parameter α exhibits a stronger dependence on Nacc with an exponent -γ of -1.18 to approximately -1.64 for MoTe2 devices, compared with -0.5 for Si devices. The raised Coulomb scattering of the carriers, particularly for a low-current regime, is considered to be caused by the unique traits of layered semiconductors such as interlayer coupling and the charge distribution strongly affected by the device structure under a gate bias, which completely change the charge screening effect in MoTe2 multilayer. Comprehensive static and LF noise analyses of MoTe2 devices with our combined model reveal that a chemical-vapor deposited h-BN monolayer underneath MoTe2 channel and the Al2O3 passivation layer have a dissimilar contribution to the reduction of current fluctuation. The three-fold enhanced carrier mobility due to the h-BN is from the weakened carrier scattering at the gate dielectric interface and the additional 30% increase in carrier mobility by Al2O3 passivation is due to the reduced interface traps. © 2016 American Chemical Society113141sciescopu

Temperature-Dependent Opacity of the Gate Field Inside MoS2 Field-Effect Transistors

© 2019 American Chemical Society.The transport behaviors of MoS2 field-effect transistors (FETs) with various channel thicknesses are studied. In a 12 nm thick MoS2 FET, a typical switching behavior is observed with an Ion/Ioff ratio of 106. However, in 70 nm thick MoS2 FETs, the gating effect weakens with a large off-current, resulting from the screening of the gate field by the carriers formed through the ionization of S vacancies at 300 K. Hence, when the latter is dual-gated, two independent conductions develop with different threshold voltage (VTH) and field-effect mobility (μFE) values. When the temperature is lowered for the latter, both the ionization of S vacancies and the gate-field screening reduce, which revives the strong Ion/Ioff ratio and merges the two separate channels into one. Thus, only one each of VTH and μFE are seen from the thick MoS2 FET when the temperature is less than 80 K. The change of the number of conduction channels is attributed to the ionization of S vacancies, which leads to a temperature-dependent intra- and interlayer conductance and the attenuation of the electrostatic gate field. The defect-related transport behavior of thick MoS2 enables us to propose a new device structure that can be further developed to a vertical inverter inside a single MoS2 flake11sciescopu