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Background: Approximately one-half of the patients with angina and nonobstructive coronary artery disease (ANOCA) have evidence of coronary microvascular dysfunction (CMD)., Objectives: This study aims to characterize patients with ANOCA by measuring their minimal microvascular resistance and to examine the pattern of vascular remodeling associated with these measurements., Methods: The authors prospectively included patients with ANOCA undergoing continuous thermodilution assessment. Lumen volume and vessel-specific myocardial mass were quantified using coronary computed tomography angiography (CTA). CMD was defined as coronary flow reserve <2.5 and high minimal microvascular resistance as >470 WU., Results: A total of 153 patients were evaluated; 68 had CMD, and 22 of them showed high microvascular resistance. In patients with CMD, coronary flow reserve was 1.9 ± 0.38 vs 3.2 ± 0.81 in controls (P < 0.001). Lumen volume was significantly correlated with minimal microvascular resistance (r = -0.59 [95% CI: -0.45 to -0.71]; P < 0.001). In patients with CMD and high microvascular resistance, lumen volume was 40% smaller than in controls (512.8 ± 130.3 mm 3 vs 853.2 ± 341.2 mm 3 ; P < 0.001). Epicardial lumen volume assessed by coronary CTA was independently associated with minimal microvascular resistance (P < 0.001). The predictive capacity of lumen volume from coronary CTA for detecting high microvascular resistance showed an area under the curve of 0.79 (95% CI: 0.69-0.88)., Conclusions: Patients with CMD and high minimal microvascular resistance have smaller epicardial vessels than those without CMD. Coronary CTA detected high minimal microvascular resistance with very good diagnostic capacity. Coronary CTA could potentially aid in the diagnostic pathway for patients with ANOCA., Competing Interests: Funding Support and Author Disclosures Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. Dr Mizukami has received consultancy fees from Zeon Medical Inc, research grants from Boston Scientific, and speaker fees from Abbott Vascular, Cath works, and Boston Scientific. Drs Buytaert and Munhoz have received research grants provided by the Cardiopath PhD program. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Vulnerable plaque presents prognostic implications in addition to functional significance., Objectives: The aim of this study was to identify relevant features of vulnerable plaque in functionally significant lesions., Methods: In this multicenter, prospective study conducted across 5 countries, including patients who had invasive fractional flow reserve (FFR) ≤0.80, a total of 95 patients with available pullback pressure gradient (PPG) and plaque analysis on coronary computed tomographic angiography and optical coherence tomography were analyzed. Vulnerable plaque was defined as the presence of plaque rupture or thin-cap fibroatheroma on optical coherence tomography. Among the 25 clinical characteristics, invasive angiographic findings, physiological indexes, and coronary computed tomographic angiographic findings, significant predictors of vulnerable plaque were identified., Results: Mean percentage diameter stenosis, FFR, and PPG were 77.8% ± 14.6%, 0.66 ± 0.13, and 0.65 ± 0.13, respectively. Vulnerable plaque was present in 53 lesions (55.8%). PPG and FFR were identified as significant predictors of vulnerable plaque (P < 0.05 for all). PPG >0.65 and FFR ≤0.70 were significantly related to a higher probability of vulnerable plaque after adjustment for each other (OR: 6.75 [95% CI: 2.39-19.1]; P < 0.001] for PPG >0.65; OR: 4.61 [95% CI: 1.66-12.8]; P = 0.003 for FFR ≤0.70). When categorizing lesions according to combined PPG >0.65 and FFR ≤0.70, the prevalence of vulnerable plaque was 20.0%, 57.1%, 66.7%, and 88.2% in the order of PPG ≤0.65 and FFR >0.70, PPG ≤0.65 and FFR ≤0.70, PPG >0.65 and FFR >0.70, and PPG >0.65 and FFR ≤0.70 (P for trend < 0.001), respectively., Conclusions: Among low-FFR lesions, the presence of vulnerable plaque can be predicted by PPG combined with FFR without additional anatomical or plaque characteristics. (Precise Percutaneous Coronary Intervention Plan [P3] Study; NCT03782688)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow and was also supported by grants from the Patient-Centered Clinical Research Coordinating Center (HI19C0481 and HC19C0305) funded by the Ministry of Health and Welfare and from the Ministry of Food and Drug Safety (RS-2023-00215667), Republic of Korea. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow; and has received speaker fees from Abbott Vascular. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; has received a research grant from GE; and has received modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath PhD program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Otake has received research grants from Abbott Vascular; and has received speaker fees from HeartFlow and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordics; and has received institutional research grants from Bayer, Philips Healthcare, and Novo Nordisk. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr De Bruyne has received consulting fees from Boston Scientific and Abbott Vascular; has received research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow, Edwards Lifesciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and has received consulting fees from HeartFlow, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary CT angiography (CCTA) is well-established for diagnosis and stratification of coronary artery disease (CAD). Its usefulness in guiding percutaneous coronary interventions (PCI) and stent sizing is unknown., Methods: This is a sub-analysis of the Precise Percutaneous Coronary Intervention Plan (P3) study (NCT03782688). We analyzed 65 vessels with matched CCTA and pre-PCI optical coherence tomography (OCT) assessment. The CCTA-guided stent size was defined by the mean distal reference lumen diameter rounded up to the nearest stent diameter. The OCT lumen-guided stent size was the mean distal reference lumen diameter rounded to the closest stent diameter. The agreement on stent diameters was determined with Kappa statistics, Passing-Bablok regression analysis, and the Bland-Altman method., Results: The distal reference lumen diameter by CCTA and OCT were 2.75 ​± ​0.53 ​mm and 2.72 ​± ​0.55 ​mm (mean difference 0.06, limits of agreement -0.7 to 0.82). There were no proportional or systematic differences (coefficient A 1.06, 95% CI 0.84 to 1.3 and coefficient B -0.22, 95% CI -0.83 to 0.36) between methods. The agreement between the CCTA and OCT stent size was substantial (Cohen's weighted Kappa 0.74, 95% CI 0.64 to 0.85). Compared to OCT stent diameter, CCTA stent size was concordant in 52.3% of the cases; CCTA overestimated stent size in 20.0% and underestimated in 27.7%., Conclusion: CCTA accurately assessed the reference vessel diameter used for stent sizing. CCTA-based stent sizing showed a substantial agreement with OCT. CCTA allows for PCI planning and may aid in selecting stent diameter., Competing Interests: Declaration of competing interest TM reports receiving consulting fees from Zeon Medical and HeartFlow Inc, and speaker fees from Abbott Vascular. BLN has received an unrestricted institutional research grant from HeartFlow Inc. MM is supported by a grant from the Novo Nordisk Foundation (grant NNF22OC0074083). BKK received an Institutional Research Grant from Abbott Vascular, Boston Scientific Corporation, and Philips. BDB reports receiving consultancy fees from Boston Scientific and Abbott Vascular, research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular, and owning equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, Celyad. CC reports receiving research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, Abbott Vascular, and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. The other authors have no further disclosures., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition., Methods: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained., Results: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m -1 , p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002)., Conclusions: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features., Clinical Trial Registration: https://clinicaltrials,gov/ct2/show/NCT03782688., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC., Patients and Methods: We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival., Results: A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%)., Conclusions: The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings., Competing Interests: Disclosure YN: research funding to my institution from Chugai, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, Pfizer; Honoraria for lectures, presentations, and speakers bureaus from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, Ono Pharma, Bristol-Myers Squibb; Participation on an Advisory Board of Daiichi Sankyo. YS: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly Japan K.K., MSD K.K., Novartis Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd., Merck Biopharma Japan Co. Ltd., Hisamitsu Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd. TK: honoraria from Bristol Myers-Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, Daiichi-Sankyo. HS: participation on a Data Safety Monitoring Board or Advisory Board of Ono Pharmaceutical Co., Ltd., Zymeworks; Other financial or non-financial interests from Ono Pharmaceutical Co., Ltd., Astellas, Takeda, Amgen, MSD, Daiichi Sankyo. TMi: research funding to my institution from Eli Lilly Japan K.K.; Honoraria for lectures from TAIHO pharmaceutical Co., Ltd, Merck Serono Pharmaceutical, Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Asahi Kasei Pharma Corporation., Otsuka Pharmaceutical Factory, Bristol Myers Squibb, Sanofi, Ono Pharmaceutical Co., Ltd. NI: grants or contracts of my institution from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda, Sanofi, Ohtsuka Pharmaceutical, Eli Lilly Japan; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan, Bristol-Byers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Ono Pharmaceutical Co., Ltd., MSD. TN: payment or honoraria for lectures from Daiichi-Sankyo Pharma, Ono pharma, Bristol Myers Squibb, Eli Lilly, Takeda Pharma, Merck Serono pharma, Chugai pharma, Taiho pharma, Yakulut Honsya; Data Safety Monitoring Board of Janssen Pharmaceutical. YY: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Servier, Yakult, Takeda, Chugai, Daiichi Sankyo, Lily, Teijin, Bayer, Insight SM: grants or contracts from Bayer; Consulting fees from Chugai Pharmaceutical Co., Ltd.; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from TAIHO Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb. MN: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer Yakuhin, Ltd., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd.; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Hokkaido Association of Supportive Care in Cancer Patients (NPO corporation). KM: research funding to my institution from Chugai, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, Pfizer; Consulting fees from AstraZeneca, Ono Pharmaceutical, Amgen, Astellas; Honoraria for lectures from Ono Pharmaceutical, Taiho, Bristol-Myers Squibb, Eli Lilly, MSD, Daiichi Sankyo; Advisory Board from Ono Pharmaceutical, Amgen, AstraZeneca, Eli Lilly, Takeda. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) can, in principle, be derived by any method assessing coronary flow., Objectives: The aim of this study was to compare CFR and MRR as derived by continuous (CFR cont and MRR cont ) and bolus thermodilution (CFR bolus and MRR bolus )., Methods: A total of 175 patients with chest pain and nonobstructive coronary artery disease were studied. Bolus and continuous thermodilution measurements were performed in the left anterior descending coronary artery. MRR was calculated as the ratio of CFR to fractional flow reserve and corrected for changes in systemic pressure. In 102 patients, bolus and continuous thermodilution measurements were performed in duplicate to assess test-retest reliability., Results: Mean CFR bolus was higher than CFR cont (3.47 ± 1.42 and 2.67 ± 0.81 [P < 0.001], mean difference 0.80, upper limit of agreement 3.92, lower limit of agreement -2.32). Mean MRR bolus was also higher than MRR cont (4.40 ± 1.99 and 3.22 ± 1.02 [P < 0.001], mean difference 1.2, upper limit of agreement 5.08, lower limit of agreement -2.71). The correlation between CFR and MRR values obtained using both methods was significant but weak (CFR, r = 0.28 [95% CI: 0.14-0.41]; MRR, r = 0.26 [95% CI: 0.16-0.39]; P < 0.001 for both). The precision of both CFR and MRR was higher when assessed using continuous thermodilution compared with bolus thermodilution (repeatability coefficients of 0.89 and 2.79 for CFR cont and CFR bolus , respectively, and 1.01 and 3.05 for MRR cont and MRR bolus , respectively)., Conclusions: Compared with bolus thermodilution, continuous thermodilution yields lower values of CFR and MRR accompanied by an almost 3-fold reduction of the variability in the measured results., Competing Interests: Funding Support and Author Disclosures Drs Paolisso and Esposito are supported by a research grant from the CardioPaTh PhD Program. Dr Barbato has received speaker fees from Abbott Vascular, Boston Scientific, and GE Healthcare. Dr Collet has received research grants from Biosensors, GE Healthcare, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and has received consultancy fees from HeartFlow, Opsens, Pie Medical Imaging, Abbott Vascular, and Philips. Dr De Bruyne has institutional consulting relationships with Boston Scientific, Abbott Vascular, CathWorks, Siemens, GE Healthcare, and Coroventis Research; has received institutional research grants from Abbott Vascular, Coroventis Research, CathWorks, and Boston Scientific; and has minor equity holdings in Philips, Siemens, GE Healthcare, Edwards Lifesciences, HeartFlow, Opsens, Celiad, Bayer, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The interplay between coronary hemodynamics and plaque characteristics remains poorly understood., Objectives: The aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics., Methods: This multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value., Results: A total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87)., Conclusions: Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)., Competing Interests: Funding and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow Inc. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow Inc; and speaker fees from Abbott Vascular. Dr Leipsic is a consultant and has holding stock options in Circle CVI and HeartFlow Inc; has received a research grant from GE; and modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath Ph.D. program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow Inc and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow Inc. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordisk; and research grants from Bayer and Philips Healthcare. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. CT is an employee of HeartFlow Inc. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) and Philips/Volcano Corporation (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses]; NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated., Objectives: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery., Methods: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization., Results: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005)., Conclusions: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels., Competing Interests: Funding Support and Author Disclosures Dr Collet received research grants from Biosensors, HeartFlow Inc, Abbott Vascular, Insight Lifetech, GE Healthcare, Siemens and Shockwave Medical. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has received significant institutional research support from St. Jude Medical (CONTRAST, NCT02184117) and Philips Volcano (DEFINE-FLOW, NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and TAVI physiology and also algorithms to correct pressure tracings from fluid-filled catheters. Dr Mizukami has received consultancy fees from Zeon Medical. Dr Fearon receives institutional research support from Abbott Vascular, Boston Scientific, Medtronic, and Edwards Lifesciences; he has a consulting relationship with CathWorks and Siemens; and he owns minor stock options in HeartFlow. Dr Berry receives research funding from the British Heart Foundation grant (RE/18/6134217); and is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health. Dr Sonck is supported by a grant provided by the CardioPath PhD program. Dr Collison has received honoraria/speaker fees from Abbott. Dr Koo has received an institutional research grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr Meneveau has received consultancy and speaker fees from Abbott Vascular, Edwards Lifesciences, Terumo, Boston Scientific, Bayer Healthcare, BMS-Pfizer, Boehringer, and AstraZeneca. Dr Oldroyd is an employee of Biosensors International. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; and has a research grant from GE Healthcare. Dr Taylor is an employee of HeartFlow Inc. Dr Ko has received consultancy fees from Abbott Vascular and Medtronic; and has received research support from Canon Medical. Dr Perera has received research grant support from Abbott Vascular, HeartFlow, and Philips. Dr Leone received consultant fees and honoraria for lectures in sponsored symposia with Abbott Vascular and Bracco Imaging/ACIST Medical. Dr Matsuo has received consultancy fees from Zeon Medical; and has received speaker fees from Abbott Vascular Japan, Philips, and Boston Scientific. Dr Amabile reports consulting/proctoring fees from Abbott Vascular, Boston Scientific, and Shockwave Medical; and has received an institutional research grant from Abbott Vascular and Boston Scientific. Dr Piróth has received consultancy and speaker fees from Abbott Vascular, Opsens, and Boston Scientific. Dr Toth has received consultancy fees and research support from Abbott, Biotronik, Medtronic, and Terumo. Dr Ihdayhid reports receiving consulting honorarium from Abbott Medical, Edwards Lifesciences, Boston Scientific, Artrya Pty Ltd (including equity interest). Dr West is an employee of Abbott Vascular. Dr Munhoz is supported with a PhD grant from CardioPath. Dr Barbato has received speaker fees from Abbott and Boston Scientific. Dr Engstrøm has received consultancy and speaker fees from Abbott Vascular, Novo Nordisk, and Bayer AS. Dr Escaned is supported by the Intensification of Research Activity project INT22/00088 from Spanish Instituto de Salud Carlos III, and served as speaker and advisory board member for Abbott and Philips. Dr Ali has received institutional grant support Abbott, Abiomed, ACIST Medical, Amgen, Boston Scientific, Cathworks, Canon, Conavi, Heartflow, Inari, Medtronic Inc, National Institute of Health, Nipro, Opsens Medical, Medis, Philips, Shockwave, Siemens, Spectrawave, Teleflex; and consulting fees from Abiomed, AstraZeneca, Boston Scientific, Cathworks, Opsens, Philips, Shockwave and equity in Elucid, Lifelink, Spectrawave, Shockwave, VitalConnect. Dr Kern has received speaker fees from Abbott, ACIST Medical, Boston Scientific, Opsens, and Philips. Dr Pijls has received research grants from Abbott and Hexacath and consultancy fees from Abbott, GE, Philips, and HeartFlow and have equity in GE, Philips, and Heartflow. Dr De Bruyne has received institutional consulting fees from Abbott Vascular, Boston Scientific, Siemens, and GE; has received institutional grant support from Abbott Vascular, Boston Scientific, Biotronic, CathWorks, Pie Medical, and HeartFlow; and holds minor equities in Philips, Siemens, GE, Bayer, HeartFlow, Edwards Lifesciences, and Ceyliad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The stimulation of local immunity by vaccination is desirable for controlling virus replication in the respiratory tract. However, the local immune stimulatory effects of adjuvanted vaccines administered through the non-mucosal route are poorly understood. Here, we clarify the mechanisms by which non-mucosal inoculation of adjuvants stimulates the plasmacytoid dendritic cell (pDC)-dependent immunoglobulin (Ig)A response in the lungs. After systemic inoculation with type 1 interferon (IFN)-inducing adjuvants, type 1 IFN promotes CXCL9/10/11 release from alveolar endothelial and epithelial cells and recruits CXCR3-expressing pDCs into the lungs. Because adjuvant-activated pulmonary pDCs highly express major histocompatibility complex II, cluster of differentiation 80, and cluster of differentiation 86, transplantation of such cells into the lungs successfully enhances antigen-specific IgA production by the intranasally sensitized vaccine. In contrast, pDC accumulation in the lungs and subsequent IgA production are impaired in pDC-depleted mice and Ifnar1 -/- mice. Notably, the combination of systemic inoculation with type 1 IFN-inducing adjuvants and intranasal antigen sensitization protects mice against influenza virus infection due to the pDC-dependent IgA response and type I IFN response. Our results provide insights into the novel mucosal vaccine strategies using non-mucosal inoculated adjuvants., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC 50 ]: 9.0-23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC 50 : 21.3-94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC 50 : 2.9-5.8 μM) and treatment of infected cells (IC 50 : 10.7-15.4 μM). The IC 50 of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: An increase in fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) is associated with improvement in angina. Coronary artery disease (CAD) patterns (focal vs diffuse) influence the FFR change after stenting and may predict angina relief., Objectives: The aim of this study was to investigate the differential improvement in patient-reported outcomes after PCI in focal and diffuse CAD as defined by the pullback pressure gradient (PPG)., Methods: This is a subanalysis of the TARGET-FFR (Trial of Angiography vs. pressure-Ratio-Guided Enhancement Techniques-Fractional Flow Reserve) randomized clinical trial. The 7-item Seattle Angina Questionnaire (SAQ-7) was administered at baseline and 3 months after PCI. The PPG index was calculated from manual pre-PCI FFR pullbacks. The median PPG value was used to define focal and diffuse CAD. Residual angina was defined as an SAQ-7 score <100., Results: A total of 103 patients were analyzed. There were no differences in the baseline characteristics between patients with focal and diffuse CAD. Focal disease had larger increases in FFR after PCI than patients with diffuse disease (0.30 ± 0.14 vs 0.19 ± 0.12; P < 0.001). Patients with focal disease who underwent PCI for focal CAD had significantly higher SAQ-7 summary scores at follow-up than those with diffuse CAD (87.1 ± 20.3 vs 75.6 ± 24.4; mean difference = 11.5 [95% CI: 2.8-20.3]; P = 0.01). After PCI, residual angina was present in 39.8% but was significantly less in those with treated focal CAD (27.5% vs 51.9%; P = 0.020)., Conclusions: Residual angina after PCI was almost twice as common in patients with a low PPG (diffuse disease), whereas patients with a high PPG (focal disease) reported greater improvement in angina and quality of life. The baseline pattern of CAD can predict the likelihood of angina relief. (Trial of Angiography vs. pressure-Ratio-Guided Enhancement Techniques-Fractional Flow Reserve [TARGET-FFR]; NCT03259815)., Competing Interests: Funding Support and Author Disclosures Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and has received consultancy fees from HeartFlow, OpSens, Abbott Vascular, and Philips Volcano. Dr Collison has received consultancy and speaker fees from Abbott. Dr Munhoz has received research grants provided by the Cardiopath PhD program. Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health; and has received research funding from the British Heart Foundation grant (RE/18/6134217) and EPSRC (EP/R511705/1, EP/S030875/1). Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; has received research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Oldroyd is an employee of Biosensors International. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent retrospective investigations have suggested that optical coherence tomography (OCT) enables the diagnosis of underlying acute coronary syndrome (ACS) causes such as plaque rupture, plaque erosion, and calcified nodule. The relationships of these etiologies with clinical outcomes, and the clinical utility of OCT-guided primary percutaneous coronary intervention (PCI) are not systematically studied in real-world ACS treatment settings., Methods: The TACTICS registry is an investigator-initiated, prospective, multicenter, observational study to be conducted at 21 hospitals in Japan. A total of 700 patients with ACS (symptom onset within 24 h) undergoing OCT-guided primary PCI will be enrolled. The primary endpoint of the study is to identify the underlying causes of ACS using OCT-defined morphological assessment of the culprit lesion. The key secondary clinical endpoints are hazard ratios of the composite of cardiovascular death, non-fatal myocardial infarction, heart failure, or ischemia-driven revascularization in patients with underlying etiologies at the 12- and 24-month follow-ups. The feasibility of OCT-guided primary PCI for ACS will be assessed by the achievement rates of optimal post-procedural results and safety endpoints., Conclusion: The TACTICS registry will provide an overview of the underlying causes of ACS using OCT, and will reveal any difference in clinical outcomes depending on the underlying causes. The registry will also inform on the feasibility of OCT-guided primary PCI for patients with ACS., Competing Interests: Declaration of competing interest Masahiko Ochiai, lecture fee – Abbott Medical Japan LLC., Asahi Intecc, Boston Scientific, and Terumo; Hiromasa Otake, lecture fee - Abbott Medical Japan LLC. and Terumo; Toshiro Shinke, personal fees and research grant - Abbot Japan LLC. The rest of the authors have none to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Low fractional flow reserve (FFR) values after percutaneous coronary intervention (PCI) carry a worse prognosis than high post-PCI FFR values. Therefore, the ability to predict post-PCI FFR might play an important role in procedural planning. Post-PCI FFR values can now be computed from pre-PCI coronary computed tomography angiography (CTA) using the fractional flow reserve derived from coronary computed tomography angiography revascularization planner (FFR CT Planner)., Objectives: The aim of this study was to validate the accuracy of the FFR CT Planner., Methods: In this multicenter, investigator-initiated, prospective study, patients with chronic coronary syndromes and significant lesions based on invasive FFR ≤0.80 were recruited. The FFR CT Planner was applied to the fractional flow reserve derived from coronary computed tomography angiography (FFR CT ) model, simulating PCI. The primary objective was the agreement between the predicted post-PCI FFR by the FFR CT Planner and measured post-PCI FFR. Accuracy of the FFR CT Planner's luminal dimensions was assessed by using post-PCI optical coherence tomography as the reference., Results: Overall, 259 patients were screened, with 120 patients (123 vessels) included in the final analysis. The mean patient age was 64 ± 9 years, and 24% had diabetes. Measured FFR post-PCI was 0.88 ± 0.06, and the FFR CT Planner FFR was 0.86 ± 0.06 (mean difference: 0.02 ± 0.07 FFR unit; limits of agreement: -0.12 to 0.15). Optical coherence tomography minimal stent area was 5.60 ± 2.01 mm 2 , and FFR CT Planner minimal stent area was 5.0 ± 2.2 mm 2 (mean difference: 0.66 ± 1.21 mm 2 ; limits of agreement: -1.7 to 3.0). The accuracy and precision of the FFR CT Planner remained high in cases with focal and diffuse disease and with low and high calcium burden., Conclusions: The FFR CT -based technology was accurate and precise for predicting FFR after PCI. (Precise Percutaneous Coronary Intervention Plan Study [P3]; NCT03782688)., Competing Interests: Funding Support and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow and Cardiopath. Drs Sonck and Munhoz have received research grants provided by the Cardiopath PhD program. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow, Edwards LifeSciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and consultancy fees from HeartFlow, OpSens, Abbott Vascular, and Philips Volcano. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow; and speaker fees from Abbott Vascular. Dr Heggermont reports that Cardiac Research Institute Aalst receives consultancy fees on his behalf from Boston Scientific, Abbott Vascular, MicroPort, Medtronic, Biotronik, and AstraZeneca. Dr Updegrove and Ms Collinsworth are employees of HeartFlow. Dr Leipsic is a consultant and reports holding stock options in Circle CVI and HeartFlow; and has received a research grant from GE and modest speaker fees from GE and Philips. Drs Norgaard and Møller Jensen have received unrestricted institutional research grants from Siemens and HeartFlow. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow and Abbott Vascular. Dr Ihdayhid has received consulting fees from Canon, Artrya Medical, and Boston Scientific. Dr Koo has received institutional research grants from HeartFlow. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordics; and research grants from Bayer and Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Wall shear stress (WSS) has been associated with atherogenesis and plaque progression. The present study assessed the value of WSS analysis derived from conventional coronary angiography to detect lesions culprit for future myocardial infarction (MI)., Methods and Results: Three-dimensional quantitative coronary angiography (3DQCA), was used to calculate WSS and pressure drop in 80 patients. WSS descriptors were compared between 80 lesions culprit of future MI and 108 non-culprit lesions (controls). Endothelium-blood flow interaction was assessed by computational fluid dynamics (10.8 ± 1.41 min per vessel). Median time between baseline angiography and MI was 25.9 (21.9-29.8) months. Mean patient age was 70.3 ± 12.7. Clinical presentation was STEMI in 35% and NSTEMI in 65%. Culprit lesions showed higher percent area stenosis (%AS), translesional vFFR difference (ΔvFFR), time-averaged WSS (TAWSS) and topological shear variation index (TSVI) compared to non-culprit lesions (p < 0.05 for all). TSVI was superior to TAWSS in predicting MI (AUC-TSVI = 0.77, 95%CI 0.71-0.84 vs. AUC-TAWSS = 0.61, 95%CI 0.53-0.69, p < 0.001). The addition of TSVI increased predictive and reclassification abilities compared to a model based on %AS and ΔvFFR (NRI = 1.04, p < 0.001, IDI = 0.22, p < 0.001)., Conclusions: A 3DQCA-based WSS analysis was feasible and can identify lesions culprit for future MI. The combination of area stenoses, pressure gradients and WSS predicted the occurrence of MI. TSVI, a novel WSS descriptor, showed strong predictive capacity to detect lesions prone to cause MI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Morphological evaluation of coronary lesion length is a paramount step during invasive assessment of coronary artery disease. Likewise, the extent of epicardial pressure losses can be measured using longitudinal vessel interrogation with fractional flow reserve (FFR) pullbacks. We aimed to quantify the mismatch in lesion length between morphological (based on quantitative coronary angiography, QCA, and optical coherence tomography, OCT) and functional evaluations., Methods: This is a prospective and multicenter study of patients evaluated by QCA, OCT and motorized fractional flow reserve pullbacks (mFFR). The difference in lesion length between the functional and anatomical evaluations was referred to as FAM., Results: 117 patients (131 vessels) were included. Median lesion length derived from angiography was 16.05 mm [11.40-22.05], from OCT was 28.00 mm [16.63-38.00] and from mFFR 67.12 mm [25.38-91.37]. There was no correlation between QCA and mFFR lesion length (r = 0.124, 95% CI -0.168-0.396, p = 0.390). OCT lesion length did correlate with mFFR (r = 0.469, 95% CI 0.156-0.696, p = 0.004). FAM was strongly associated with the improvement in vessel conductance with percutaneous coronary intervention (PCI), higher mismatch was associated with lower post-PCI FFR., Conclusions: Lesion length assessment differs between morphological and functional evaluations. The morphological-functional mismatch in lesion length is frequent, and influences the results of PCI in terms of post-PCI FFR. Integration of the extent of pressure losses provides clinically relevant information that may be useful for clinical decision-making concerning revascularization strategy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Coronary microvascular dysfunction is a highly prevalent condition in both obstructive and nonobstructive coronary artery disease. Intracoronary thermodilution is a promising technique to investigate coronary microvascular (dys)function in vivo and to assess its most important metric: microvascular resistance. Here, the authors provide a practical review of bolus and continuous thermodilution for the measurement of coronary flow and microvascular resistance. The authors describe the basic principles of indicator-dilution theory and of coronary thermodilution and detail the practicalities of their application in the catheterization laboratory. Finally, the authors discuss contemporary clinical applications of coronary thermodilution-based microvascular assessment in humans and future perspectives., Competing Interests: Funding Support and Author Disclosures Drs. Kodeboina, Fournier, Di Gioia, and Sonk are supported by a research grant from CardioPaTh. Dr. Di Gioia is supported by the STAR program of Compagnia di San Paolo. Dr. Collet has received institutional consultancy fees from HeartFlow and Philips Volcano. Dr. van ’t Veer has received speaker fees from Abbott. Dr. Pijls has received institutional research grants from Abbott and Hexacath; has received consultancy fees from Abbott, Opsens, and GE; and holds minor equity positions in Philips, ASML, and HeartFlow. Dr. De Bruyne has received institutional consulting fees from Abbott Vascular, Boston Scientific, Opsens, and Siemens; has received institutional grant support from Abbott Vascular, Boston Scientific, Biotronik, and Medtronic; and holds equity positions in Philips, Siemens, GE, Bayer, HeartFlow, Edwards Lifesciences, and Ceyliad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The aim of this study was to investigate the accuracy of pre-percutaneous coronary intervention (PCI) predicted nonhyperemic pressure ratios (NHPRs) with actual post-PCI NHPRs and to assess the efficacy of PCI strategy using pre-PCI NHPR pullback., Background: Predicting the functional results of PCI is feasible using pre-PCI longitudinal vessel interrogation with the instantaneous wave-free ratio (iFR), a pressure-based, adenosine-free NHPR. However, the reliability of novel NHPRs (resting full-cycle ratio [RFR] and diastolic pressure ratio [dPR]) for this purpose remains uncertain., Methods: In this prospective, multicenter, randomized controlled trial, vessels were randomly assigned to receive pre-PCI iFR, RFR, or dPR pullback (50 vessels each). The pre-PCI predicted NHPRs were compared with actual NHPRs after contemporary PCI using intravascular imaging. The number and the total length of treated lesions were compared between NHPR pullback-guided and angiography-guided strategies., Results: The predicted NHPRs were strongly correlated with actual NHPRs: iFR, r = 0.83 (95% confidence interval: 0.72 to 0.90; p < 0.001); RFR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001), and dPR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001). The number and the total length of treated lesions were lower with the NHPR pullback strategy than with the angiography-guided strategy, leading to physiological improvement., Conclusions: Predicting functional PCI results on the basis of pre-procedural RFR and dPR pullbacks yields similar results to iFR. Compared with an angiography-guided strategy, a pullback-guided PCI strategy with any of the 3 NHPRs reduced the number and the total length of treated lesions. (Study to Examine Correlation Between Predictive Value and Post PCI Value of iFR, RFR and dPR; UMIN000033534)., Competing Interests: Author Relationship With Industry Dr. Escaned has provided consulting and speaking services at educational events for Abbott, Boston Scientific, and Philips Healthcare. Dr. Mizukami has received consulting fees from HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background: Graft occlusion after coronary artery bypass graft surgery (CABG) has been associated with native coronary artery competitive flow., Objectives: The present study aims to characterize the functional progression of coronary artery disease (CAD) in native vessels after CABG, and to assess the relationship between preoperative FFR as derived from angiography and graft occlusion., Methods: Multicenter study of consecutive patients undergoing CABG between 2013 and 2018, in whom a follow-up angiogram had been performed. Serial vessel-fractional flow reserve (vFFR) analyses were obtained in each major native coronary vessel before and after CABG, excluding post-anastomotic segments and graft conduits., Results: In 73 patients, serial angiograms were suitable for vFFR analysis, including 118 grafted (86 arterial and 32 saphenous grafts) and 64 non-grafted vessels. The median time between CABG and follow-up angiography was 2.4 years [IQR 1.5, 3.3]. Functional CAD progression, by means of decline in vFFR, was observed in grafted but not in non-grafted vessels (delta vFFR in grafted vessels 0.10 [IQR 0.05, 0.18] vs. 0.01 [IQR -0.01, 0.03], in non-grafted vessels, p < 0.001). Preoperative vFFR predicted graft occlusion (AUC: 0.66, 95% CI 0.52 to 0.80, p = 0.031)., Conclusions: In patients undergoing CABG, preoperative vFFR derived from conventional angiograms without use of pressure wire was able to predict graft occlusion. Graft occlusion was more frequent in vessels with high vFFR values. Grafted native coronary vessels exhibited accelerated functional CAD progression, whereas in non-grafted native coronaries the functional status remained unchanged., Competing Interests: Declaration of competing interest CC report receiving research grants from Biosensor, Heart Flow Inc. and Abbott Vascular; and consultancy fees from Heart Flow Inc. and Philips Volcano. JS reports a research grant provided by Cardiopath Ph.D program. TM report receiving consultancy fees from Heart Flow Inc. EM reports institutional grant support from Abbott Vascular, Boston Scientific, and Biotronik. DA reports institutional fees as a speaker and clinical research grants from GE, Bracco, and Heartflow. BDB reports receiving consultancy fees on his behalf from Boston Scientific and Abbott Vascular. The other authors have nothing to disclose. This study was supported by the VZW Cardiovascular Research Centre, Aalst, Belgium., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: The aim of this study was to compare clinical outcomes of different bifurcation percutaneous coronary intervention (PCI) techniques., Background: Despite several randomized trials, the optimal PCI technique for bifurcation lesions remains a matter of debate. Provisional stenting has been recommended as the default technique for most bifurcation lesions. Emerging data support double-kissing crush (DK-crush) as a 2-stent technique., Methods: PubMed and Scopus were searched for randomized controlled trials comparing PCI bifurcation techniques for coronary bifurcation lesions. Outcomes of interest were major adverse cardiovascular events (MACE). Secondary outcomes of interest were cardiac death, myocardial infarction, target vessel or lesion revascularization, and stent thrombosis. Summary odds ratios (ORs) were estimated using Bayesian network meta-analysis., Results: Twenty-one randomized controlled trials including 5,711 patients treated using 5 bifurcation PCI techniques were included. Investigated techniques were provisional stenting, T stenting/T and protrusion, crush, culotte, and DK-crush. Median follow-up duration was 12 months (interquartile range: 9 to 36 months). When all techniques were considered, patients treated using the DK-crush technique had less occurrence of MACE (OR: 0.39; 95% credible interval: 0.26 to 0.55) compared with those treated using provisional stenting, driven by a reduction in target lesion revascularization (OR: 0.36; 95% credible interval: 0.22 to 0.57). No differences were found in cardiac death, myocardial infarction, or stent thrombosis among analyzed PCI techniques. No differences in MACE were observed among provisional stenting, culotte, T stenting/T and protrusion, and crush. In non-left main bifurcations, DK-crush reduced MACE (OR: 0.42; 95% credible interval: 0.24 to 0.66)., Conclusions: In this network meta-analysis, DK-crush was associated with fewer MACE, driven by lower rates of repeat revascularization, whereas no significant differences among techniques were observed for cardiac death, myocardial infarction, and stent thrombosis. A clinical benefit of 2-stent techniques was observed over provisional stenting in bifurcation with side branch lesion length ≥10 mm., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Fractional flow reserve (FFR) pullback allows to assess the distribution of pressure loss along the coronary vessels. FFR derived from CT (FFR CT ) provides a virtual pullback curve that may also aid in the assessment of the distribution of epicardial coronary resistance in the non-invasive setting. The present study aims to determine the accuracy of the virtual FFR CT pullback curve using a motorized invasive FFR pullback as reference in patients with stable coronary artery disease., Methods and Results: FFR values were extracted from coronary vessels at approximately 1 mm to generate pullback curves. Invasive motorized FFR pullbacks were acquired using a dedicated device at a speed of 1 mm/s. A total of 3172 matched FFR CT and FFR values were obtained in 24 vessels. The correlation coefficient between FFR CT and FFR was 0.76 (95%CI 0.75 to 0.78; p < 0.001). The area under the pullback curve was similar between FFR CT and invasive FFR (79.0 ± 16.1 vs. 85.3 ± 16.4, p = 0.097). The mean difference in lesion gradient between FFR CT and FFR was -0.07 (LOA -0.26 to 0.13) whereas in non-obstructive segments was -0.01 (LOA -0.06 to 0.05)., Conclusion: The evaluation of epicardial coronary resistance using coronary CT angiography with FFR CT was feasible. FFR CT virtual pullback appears to be accurate for the evaluation of pressure gradients. FFR CT has the potential to identify the pathophysiological pattern of coronary artery disease in the non-invasive setting., Competing Interests: Declaration of competing interest TM has been supported by a research grant provided by HeartFlow Inc. JS reports receiving research grant from the Cardiopath PhD. program. CC has been supported by a research grant provided by HeartFlow Inc and Biosensors. BDB declares that the Cardiovascular Center Aalst receives on his behalf grant support from Abbott, Boston Scientific, Biotronik, and St. Jude Medical and consulting fees from St. Jude Medical, Opsens, and Boston Scientific. He is a shareholder for Siemens, GE, Bayer, Philips, Heartflow Inc, Edwards LifeSciences, Sanofi, and Omega Pharma. DA received research grant from GE Healthcare and Bracco. The other authors have nothing to disclose., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Coronary computed tomography angiography (CCTA) is at the frontline of the diagnostic strategies to detect coronary artery disease (CAD). Anatomical information have proven to be insufficient to detect hemodynamic significant epicardial stenosis. In the present invited review we discuss on FFR CT and stress CTP, emerging technologies for an accurate and comprehensive evaluation of patients with suspected CAD, offering both anatomical (i.e. luminal and plaque) and functional assessment in one single technique., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: To clarify the influence of intra- and extra-uterine growth on subsequent psychomotor development in very-low-birth-weight (VLBW) infants., Methods: Two hundred and eighty VLBW infants (28.4 ± 2.6 weeks, 1000 ± 294 g) were enrolled. Psychomotor development was determined at 37.1 ± 2.1 months after birth using the Kyoto Scale of Psychological Development (KSPD), which includes Postural-Motor (P-M), Cognitive-Adaptive (C-A) and Language-Social (L-S) subscales. Subjects were divided into two groups based on whether each developmental quotient (DQ) was ≥85, and the perinatal variables that contributed to a DQ of ≥85 (for each DQ) were determined. The twelve variables that were evaluated included the z scores for body weight (zBW), body length (zBL), head circumference (zHC), which were obtained at birth and at term., Results: The median P-M, C-A, L-S values and total DQ were 92, 83, 81 and 83, respectively, and the percentage of patients with a DQ of ≥85 were 53%, 44%, 35% and 39%, respectively. A multivariate analysis revealed significant associations between the following variables and the DQs: P-M ≥ 85, GA [odds ratio; OR = 1.11] and zBL at term [OR = 1.26]; C-A ≥ 85, male gender [OR = 0.30], GA [OR = 1.14] and zHC at term [OR = 1.84]; L-S ≥ 85, male gender [OR = 0.55], GA [ OR = 1.20] and zHC at term [OR = 1.45]; total DQ ≥ 85, male gender [OR = 0.39], GA [OR = 1.19] and zBL at term [OR = 1.69]., Conclusion: In addition to less prematurity and female gender, a longer body length and larger head circumference at term were important indicators that influenced better psychomotor development in VLBW infants at three years of chronological age., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients., Patients and Methods: The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome., Results: Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy., Conclusion: Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully., Competing Interests: Competing interests: MN has received honoraria from Daiichi Sankyo and Taiho Pharmaceutical. MasM has received research grants from Chugai, Kyowa Hakko Kirin, Takeda, Daiichi Sankyo, Astellas, Otsuka, Baxter, Teijin Pharma and Shionogi. TS has received research grants from Baxter, Astellas, Kyowa Hakko Kirin, Teijin Pharma and Takeda. EB has received research grants from Takeda, Chugai, Eli Lilly, Merck Serono, Shionogi and Taiho. He has also received honorarium from Eli Lilly. KT has received research grants from Kyowa Hakko Kirin, Chugai, Takeda, Kissei, Otsuka, Daiichi Sankyo and Torii. He has also received honoraria from Kyowa Hakko Kirin, Chugai and Sanofi. His institution has received funding from Baxter. AN has received research grant from Daiichi Sankyo. HY has received honoraria from Medicon, Taiho, Chugai, Yakult Honsha, Bristol-Myers Squibb, Takeda and Kyowa Hakko Kirin. MY has been on the advisory board of Astellas and received research grants from Astellas, Chugai, Daiichi Sankyo, Fuji Yakuhin, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Baxter, Takeda Pharmaceutical Company, Fuso Pharmaceutical Industries and Terumo Corporation. ManM has received research grant from Chugai, Yakult Honsha, Ono Pharmaceutical, Ayumi Pharmaceutical, Showa Yakuhin Kako, Shionogi, Taiho, Terumo and Nippon Zoki Pharmaceutical Corporations.

Objectives: Hepcidin-25 serves as a key peptide in the regulation of iron homeostasis and inflammation. It remains unknown whether hepcidin-25 plays an adverse role in atherosclerotic diseases. The aim of this study was to investigate whether hepcidin-25 is involved in the pathophysiology of coronary plaque vulnerability., Methods and Results: Serum hepcidin-25 levels were quantitatively determined by the LC-MS/MS assay system. Peripheral blood was collected from patients with acute myocardial infarction (MI, n=33) and patients with stable angina pectoris (sCAD, n=19). The levels of hepcidin-25, IL-6, and CRP were significantly higher in the patients with acute MI than in the patients with sCAD. Coronary blood was aspirated from the culprit arteries via a thrombectomy catheter in 16 of the MI patients. Serum from the aspirates contained higher levels of hepcidin-25 and IL-6 compared with the peripheral blood. In immunohistochemical staining, the macrophages of the plaques in the solid component of the aspirates were immunoreactive for hepcidin-25. To confirm the clinical observation, an in vitro study was performed using human macrophages and coronary endothelial cells. The hepcidin gene and protein were detected in the cultured macrophages but not in the endothelial cells. Hepcidin-25 exposure induced ferroportin degradation and reduced the survival rate of endothelial cells., Conclusions: The results of the present study demonstrated that circulating hepcidin-25 and IL-6 were both elevated in the acute phase of MI and that hepcidin-25 released from plaque macrophages and other cell sources contributed to the plaque instability by inducing endothelial cell death., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

CUB and Sushi multiple domains 3 (CSMD3) is a large protein expressed in fetal and adult brain. Recently, mutations of the CSMD3 gene were identified in schizophrenia and autism patients. However, biochemical properties and functions of the CSMD3 protein remain unknown. Here, we demonstrate that CSMD3 is an oligomeric type I transmembrane protein localized in the apical dendrites of hippocampal pyramidal neurons in the postnatal brain. In cultured hippocampal neurons, CSMD3 is expressed only after 7 days in vitro. Overexpression of CSMD3 induced dendritic branching in hippocampal neurons. Regulation of dendritic morphology by CSMD3 depended on the presence of its extracellular region, while CSMD3 intracellular region was dispensable for this activity. These results suggest that CSMD3 acts as a co-receptor of an unidentified membrane protein to regulate dendrite development. Therefore, malfunctions of CSMD3 may be one of the factors in the pathogenesis of psychiatric disorders., (Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Although muscle wasting and/or degeneration are prevalent in patients with chronic kidney disease, it remains unknown whether FGF-23 influences muscle homeostasis and regeneration. Mesenchymal stem cells (MSCs) in skeletal muscle are distinct from satellite cells and have a known association with muscle degeneration. In this study we sought to investigate the effects of FGF-23 on MSCs isolated from human skeletal muscle in vitro. The MSCs expressed FGF receptors (1 through 4) and angiotensin-II type 1 receptor, but no traces of the Klotho gene were detected. MSCs and satellite cells were treated with FGF-23 and angiotensin-II for 48 h. Treatment with FGF-23 significantly decreased the number of MSCs compared to controls, while treatment with angiotensin-II did not. FGF-23 and angiotensin-II both left the cell counts of the satellite cells unchanged. The FGF-23-treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay, cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also significantly altered the gene expression of oxidative stress regulators in the cells. In conclusion, FGF-23 induced premature senescence in MSCs from skeletal muscle via the p53/p21/oxidative-stress pathway. The interaction between the MSCs and FGF-23 may play a key role in the impaired muscle reparative mechanisms of chronic kidney disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-γ. In addition, T-5224 blocked the nuclear translocation of c-Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: We have developed a novel method of measuring spinal cord-evoked potentials with stimulation and recording at the intercostal nerves (transintercostal-evoked spinal cord potential: Tic-ESCP). The purpose of this study was to examine the feasibility and accuracy of Tic-ESCP during thoracic aortic surgery., Methods: In addition to the conventional electrodes (cranial and intrathecal), stimulating and recording electrodes were placed on the intercostal nerves that were located at a cephalad and caudal level relative to the aneurysm after the pleura on the intercostal nerves was opened. Specially designed hook-type electrodes were anchored to the nerves and surroundings atraumatically and fixed on the pleura. The conventional transcranial motor-evoked potential (Tc-MEP) and Tic-ESCP were recorded simultaneously. Eight patients were examined in this study., Results: In all patients, Tic-ESCP could be clearly recorded with biphasic waveforms consisting of first a positive wave and a subsequent negative wave. In all 8 patients, the waveform of Tc-MEP and Tic-ESCP changed during aortic reconstruction. In 2 cases, the waveform of Tc-MEP and Tic-ESCP decreased below 50% of baseline during aortic clamping and the intercostal arteries were reconstructed with no resultant spinal cord injury. In 1 case with a shaggy aorta, Tc-MEP and Tic-ESCP had different values and each evoked potential could have reflected that regional spinal cord infarction and paraplegia had occurred., Conclusions: Tic-ESCP was clinically feasible and changes were compatible with the conventional Tc-MEP. The Tic-ESCP waveforms were simple and appeared to be specific to the spinal cord within the target range, in contrast to the other evoked potentials which are multimorphic and reflect the amplitudes at the brain and multiple levels of the spinal cord., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Oncogenic RET fusion, caused by an inversion in chromosome 10, was recently identified as a driver mutation for the development of lung adenocarcinoma (LADC). Nevertheless, the molecular mechanism(s) underlying the rearrangement of the RET locus during lung carcinogenesis are unknown., Methods: Genomic segments containing breakpoint junctions for RET fusions were cloned and analyzed by genomic polymerase chain reaction and genome capture sequencing using a next-generation sequencer to identify the mechanisms involved in DNA strand breaks and illegitimate joining of DNA ends. Of the 18 cases studied, 16 were identified by screening 671 LADC cases and two were previously published., Results: Almost all (17 of 18, 94%) of the breakpoints in RET were located within a 2.0-kb region spanning exon 11 to intron 11 and no breakpoint occurred within 4 bp of any other. This suggested that as in papillary thyroid carcinoma, DNA strand breaks formed at nonspecific sites within this region trigger RET fusion. Just over half of the RET fusions in LADC (10 of 18, 56%) were caused by simple reciprocal inversion, and two DNA-repair mechanisms, namely nonhomologous end joining and break-induced replication, were deduced to have contributed to the illegitimate joining of the DNA ends., Conclusions: Oncogenic RET fusion in LADC occurs through multiple pathways and involves the illegitimate repair of DNA strand breaks through mechanisms different from those identified in papillary thyroid carcinoma, where RET fusion also functions as a driver mutation.

Background: Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as targets for molecular therapy, limited information is available regarding BRAF-mutated lung carcinomas., Materials and Methods: BRAF mutation status was determined in 2001 surgically resected nonsmall-cell lung cancer (NSCLC) cases using high-resolution melting analysis (HRMA) followed by Sanger sequencing and/or deep sequencing using next generation sequencer., Results: BRAF mutations were detected in 26 (1.3%) of 2001 NSCLC cases (25 adenocarcinomas and 1 squamous cell carcinoma). In the 26 cases, 13 mutation genotypes were identified, including V600E (8 of 26; 30.8%), G469A (6 of 26; 23.1%), K601E (4 of 26; 15.4%), and other residual mutations (1 of 26; 0.04%). Of the 13 genotypes, 4 genotypes (G464E, G596R, A598T, and G606R) had not been previously reported in lung cancer. The overall survival rate was not significantly different between patients with wild-type BRAF and those with V600E or non-V600E BRAF mutations (P = 0.49 and P = 0.15, respectively). Histomorphological analysis revealed that focal clear cell changes were present in 75% of V600E-mutated tumors. All V600E BRAF-mutated tumors were negative for other driver gene alterations including epidermal growth factor receptor (EGFR) and KRAS mutations and the anaplastic lymphoma kinase gene translocation, whereas five tumors with non-V600E BRAF mutations (four G469A and one G464E/G466R) showed concomitant EGFR mutations., Conclusion: The frequency of BRAF mutations in lung cancer was low in an Asian cohort. Furthermore, BRAF mutation status lacked prognostic significance in this patient population.

Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-κB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL-ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients.

Fifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs). To identify new mutations, we investigated large deletions in the RP genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26. We developed an easy method based on quantitative-PCR in which the threshold cycle correlates to gene copy number. Using this approach, we were able to diagnose 7 of 27 Japanese patients (25.9%) possessing mutations that were not detected by sequencing. Among these large deletions, similar results were obtained with 6 of 7 patients screened with a single nucleotide polymorphism array. We found an extensive intragenic deletion in RPS19, including exons 1-3. We also found 1 proband with an RPL5 deletion, 1 patient with an RPL35A deletion, 3 with RPS17 deletions, and 1 with an RPS19 deletion. In particular, the large deletions in the RPL5 and RPS17 alleles are novel. All patients with a large deletion had a growth retardation phenotype. Our data suggest that large deletions in RP genes comprise a sizable fraction of DBA patients in Japan. In addition, our novel approach may become a useful tool for screening gene copy numbers of known DBA genes.

Objective: This study aims to establish a superior procedure to prevent spinal cord damage after severe spinal cord ischemia during aortic surgery. We examined the synergistic effect of topical hypothermia of the spinal cord combined with radical scavenger infusion into the clamped segment of the aorta to prevent spinal cord damage in an animal model., Methods: Spinal cord ischemia was induced in rabbits by clamping the aorta between the renal artery and aortic bifurcation for 30 minutes. Rabbits were divided into four groups of 16 each: group I, sham-operated; group II, edaravone (6 mL, 4°C, 1 mg/kg); group III, saline (6 mL, 4°C) with transvertebral cooling pads; group IV, edaravone (6 mL, 4°C, 1 mg/kg) and transvertebral cooling pads. Solutions were injected into the clamped segment of the aorta. Postoperative assessments included the Tarlov score, spinal cord histopathology, and measurement of malondialdehyde levels in the spinal cord tissue., Results: At 48 hours after reperfusion, the mean Tarlov scores in groups I, II, III, and IV were 4.0, 1.5, 1.9, and 4.0, respectively. The mean number of normal motor neurons was significantly higher in groups I (54.1) and IV (53.7) than in groups II (32.8) and III (36.3; P < .001). The mean malondialdehyde level in groups I (19.8 nmol/mL) and IV (22.6 nmol/mL) was significantly lower than in groups II (64.8 nmol/mL) and III (60.9 nmol/mL; P < .001). At 168 hours after reperfusion, the mean Tarlov scores in groups I, II, III, and IV were 4.0, 1.1, 1.3, and 4.0, respectively. The mean number of normal motor neurons was significantly higher in groups I (52.9) and IV (50.8) than in groups II (22.4) and III (25.9; P < .001). The mean malondialdehyde level in groups I (20.7 nmol/mL) and IV (23.4 nmol/mL) was significantly lower than in groups II (68.9 nmol/mL) and III (61.6 nmol/mL; P < .001)., Conclusion: In a rabbit model with aortic clamping up to 30 minutes, which consistently produces complete paraplegia in rabbits, spinal cord damage was partially reduced by topical cooling with transvertebral cooling pads or the injection of edaravone into the clamped segment of aorta, but was more effectively protected by a combined use of these two strategies., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Delayed paraplegia after operation on the thoracoabdominal aorta is considered to be related to vulnerability of motor neurons to ischemia. Previous studies have demonstrated the relationship between neuronal vulnerability and endoplasmic reticulum (ER) stress after transient ischemia in the spinal cord. The aim of this study was to investigate whether sodium 4-phenylbutyrate (PBA), a chemical chaperone that reduces the load of mutant or unfolded proteins retained in the ER during cellular stress, can protect against ischemic spinal cord damage., Methods: Spinal cord ischemia was induced in rabbits by direct aortic cross-clamping (below the renal artery and above the bifurcation) for 15 minutes at normothermia. Group A (n = 6) was a sham operation control group. In group B (n = 6) and group C (n = 6), vehicle or 15 mg/kg/h of sodium 4-PBA was infused intravenously, respectively, from 30 minutes before the induction of ischemia until 30 minutes after reperfusion. Neurologic function was assessed at 8 hours, and 2 and 7 days after reperfusion with a Tarlov score. Histologic changes were studied with hematoxylin-eosin staining. Immunohistochemistry analysis for ER stress-related molecules, including caspase12 and GRP78 were examined., Results: The mean Tarlov scores were 4.0 in every group at 8 hours, but were 4.0, 2.5, and 3.9 at 2 days; and 4.0, 0.7, and 4.0 at 7 days in groups A, B, and C, respectively. The numbers of intact motor neurons at 7 days after reperfusion were 47.4, 21.5, and 44.9 in groups A, B, and C, respectively. There was no significant difference in terms of viable neurons between groups A and C. Caspase12 and GRP78 immunoreactivities were induced in motor neurons in group B, whereas they were not observed in groups A and C., Conclusion: Reduction in ER stress-induced spinal cord injury was achieved by the administration of 4-PBA. 4-PBA may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury., (Copyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

An interval node in the upper limb termed the mid-arm node was recently identified. However, its surgical anatomy remains unclear. We report a patient with metastatic melanoma of the mid-arm node and the epitrochlear node at 10 years after removal of the primary tumour from the forearm and therapeutic axillary lymph node dissection. The mid-arm node is located halfway up the upper arm on the medial intermuscular septum, at the site where the brachial vessels, the median nerve and the ulnar nerve run adjacent to each other. The mid-arm node lies adjacent to the basilic vein where lymphatic vessels ascend and converge. This is the first report regarding the surgical anatomy of the mid-arm node., (Copyright 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)