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Objective: In interventional neuroradiology (INR), the evaluation of the peak skin dose (PSD) and lens dose is important because the patient radiation dose increases in cases in which the procedure is more difficult and complex. This study evaluated the radiation doses during INR procedures using a direct measurement system., Methods: Radiation dose measurements during INR were performed in 332 patients with unruptured aneurysm (URAN), dural arteriovenous fistula (DAVF), and arteriovenous malformation (AVM). The PSD and bilateral lens doses were analyzed for each disease. The Pearson correlation test was used to determine whether the PSD and lens doses were linearly related to the reference air kerma (K a,r )., Results: In all cases, the PSD and right and left lens doses were 2.36 ± 1.28 Gy, 114.2 ± 54.6 mGy, and 189.8 ± 160.3 mGy, respectively. The PSD and lens doses of the DAVF and AVM cases were significantly higher than those of the URAN case. The Pearson correlation test revealed statistically significant positive correlations between K a,r and PSD, K a,r and right lens dose, and K a,r and left lens dose., Conclusion: The characteristics of radiation dose in INR were clarified. Owing to the concern of increased radiation doses exceeding the threshold values in DAVF and AVM cases, protection from radiation is required. Simple regression analysis revealed the possibility of precisely predicting PSD using K a,r ., Competing Interests: The authors declare that they have no conflicts of interest., (©2022 The Japanese Society for Neuroendovascular Therapy.)

Since Agatston et al. first reported quantification of the coronary artery calcification score (CACS) in 1990, discussion of its clinical significance and use in diagnostic management has continued. Recent papers have reported the relationship between CACS and myocardial perfusion single photon emission computed tomography (SPECT: MPS) and its combined diagnostic value. When interpreting CACS results, it should be noted that the frequency of significant ischemia detected by MPS, likelihood of coronary artery disease (CAD), and event rate gradually increased from mild to moderate CACS (1-400). At present, high CACS is considered to be moderately consistent with abnormal MPS, and abnormal CACS in normal MPS may contribute to CAD risk stratification. However, it should be noted that CACS=0 does not completely exclude CAD, which is particularly important when using CACS as a gatekeeper for MPS. Both stand-alone computed tomography (CT) scanner and hybrid SPECT-CT scanner are available for combined risk stratification of CACS and MPS in addition to improvement of image quality with attenuation correction., Competing Interests: None., (2022, Japanese Society of Nuclear Cardiology.)

The relationship between the socioeconomic status, including the health insurance status, and prognosis of heart failure (HF) has been recognized as an important concept for stratifying the risk in HF patients and is gaining increasing attention worldwide even in countries with a universal healthcare system. However, the impact of the Japanese health insurance status on outcomes among patients admitted for acute HF has not been fully clarified. We enrolled 771 patients admitted for acute HF between January 2018 and December 2019 and collected data on the in-hospital mortality, length of the hospital stay, and cardiac events, defined as cardiovascular death and readmission for HF within 1 year after discharge. Patients were divided into two groups according to their insurance status, i.e., public assistance (n = 87) vs. other insurance (n = 684). The public assistance group was significantly younger and had a higher rate of diabetes, smoking, ischemic and hypertensive heart disease, and low estimated glomerular filtration rate (all P < 0.05). Pharmacological/invasive heart failure therapy, in-hospital mortality, and the 90-day cardiac event rate after discharge did not differ between the groups. However, the public assistance group had a significantly higher 1-year cardiac event rate than the other insurance groups (P = 0.025). After adjusting for covariates, public assistance was independently associated with the 1-year cardiac event rate (HR: 2.15, 95% CI: 1.42-3.26, P < 0.001). Acute HF patients covered by public assistance received the same quality of medical care, including invasive therapy. As a result, no health disparities were found in terms of the in-hospital mortality and 90-day cardiac event rate, unlike overseas surveys. Nevertheless, HF patients with public assistance had a higher risk for the long-term prognosis than those with other insurance. Comprehensive HF management is required post-discharge., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Random forest regression was applied to optimize the melt-blending process of polyphenylene sulfide (PPS) with poly(ethylene-glycidyl methacrylate-methyl acrylate) (E-GMA-MA) elastomer to improve the Charpy impact strength. A training dataset was constructed using four elastomers with different GMA and MA contents by varying the elastomer content up to 20 wt% and the screw rotation speed of the extruder up to 5000 rpm at a fixed barrel temperature of 300 °C. Besides the controlled parameters, the following measured parameters were incorporated into the descriptors for the regression: motor torque, polymer pressure, and polymer temperatures monitored by infrared-ray thermometers installed at four positions (T1 to T4) as well as the melt viscosity and elastomer particle diameter of the product. The regression without prior knowledge revealed that the polymer temperature T1 just after the first kneading block is an important parameter next to the elastomer content. High impact strength required high elastomer content and T1 below 320 °C. The polymer temperature T1 was much higher than the barrel temperature and increased with the screw speed due to the heat of shear. The overheating caused thermal degradation, leading to a decrease in the melt viscosity and an increase in the particle diameter at high screw speed. We thus reduced the barrel temperature to keep T1 around 310 °C. This increased the impact strength from 58.6 kJ m -2 as the maximum in the training dataset to 65.3 and 69.0 kJ m -2 at elastomer contents of 20 and 30 wt%, respectively., (© 2021. The Author(s).)

Objective This retrospective study was aimed at determining whether or not stress phase bandwidth (SPBW), a left ventricular (LV) mechanical dyssynchrony index, predicts major cardiac events (MCEs) and stratifies the risk of those in patients with coronary artery disease (CAD) who undergo revascularization. Methods Patients were followed up to confirm the prognosis for at least one year. The SPBW was calculated by a phase analysis using the Heart Risk View-F software program. The composite endpoint was the onset of MCEs, consisting of cardiac death, non-fatal myocardial infarction, unstable angina pectoris, and severe heart failure requiring hospitalization. Patients The study subjects were 332 patients with CAD who underwent coronary angiography and revascularization after confirming ≥5% ischemia detected by rest 201 Tl and stress 99m Tc-tetrofosmin electrocardiogram-gated single-photon emission computed tomography myocardial perfusion imaging. Results During the follow-up, 35 patients experienced MCEs of cardiac death (n=5), non-fatal myocardial infarction (n=3), unstable angina pectoris (n=11), and severe heart failure requiring hospitalization (n=16). A receiver operating characteristics analysis indicated that the optimal cut-off value of the SPBW was 52° for predicting MCEs, and the MCE rate was significantly higher in the patients with an SPBW >52° than in those with an SPBW ≤52°. Results of the multivariate analysis showed the SPBW and estimated glomerular filtration rate to be independent predictors for MCEs. In addition, the cut-off value of the SPBW significantly stratified the risk of MCEs according to the results of the Kaplan-Meier analysis. Conclusion Evaluating the SPBW before revascularization may help predict future MCEs in patients with CAD who intended to undergo treatment.

The ultra-short dual antiplatelet therapy (DAPT) followed by P2Y 12 inhibitor monotherapy might be promising after percutaneous coronary intervention (PCI). However, CYP2C19 loss-of-function (LOF) alleles have been reported to diminish the effect of clopidogrel, and clopidogrel monotherapy has a concern about the increased ischemic risk for patients with such alleles. STOPDAPT-2 is the multicenter prospective open-label, but adjudicator-blinded randomized control study comparing 1-month DAPT followed by clopidogrel monotherapy with the standard 12-month DAPT after PCI with cobalt-chromium everolimus-eluting stents. Among the participants of STOPDAPT-2, selected patients participated in a substudy of the CYP2C19 gene test. Patients with two CYP2C19*2 or *3 alleles were defined as the poor metabolizer (PM), one allele as the intermediate metabolizer (IM), and no allele as the extensive metabolizer (EM). The primary endpoint was the composite of cardiovascular and bleeding events, as defined in STOPDAPT-2. Among 750 (24.9%) patients with known CYP2C19 genotypes, 129 (17.2%) were PM, 367 (49.0%) were IM, and 254 (33.9%) were EM. The hazard ratios of 1-month DAPT relative to 12-month DAPT for the primary endpoint in PM, IM, and EM strata were 0.66 (95% CI 0.11-3.94), 1.94 (95% CI 0.60-6.31), and 0.21 (95% CI 0.02-1.78), respectively (P interaction = 0.17), and those for cardiovascular composite endpoint were 1.00 (95% CI 0.14-7.10), 6.10 (95% CI 0.75-49.55), and 0.26 (95% CI 0.03-2.34), respectively (P interaction = 0.12). In conclusion, for the selected patients in STOPDAPT-2 trial, CYP2C19 LOF alleles had no significant, consistent interaction with the effect of 1-month DAPT relative to 12-month DAPT for clinical outcomes, although the study was overtly underpowered. TRIAL REGISTRY: STOPDAPT-2 ClinicalTrials.gov number, NCT02619760., (© 2020. Japanese Association of Cardiovascular Intervention and Therapeutics.)

Tegafur is a prodrug of fluoropyrimidine 5-fluorouracil (5-FU), while TS-1 TM is an oral fixed-dose combination of three active drugs, tegafur, gimeracil, and oteracil. This pilot study evaluated the safety of tegafur/gimeracil/oteracil in the treatment of cancers in dogs. Tegafur/gimeracil/oteracil was administered orally at a mean dose of 1.1 mg/kg twice daily on alternate days, Monday-Wednesday-Friday, every week to 11 dogs with tumors. Partial response and stable disease were observed in one dog each, whereas six exhibited progressive disease. Three dogs were not assessed. Adverse events, the most serious being grade 2, were noted in seven dogs. Adverse events were acceptable, and the drug was effective in some dogs. Therefore, tegafur/gimeracil/oteracil may be useful for treating malignant solid tumors in canines.

Aims: Wall shear stress (WSS) has been considered a major determinant of aortic atherosclerosis. Recently, non-obstructive general angioscopy (NOGA) was developed to visualize various atherosclerotic pathologies, including in vivo ruptured plaque (RP) in the aorta. However, the relationship between aortic RP and WSS distribution within the aortic wall is unclear. This study aimed to investigate the relationship between aortic NOGA-derived RP and the stereographic distribution of WSS by computational fluid dynamics (CFD) modeling using three-dimensional computed tomography (3D-CT) angiography., Methods: We investigated 45 consecutive patients who underwent 3D-CT before coronary angiography and NOGA during coronary angiography. WSS in the aortic arch was measured by CFD analysis based on the finite element method using uniform inlet and outlet flow conditions. Aortic RP was detected by NOGA., Results: Patients with a distinct RP showed a significantly higher maximum WSS value in the aortic arch than those without aortic RP (56.2±30.6 Pa vs 36.2±19.8 Pa, p=0.017), no significant difference was noted in the mean WSS between those with and without aortic RP. In a multivariate logistic regression analysis, the presence of a maximum WSS value more than a specific value was a significant predictor of aortic RP (odds ratio 7.21, 95% confidence interval 1.78-37.1,p=0.005)., Conclusions: Aortic RP detected by NOGA was strongly associated with a higher maximum WSS in the aortic arch derived by CFD using 3D-CT. The maximum WSS value may have an important role in the underlying mechanism of not only aortic atherosclerosis, but also aortic RP.

Atrial fibrillation (AF) is a progressive disease that starts with structural or functional changes in the left atrium and left ventricle, and evolves from paroxysmal toward sustained forms. Early detection of structural or functional changes in the left atrium and left ventricle in the paroxysmal stage could be useful for identifying a higher risk of progression to persistent AF and future cardio-cerebrovascular events. The aim of this study was to test the hypothesis that the feature tracking (FT) left atrial (LA) strain and left ventricular (LV) extracellular volume fraction (ECV) derived from cardiovascular magnetic resonance (CMR) could detect early changes in remodeling of the left atrium and ventricle in the paroxysmal AF (PAF) stage. The participants were comprised of 106 PAF patients (age, 66.1 ± 10.7 years; 66% male) who underwent clinical CMR before pulmonary vein isolation and 20 control subjects (age, 68.3 ± 8.6 years; 55% male). The CMR-FT LA strain/phasic function and LV-ECV were compared between the PAF and control groups. The total and passive LA empty fraction (LAEF) and LA strain (corresponding to LA reservoir and conduit function) were decreased in the PAF group as compared to the control group. However, active LAEF (corresponding to the LA booster pump function) did not differ significantly between the PAF group (33.9 ± 10.9%) and control group (37.9 ± 13.3%, p = 0.15), while the active LA strain (corresponding to the LA booster pump function) was significantly decreased in the PAF group (11.4 ± 4.3 vs. 15.2 ± 5.6%, p = 0.002). The LV-ECV was significantly greater in the PAF group (28.7 ± 2.8%) than control group (26.6 ± 2.0%, p = 0.002). In the PAF group, the LV-ECV correlated significantly with the E/e' and LA volume index. Regarding the LA strain, correlations were seen between the LV-ECV and both the reservoir function and conduit function. CMR-FT LA strain in combination with the LV-ECV in a single clinical study offers a potential imaging marker that identifies LA/LV remodeling including subtle LA booster pump dysfunction undetectable by the conventional booster pump LAEF in the PAF stage.

Background: The incremental predictive value of the coronary artery calcium score (CACS) for risk stratification of coronary revascularization in patients with normal or mildly abnormal nuclear myocardial perfusion single photon emission computed tomography (MPS) scores is unknown., Methods and results: We analyzed 528 patients in whom CACS was calculated and who underwent stress MPS within 3 months. Patients with known coronary artery disease, prior coronary revascularization, and those undergoing hemodialysis were excluded. Patients were followed-up with coronary revascularization based on the evidence of physiological ischemia defined by fractional flow reserve or severe coronary stenosis (≥90%). CACS was significantly associated with the summed stress score (SSS) from MPS assessment. Multivariate logistic regression analysis showed that high CACS (≥300; odds ratio [OR] 5.44, 95% confidence interval [CI] 2.28-13.0) and SSS (OR 1.29, 95% CI 1.18-1.40) were significant (P<0.001) predictors of future coronary revascularization. The log-rank test showed that high CACS stratified coronary revascularization in normal SSS (0-3; P<0.001) or mildly abnormal SSS (4-8; P=0.028) groups, whereas high CACS did not significantly stratify coronary revascularization in moderate to severe SSS (≥9; P=0.757)., Conclusions: Risk stratification using CACS with a cut-off value 300 may have incremental predictive value for revascularization in patients with normal or mildly abnormal MPS.

Purpose: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ( ROS1 )-positive (ROS1 + ) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1 + NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1 + disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib., Experimental Design: Biopsies from patients with ROS1 + NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing., Results: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1 L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1 L2086F , ROS1 G2032R/L2086F , and ROS1 S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%)., Conclusions: ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms., (©2021 American Association for Cancer Research.)

Two-dimensional (2D) culture of tumor cells fails to recapitulate some important aspects of cellular organization seen in in vivo experiments. In addition, cell cultures traditionally use non-physiological concentration of nutrients. Here, we describe a protocol for a facile three-dimensional (3D) culture format for cancer cells. This 3D platform helps overcome the 2D culture limitations. In addition, it allows for longitudinal modeling of responses to cancer therapeutics. For complete details on the use and execution of this protocol, please refer to Lhuissier et al. (2017), Lehmann et al. (2016), Liu et al. (2016), and Duval et al. (2011)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

In a Batesian mimic butterfly Papilio polytes , mimetic females resemble an unpalatable model, Pachliopta aristolochiae , but exhibit a different color pattern from nonmimetic females and males. In particular, the pale-yellow region on hind wings, which correspondingly sends important putative signals for mimicry and mate preference, is different in shape and chemical features between nonmimetic and mimetic morphs. Recently, we found that mimetic-type doublesex [ dsx (H) ] causes mimetic traits; however, the control of dimorphic pale-yellow colors remains unclear. Here, we revealed that dsx (H) switched the pale-yellow colors from UV-excited fluorescent type (nonmimetic) to UV-reflecting type (mimetic), by repressing the papiliochrome II synthesis genes and nanostructural changes in wing scales. Photoreceptor reactivities showed that some birds and butterflies could effectively recognize mimetic and nonmimetic pale-yellow colors, suggesting that a genetic switch in the UV response of pale-yellow colors may play essential roles in establishing the dimorphic female-limited Batesian mimicry., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Understanding the trend toward later and less marriage is particularly important in low-fertility societies where alternatives to marriage are limited and childbearing outside of marriage remains rare., Objective: Our goal in this paper is to advance our understanding of the wide variety of explanations offered for later and less marriage in Japan by focusing explicitly on marriage intentions and desires., Methods: Using two sources of nationally representative data, we describe the prevalence of positive, negative, and passive marriage intentions and desires among men and women who have never been married. We also examine socioeconomic differences in intentions, patterns of marriage desires across young adulthood, and relationships between marriage desires and outcomes. By linking three pathways to later and less marriage (rejection of marriage, failure to realize marriage desires, and unplanned drifting into singlehood) to specific theoretical frameworks, we generate indirect insights into explanations for later and less marriage., Conclusions: Although the large majority of unmarried men and women want to marry, less than half of respondents married across nine waves of the Japanese Life Course Panel Survey. Among those who remained unmarried, roughly two-thirds can be classified as 'drifting' into singlehood, about 30% as 'failing to realize marriage desires,' and no more than 5% as 'rejecting marriage.', Contribution: By extending the small body of research on marriage intentions and desires, this study provides a framework for thinking broadly about explanations for later and less marriage in Japan and highlights the importance of both failure to realize marriage desires and unplanned drifting into singlehood.

Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited., Patients and Methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH., Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation., Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients., Competing Interests: Disclosure JJL has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, Blueprint Medicines, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Roche/Genentech, Pfizer, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health; and received travel support from Pfizer. SVL served as a compensated consultant or on the advisory board for AstraZeneca, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Inivata, Janssen, Jazz, Lilly, Merck/MSD, PharmaMar, Pfizer, Regeneron, and Takeda; and received institutional research funding from Alkermes, AstraZeneca, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Lilly, Merck, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point Therapeutics. CEM received honorarium from Novartis and Guardant Health; served on the advisory board for Genentech; and received research funding from Novartis and Revolution Medicines. ACT has served as a compensated consultant or received honorarium from Thermo Fisher. ID-J has received honoraria from Foundation Medicine; consulting fees from Boehringer Ingelheim and AstraZeneca; research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. LJW has received personal fees from Bayer, Blueprint Medicines, Cue Biopharma, Exelixis, Genentech, and Rakuten Medical; received personal fees and nonfinancial support from Eisai, Lilly, Loxo Oncology, and Merck; and received institutional research funding from Loxo Oncology. ANH has received research support from Amgen, Pfizer, Novartis, Blueprint Medicines, Eli Lilly, Roche/Genentech, and Relay Therapeutics. MM-K has served as a compensated consultant for H3 Biomedicine and AstraZeneca; received institutional research support from Novartis. S-HIO has received personal fees from Pfizer, Merck, Takeda, AstraZeneca, Roche/Genentech, Daiichi Sankyo, Blueprint Medicines, and Janssen JNJ; and has stock ownership in Turning Point Therapeutics. DS-WT has served as a compensated consultant or received honorarium from Amgen, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Takeda, Bristol-Myers Squibb, MSD, Bayer, and Novartis; received institutional research funds from AstraZeneca, Pfizer, and Amgen; and received travel support from Pfizer and MSD. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, and Array; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee of Ironwood Pharmaceuticals. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Sequential assessment using CT coronary angiography (coronary CT) and nuclear myocardial perfusion imaging (MPI) is considered an anatomical and functional evaluation of coronary artery disease (CAD). However, there can be unexpected radiation exposure. Hybrid MPI with stress-only nuclear MPI and rest CT-MPI using coronary CT may contribute to reducing the radiation dose in sequential assessment with nuclear MPI after coronary CT. We analyzed the diagnostic performance and total radiation dose of hybrid MPI for detection of significant CAD compared with sequential assessment using nuclear MPI after coronary CT., Methods and results: The results for 101 patients who underwent coronary CT, nuclear MPI and invasive coronary angiography within 3 months of all imaging were analyzed. We calculated the summed difference score (SDS) from standard nuclear MPI and hybrid SDS from hybrid MPI, which revealed myocardial ischemia. The diagnostic performance of SDS and hybrid SDS for detecting significant CAD was analyzed using receiver-operating characteristic (ROC) curve analysis. We also compared the total radiation dose of both methods. The area under the ROC curve was not different between SDS and hybrid SDS (0.901 and 0.815, P=0.079). Total radiation dose of hybrid MPI was significantly lower than standard nuclear MPI with CT angiography (4.62 mSv vs. 9.72 mSv, P<0.0001)., Conclusions: Hybrid MPI showed a precise diagnostic accuracy for significant CAD detection.

Left ventricular (LV) mechanical dyssynchrony assessed with phase analysis of electrocardiogram (ECG) -gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is useful for predicting major cardiac events (MCEs) in patients with cardiac dysfunction. However, there is no report on its usefulness in Japanese patients with known or suspected stable coronary artery disease (CAD) with preserved LV ejection fraction (LVEF).We retrospectively investigated 3,374 consecutive patients with known or suspected CAD who underwent rest 201 Tl and stress 99m Tc-tetrofosmin ECG-gated SPECT MPI and had preserved LVEF (≥ 45%), and followed them up to confirm their prognosis for three years. The composite endpoint was the onset of MCEs consisting of cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris, and severe heart failure requiring hospitalization. LV mechanical dyssynchrony was evaluated with phase analysis with the Heart Risk View-F software to obtain the phase bandwidth and standard deviation.During the follow-up, 179 patients experienced MCEs: cardiac death (n = 42); non-fatal MI (n = 34); unstable angina pectoris (n = 54); and severe heart failure (n = 49). Results of the multivariate analysis showed age, a history of MI, diabetes mellitus, summed stress score, and stress phase bandwidth to be independent predictors for MCEs. In Kaplan-Meier analysis, prognoses were significantly stratified with the tertiles of stress phase bandwidth.LV mechanical dyssynchrony assessed with ECG-gated SPECT MPI is useful for predicting a prognosis and stratifying the risk of MCEs in Japanese patients with known or suspected stable CAD with preserved LVEF.

In most Papilio species, a younger larva mimics bird droppings but changes its pattern to match host plant colors in its final instar. This change is determined by juvenile hormone (JH) during the JH-sensitive period (JHSP) early in the fourth instar. Recently, we found that homeobox genes control the pre-pattern formation specifically during JHSP, but the molecular mechanisms underlying final patterning and pigmentation at molt are unknown. By knockdown of Delta and Notch in Papilio xuthus larvae, we here showed that these genes define the edge and pigmentation area in final patterns, during and even after JHSP, suggesting that they bridge the JHSP and molt. Knockdown of Delta in Papilio machaon led to similar phenotypic changes, and knockdown of Notch caused pigmentation loss in twin spots of the silkworm Multilunar (L) mutant. Our findings suggest the importance of the Notch signaling pathway in caterpillars' adaptive evolution of color pattern formation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFR CT ) is an established tool for identifying lesion-specific ischemia that is now approved for use by the Japanese insurance system. However, current clinical reimbursement is strictly limited to institutions with designated appropriate use criteria (AUC). This study assessed differences in physicians' behavior (e.g., use and interpretation of FFR CT , final management) according to Japanese AUC and non-AUC site designation. Methods and Results: Of 5,083 patients in the ADVANCE Registry, 1,829 from Japan were enrolled in this study. Physicians' behavior after interrogating CCTA and FFR CT was analyzed separately according to AUC and non-AUC site designation. Compared with AUC sites, patients referred for FFR CT from non-AUC sites had a higher rate of negative FFR CT , less severe anatomic stenosis, and a slightly lower rate of management plan reclassification (51.2% vs. 61.3%), with near-identical utility in both groups. Actual care corresponded equally well to post-FFR CT plans in both groups. The likelihood of revascularization for positive or negative FFR CT was similar between the 2 groups. Importantly, AUC and non-AUC sites were equally unlikely to revascularize patients with negative FFR CT and stenosis >50% or patients with positive FFR CT and stenosis <50%. Conclusions: Compared with AUC sites, non-AUC sites had lower disease burden and reclassification of management plans, but nearly identical clinical integration. Actual care corresponded equally well to post-FFR CT recommendations at both sites., Competing Interests: H.M. declares speaker fees from Abbott Vascular Japan, Phillips, Zeon Medical, Boston Scientific Japan. H.O. declares payments for lectures, including service on speakers bureaus, from HeartFlow Inc. N.T. declares consulting fees from Abbott Vascular Japan, Boston Scientific Japan and KANEKA Medix Co. C.R. is an employee of and has equity in HeartFlow. G.R. has received an institutional research grant from HeartFlow. L.M.H.K. has received departmental grant funding from Siemens Healthineers, HeartFlow, Verily, and Mallinckrodt. B.L.N. has received institutional unrestricted grants from Siemens and HeartFlow. J.L. declares consultant and stock options with CIRCLE CVI and HeartFlow, and research support from GE Healthcare. H.I. is a member of the Editorial Board of Circulation Reports. Y.M. is an Associate Editor of Circulation Reports. The remaining authors declare no conflicts of interest., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

Objective There is no report on the risk stratification of major cardiac events (MCEs) with a combination of the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score and ischemic reduction detected with rest 201 Tl and stress 99m Tc-tetrofosmin myocardial perfusion single-photon-emission computed tomography (SPECT) after revascularization in Japanese patients with coronary artery disease (CAD). Methods This was a retrospective study. The patients were followed up to confirm their prognosis for at least one year. Ischemia was evaluated based on the summed difference scores converted to the percentage of the total myocardium Safety Data Sheet (SDS%). The SYNTAX score and SDS% were calculated before and after revascularization. The endpoint was the occurrence of MCEs. Patients Study subjects were 293 patients who had a ≥75% stenotic lesion detected with coronary angiography following confirmation of ≥5% ischemia with SPECT, underwent revascularization, and thereafter received a re-evaluation with SPECT and coronary angiography. Results During the follow-up, 25 patients experienced MCEs of cardiac death (n=2), non-fatal myocardial infarction (n=3), and unstable angina pectoris (n=20). A receiver operating characteristic analysis indicated that the best cut-off values of the residual SYNTAX score and ΔSDS% were 12 and 5%, respectively, for the prediction of MCEs. The patients with a low residual SYNTAX score (<12) and high ΔSDS% (≥5%) had the best prognosis, while those with a high residual SYNTAX score (≥12) and low ΔSDS% (<5%) had the worst prognosis. Conclusion The combination of the residual SYNTAX score and ischemic reduction detected with nuclear cardiology is useful for predicting MCEs after revascularization.

Purpose: Most ALK -positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed., Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue ( n = 101) or plasma ( n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance., Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib ( P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy., Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET., (©2020 American Association for Cancer Research.)

Introduction: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described., Methods: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays., Results: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs., Conclusions: RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate a new scoring balloon, the non-slip element (NSE) percutaneous transluminal angioplasty (PTA) balloon, in the treatment of femoropopliteal lesions by comparing angiographic dissection patterns to those of a conventional balloon. Methods: This retrospective, single-center study included 71 symptomatic patients (mean age 77.4±8.8 years; 33 men) with de novo femoropopliteal lesions <20 cm long treated with balloon angioplasty between January 2017 and May 2018. Thirty-four patients were treated with 3 inflations of an NSE balloon and 37 patients were treated with a conventional balloon. Results: Severe dissections were fewer (8.8% vs 29.7%, p=0.027) and the total dissection length was shorter (11.5±12.8 vs 35.7±24.1 mm, p=0.027) in the NSE group. The bailout stenting rate was also lower in the NSE group (17.6% vs 40.5%, p=0.035). There were no significant differences between the groups regarding lesion length (70.3±50.4 vs 77.8±56.6 mm, p=0.28), inflation time (294±162 vs 353±179 seconds, p=0.08), or inflation pressure (10.6±5.0 vs 11.3±5.3 atm, p=0.31). Conclusion: Three NSE balloon inflations may reduce severe dissections induced by balloon angioplasty in femoropopliteal lesions.

Objective We aimed to stratify the risk of major cardiovascular (MCV) events in Japanese patients with known or suspected coronary artery disease (CAD) who had normal single-photon emission computed tomographic myocardial perfusion imaging (SPECT MPI) findings and to compare the risk by generation. Methods This was a retrospective study. The composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Patients The study subjects were 2,035 patients with normal SPECT MPI findings at baseline who had been followed up to confirm their prognosis for 3 years. The patients were categorized into 3 age groups: very elderly (≥80 years old, n=311), elderly (65-79 years old, n=1,097), and younger (<65 years old, n=542). Results During the follow-up, 68 patients experienced MCV events: cardiovascular death (n=29), non-fatal myocardial infarction (n=15), and non-fatal stroke (n=24). The MCV event rate was significantly higher in very elderly patients than in other patients. Multivariate predictors were age categories, the estimated glomerular filtration rate, atrial fibrillation, and stress left ventricular ejection fraction. The MCV event rate was 6.1% in very elderly patients. However, the MCV event rate in those with normal cardiac and renal functions without atrial fibrillation was 3.3%, which was similar to that in elderly and younger patients. Conclusion The MCV event rate was high in very elderly patients despite their normal SPECT MPI findings at baseline. Therefore, very elderly patients with multivariate risks should be carefully followed to avoid a poor prognosis.

Background: No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients., Methods: In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS)., Results: Twenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8-63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3-4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%)., Conclusions: The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment., Clinical Trials Registration Number: UMIN ID: 000013125.

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

The purpose of this study was to investigate the dose distribution and lens doses associated with C-arm cone-beam computed tomography (CBCT), using a head phantom, and to estimate the contribution ratio of C-arm CBCT to each patient's lens dose during interventional neuroradiology ('lens dose ratio') in 109 clinical cases. In the phantom study, the peak skin doses and respective right and left lens doses of C-arm CBCT were as follows: 63.0 ± 1.9 mGy, 19.7 ± 1.4 mGy and 21.9 ± 0.8 mGy in whole brain C-arm CBCT and 39.2 ± 1.4 mGy, 4.7 ± 0.9 mGy and 3.6 ± 0.3 mGy in high-resolution C-arm CBCT. In the clinical study, the lens dose ratios were 25.4 ± 8.7% in the right lens and 19.1 ± 9.8% in the left lens. This study shows that, on average, ~25% of patients' total lens dose was contributed by C-arm CBCT., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The diagnostic performance of 320-detector cardiac computed tomography (CCT) for the detection of thrombi in the left atrial appendage (LAA), relative to transesophageal echocardiography (TEE) as the gold standard, has not yet been evaluated. A total of 91 consecutive patients who were scheduled to undergo pulmonary vein isolation and underwent TEE and CCT were enrolled in this study. Delayed scanning on CCT was performed following early scanning, at 60 seconds after the start of the contrast injection. The radiation dose was estimated for both scans. The early scans showed a contrast medium filling defect (FD) in the LAA in 27 patients, whereas the delayed scans showed an FD in the LAA in six patients. Of these, five patients were confirmed to have a thrombus in the LAA by TEE. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 100, 74.4, 18.5, 100, and 75.8% for early scanning and 100, 98.8, 83.3, 100, and 98.9% for delayed scanning, respectively. The area under the curve for the detection of a thrombus in the LAA on the delayed scans was significantly larger than that for the detection on the early scans (0.99 versus 0.87, P < 0.001). The estimated median radiation doses for the early and delayed scans were 2.86 and 0.42 mSv, respectively. Addition of delayed scanning to early scanning improved the diagnostic performance for the detection of a thrombus in the LAA and may obviate unnecessary TEE, with minimal additional radiation exposure.

The swallowtail butterfly Papilio polytes is sexually dimorphic and exhibits female-limited Batesian mimicry. This species also has two female forms, a non-mimetic form with male-like wing patterns, and a mimetic form resembling an unpalatable model, Pachliopta aristolochiae . The mimicry locus H constitutes a dimorphic Mendelian 'supergene', including a transcription factor gene doublesex ( dsx ). However, how the mimetic-type dsx ( dsx-H ) orchestrates the downstream gene network and causes the mimetic traits remains unclear. Here we performed RNA-seq-based gene screening and found that Wnt1 and Wnt6 are up-regulated by dsx-H during the early pupal stage and are involved in the red/white pigmentation and patterning of mimetic female wings. In contrast, a homeobox gene abdominal-A is repressed by dsx-H and involved in the non-mimetic colouration pattern. These findings suggest that dual regulation by dsx-H , induction of mimetic gene networks and repression of non-mimetic gene networks, is essential for the switch from non-mimetic to mimetic pattern in mimetic female wings., Competing Interests: Competing interestsThe authors declare no competing interests.

Background: Coronary computed tomography angiography (cCTA)-derived fractional flow reserve (FFR CT ) is a promising diagnostic method for the evaluation of coronary artery disease (CAD). However, clinical data regarding FFR CT in Japan are scarce, so we assessed the clinical impact of using FFR CT in a Japanese population.Methods and Results:The ADVANCE registry is an international prospective FFR CT registry of patients suspected of CAD. Of 5,083 patients, 1,829 subjects enrolled from Japan were analyzed. Demographics, symptoms, cCTA, FFR CT , treatment strategy, and 90-day major cardiovascular events (MACE) were assessed. Reclassification of treatment strategy between cCTA alone and cCTA+FFR CT occurred in 55.8% of site investigations and in 56.9% in the core laboratory analysis. Patients with positive FFR (FFR CT ≤0.80) were less likely to have non-obstructive disease on invasive coronary angiography than patients with negative FFR (FFR CT >0.80) (20.5% vs. 46.1%, P=0.0001). After FFR CT , 67.0% of patients with positive results underwent revascularization, whereas 96.1% of patients with negative FFR CT were medically treated. MACE occurred in 5 patients with positive FFR CT , but none occurred in patients with negative FFR CT within 90 days., Conclusions: In this Japanese population, FFR CT modified the treatment strategy in more than half of the patients. FFR CT showed potential for stratifying patients suspected of CAD properly into invasive or non-invasive management pathways.

Supercritical drying is widely considered as the gold standard to produce aerogels that preserve the microstructure of the gels, but we have found this is not always the case. Chitosan aerogel, one of the emerging biopolymer aerogels, was prepared by chemical cross-linking gelation, followed by solvent exchange with methanol and supercritical drying using CO 2 . Small-angle X-ray scattering analysis shows that the structure of the wet gel, which consists of Gaussian chains of individual molecular strands, converts into a nanofibrous network during CO 2 processing. In situ observation reveals a drastic shrinkage of the gel in CO 2 , demonstrating that physical coagulation caused by the low affinity between chitosan and CO 2 is the main structure-forming step. These results challenge the common perception of supercritical drying: it is no longer an inactive drying method, but rather an active nanostructure forming a tool to produce porous biopolymer materials with tailored structure and properties.

Background: Myocardial perfusion imaging (MPI) is considered useful for risk stratification among patients with chronic kidney disease (CKD), without renal deterioration by contrast media., Methods and Results: The Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS 3) is a multicenter, prospective cohort study investigating the ability of MPI to predict cardiac events in 529 CKD patients without a definitive coronary artery disease. All patients were assessed by stress and rest MPI with 99m Tc-tetrofosmin and data were analyzed using a defect scoring method and QGS software. Major cardiac events were analyzed for 3 years after registration. The mean eGFR was 29.0 ± 12.8 (mL/minute/1.73 m 2 ). The mean summed stress/rest/difference (SSS, SRS, SDS) scores were 1.9 ± 3.8, 1.1 ± 3.0, and 0.8 ± 1.8, respectively. A total of 60 cardiac events (three cardiac deaths, six sudden deaths, five nonfatal myocardial infarctions, 46 hospitalization cases for heart failure) occurred. The event-free survival rate was lower among patients with kidney dysfunction, higher SSS, and higher CRP values. Multivariate Cox regression analysis independently associated SSS ≥8, eGFR <15 (mL/minute/1.73 m 2 ), and CRP ≥0.3 (mg/dL) with cardiac events., Conclusions: Together with eGFR and CRP, MPI can predict cardiac events in patients with CKD.

Recently, polymeric foams filled with a silica aerogel have been developed. The phase behavior of CO₂/silicon alkoxide binary systems and CO₂/silicon alkoxide/polymer ternary systems is an important factor that affects the design of novel processes. The phase behavior of a carbon dioxide (CO₂)/methyl trimethoxy silane (MTMS)/polystyrene (PS) ternary system was measured using a synthetic method involving the observation of the bubble and cloud point. The phase boundaries were measured at temperatures ranging from 313.2 to 393.2 K and CO₂ weight fractions between 0.01 and 0.08. The CO₂/MTMS/PS system showed a similar CO₂ mass fraction dependence of the phase behavior to that observed for the CO₂/tetramethyl orthosilicate (TMOS)/PS system. When the phase boundaries of these systems were compared, the vapor-liquid (VL) and vapor-liquid-liquid (VLL) lines were found to be nearly identical, while the liquid-liquid (LL) lines were different. These results indicate that the affinity between the silicon alkoxide and polymer greatly influences the liquid-liquid phase separation.

Targeted therapies have changed the landscape of treatments for non-small cell lung cancer (NSCLC). Specific targeted therapies have been approved for NSCLC patients harboring genetic alterations in four oncogenes, and agents targeting additional oncogenic drivers are under investigation. Standard first-line chemotherapy has been supplanted by these targeted therapies due to superior efficacy and lower toxicity. Despite excellent response rates and durable responses in some cases, most patients experience relapse within a few years due to the development of acquired drug resistance. Next generation targeted therapies are being developed to overcome drug resistance and extend the duration of therapy. In this review, we summarize the current treatment strategies for the major targetable oncogenic mutations/alterations in NSCLC and discuss the mechanisms leading to acquired drug resistance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired CCDC6-RET fusion. Although RET fusions have been identified in resistant EGFR -mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR -mutant cancer, we expressed CCDC6-RET in PC9 ( EGFR del19) and MGH134 ( EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with EGFR -mutant NSCLC and RET -mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. SIGNIFICANCE: The role of RET fusions in resistant EGFR -mutant cancers is unknown. We report that RET fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic. This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

Background: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM., Methods: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke., Findings: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45)., Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Background: Metabolic syndrome/epicardial adipose tissue (EAT) plays an important role in atrial fibrillation (AF). Although reverse atrial remodeling (RAR) often occurs after AF ablation, the effects of EAT on RAR remain unknown., Methods: Study subjects were 104 patients in whom transthoracic echocardiography (TTE) was performed before AF ablation and 3, 6, and 12 months afterward. EAT was assessed in terms of its thickness adjacent to the right ventricular anterior wall in the TTE parasternal view. RAR was defined as >10% reduction in the left atrial volume (LAV) index by the 3-month follow-up examination., Results: Postablation RAR occurred in 57/104 (55%) patients. RAR absence was associated with a relatively thick EAT (4.92 ± 1.65 vs. 3.92 ± 1.17 mm, P  =   0.0005), small LAV index (24.6 ± 7.5 vs. 28.8 ± 10.6 mL/m 2 , P  =   0.0233), and metabolic syndrome (62% vs. 28%, P  =   0.0006). Metabolic syndrome and EAT were shown to be independent predictors of RAR absence. Thick EAT was significantly associated with AF recurrence after ablation (5.05 ± 2.19 mm vs. 4.17 ± 1.16 mm for no AF recurrence group, P  =   0.0116), but metabolic syndrome was not (48% vs. 42%, P  =   0.6189). Despite no change in body weight, EAT thickness decreased significantly by 12 months in patients without AF recurrence (4.17 ± 1.16 vs. 3.65 ± 1.16 mm, P  <   0.0001)., Conclusions: EAT and metabolic syndrome appear to be strongly associated with RAR absence, but only the thick EAT was significantly associated with the postablation AF recurrence. Our findings, especially the thinning of EAT, suggest that thick EAT lead to AF vulnerability but that EAT reduction favorably affects ablation outcome.

Aim: Whether myocardial ischemia identified using myocardial perfusion imaging (MPI) can be an alternative target of coronary revascularization to reduce the incidence of cardiac events remains unclear., Methods and Results: This multicenter, prospective cohort study aimed to clarify the prognostic impact of reducing myocardial ischemia. Among 494 registered patients with possible or definite coronary artery disease (CAD), 298 underwent initial pharmacological stress 99m Tc-tetrofosmin MPI before, and eight months after revascularization or medical therapy, and were followed up for at least one year. Among these, 114 with at least 5% ischemia at initial MPI were investigated. The primary endpoints were cardiac death, non-fatal myocardial infarction and hospitalization for heart failure. Ischemia was reduced ≥5% in 92 patients. Coronary revascularization reduced ischemia (n = 89) more effectively than medical therapy (n = 25). Post-stress cardiac function also improved after coronary revascularization. Ejection fraction significantly improved at stress (61.0% ± 10.7% vs. 65.4% ± 11.3%; p < 0.001) but not at rest (67.1% ± 11.3% vs. 68.3% ± 11.6%; p = 0.144), among patients who underwent revascularization. Rates of coronary revascularization and cardiac events among the 114 patients were significantly higher (13.6%, p = 0.035) and lower (1.1% p = 0.0053), respectively, in patients with, than without ≥5% ischemia reduction. Moreover, patients with complete resolution of ischemia at the time of the second MPI had a significantly better prognosis., Conclusions: Reducing ischemia by ≥5% and the complete resolution of ischemia could improve the prognosis of patients with stable CAD., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Limited data exist on indicators of durable pulmonary vein isolation (PVI) undergoing cryoballoon ablation (CBA) for atrial fibrillation (AF). We investigated whether balloon temperature and time to PVI can be used to predict early PV reconduction (EPVR), including residual PV conduction and adenosine triphosphate-induced dormant conduction and the relation between touch-up ablation of EPVR sites and mid-term recurrence of AF., Methods: We obtained procedural and outcome data from the records of 130 consecutive patients who underwent CBA and followed up for 13.4 months., Results: EPVR was identified in 86 (17%) PVs of 61 (47%) patients. Balloon temperatures during 30 seconds (-27 ± 5.7°C vs -31 ± 5.5°C), 60 seconds (-36 ± 5.6°C vs -41 ± 5.4°C), and at the nadir point (-41 ± 7.4°C vs -49 ± 7.0°C) were significantly higher, and the time to PVI was longer (90 ± 50 seconds vs 52 ± 29 seconds) in PVs with EPVR than in those without ( P  < 0.0001 for all). Among PVs without EPVR, the time to PVI was longer and balloon temperature was lower for the left superior pulmonary vein/ right inferior pulmonary vein (LSPV/RIPV) than for the right superior pulmonary vein/left inferior pulmonary vein (RSPV/LIPV) (time: 60 ± 25/73 ± 37 seconds vs 41 ± 31/45 ± 20 seconds, P  < 0.0001) (temp: -39.2 ± 11.3/-39.4 ± 8.3°C vs -33.8 ± 10.6/-33.6 ± 6.8°C, P  = 0.0023). AF recurrence rates were equivalent between patients with and without EPVR (13% [8/69] vs 15% [9/61], P  = 0.845)., Conclusions: Cryoballoon temperature and time to PVI appear to be useful in predicting durable PVI, that is, prevention of EPVR, but the balloon temperature and time required for PVI differ between PVs. Although EPVR does not predict AF recurrence, high success rates can be expected when touch-up ablation of EPVR sites is performed.

Vascular endothelial dysfunction plays an important role in the process of atherosclerosis up to the final stage of plaque rupture. Vascular endothelial dysfunction is reversible, and can be recovered by medications and life-style changes. Improvement in endothelial function may reduce cardiovascular events and improve long-term prognosis. A total of 50 patients with stable angina and dyslipidemia were enrolled, including patients who had not received prior treatment with statins and had serum LDL-C levels ≥ 100 mg/dL, and patients who had previously received statin treatment. All agreed to register regardless of their LDL-C level. Rosuvastatin was initially administered at a dose of 2.5 mg and appropriately titrated up to the maximum dose of 20 mg or until LDL-C levels lower than 80 mg/dL were achieved, for 24 weeks. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index in the radial artery by Endo-PAT ® 2000 (Endo-PAT ® 2000, software version 3.0.4, Itamar Medical Ltd., Caesarea, Israel). RH-PAT data were digitally analyzed online by Endo-PAT ® 2000 at baseline and at 24 weeks. LDL-C and MDA-LDL-C decreased from 112.6 ± 23.3 to 85.5 ± 20.2 mg/dL and from 135.1 ± 36.4 to 113.9 ± 23.5 mg/dL respectively (p < 0.0001). However, HDL-C, hs-CRP and TG did not change significantly after treatment. RH-PAT index levels significantly improved, from 1.60 ± 0.31 to 1.77 ± 0.57 (p = 0.04) after treatment, and the percent change of the RH-PAT index was 12.8 ± 36.9%. Results of multivariate analysis show that serum LDL-C levels over 24 weeks did not act as a predictor of improvement of the RH-PAT index. However, HbA1c at baseline was an independent predictor which influenced the 24-week RH-PAT index level. The RH-PAT index of patients with high HbA1c at baseline did not improve after administration of rosuvastatin but it did improve in patients with low HbA1c at baseline. Aggressive lowering of LDL-C with rosuvastatin significantly improved the RH-PAT index, suggesting that it may improve endothelial function in patients with coronary artery disease.Clinical Trial Registration No: UMIN-CTR, UMIN000010040.

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N -ethyl- N -nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies. Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663 ., (©2018 American Association for Cancer Research.)

Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.

Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.