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Background: Angiography-derived fractional flow reserve (virtual FFR) has shown excellent diagnostic performance compared with wire-based FFR. However, virtual FFR pullback curves have not been validated yet., Objectives: To validate the accuracy of virtual FFR pullback curves compared to wire-based FFR pullbacks and to assess their clinical utility using patient-reported outcomes., Methods: Pooled analysis of two prospective studies, including patients with hemodynamically significant (FFR ≤ 0.80) coronary artery disease (CAD). Virtual and wire-based FFR pullbacks were compared to assess the accuracy of virtual pullbacks to characterize CAD as focal or diffuse. Pullbacks were analyzed visually and quantitatively using the pullback pressure gradient (PPG). Patients underwent PCI, and the Seattle Angina Questionnaire (SAQ) was administered at 3-month follow-up., Results: A total of 298 patients (300 vessels) with both virtual and wire-based pullbacks who underwent PCI were included in the analysis. The mean age was 61.8 ± 8.8, and 15% were female. The agreement on the visual adjudication of the CAD pattern was fair (Cohen's Kappa: 0.31, 95% confidence interval: 0.18-0.45). The mean PPG were 0.65 ± 0.18 from virtual pullbacks and 0.65 ± 0.13 from wire-based pullbacks (r = 0.68, mean difference 0, limits of agreement -0.27 to 0.28). At follow-up, patients with high virtual PPG (>0.67) had higher SAQ angina frequency scores (i.e., less angina) than those with low virtual PPG (SAQ scores 92.0 ± 14.3 vs. 85.5 ± 23.1, p = 0.022)., Conclusion: Virtual FFR pullback curves showed moderate agreement with wire-based FFR pullbacks. Nonetheless, patients with focal disease based on virtual PPG reported greater improvement in angina after PCI., (© 2024 Wiley Periodicals LLC.)

Background: Two invasive methods are available to estimate microvascular resistance: bolus and continuous thermodilution. Comparative studies have revealed a lack of concordance between measurements of microvascular resistance obtained through these techniques., Aims: This study aimed to examine the influence of vessel volume on bolus thermodilution measurements., Methods: We prospectively included patients with angina with non-obstructive coronary arteries (ANOCA) undergoing bolus and continuous thermodilution assessments. All patients underwent coronary CT angiography to extract vessel volume. Coronary microvascular dysfunction was defined as coronary flow reserve (CFR) < 2.0. Measurements of absolute microvascular resistance (in Woods units) and index of microvascular resistance (IMR) were compared before and after volumetric adjustment., Results: Overall, 94 patients with ANOCA were included in this study. The mean age was 64.7 ± 10.8 years, 48% were female, and 19% had diabetes. The prevalence of CMD was 16% based on bolus thermodilution, while continuous thermodilution yielded a prevalence of 27% (Cohen's Kappa 0.44, 95% CI 0.23-0.65). There was no correlation in microvascular resistance between techniques (r = 0.17, 95% CI -0.04 to 0.36, p = 0.104). The adjustment of IMR by vessel volume significantly increased the agreement with absolute microvascular resistance derived from continuous thermodilution (r = 0.48, 95% CI 0.31-0.63, p < 0.001)., Conclusions: In patients with ANOCA, invasive methods based on coronary thermodilution yielded conflicting results for the assessment of CMD. Adjusting IMR with vessel volume improved the agreement with continuous thermodilution for the assessment of microvascular resistance. These findings strongly suggest the importance of considering vessel volume when interpreting bolus thermodilution assessment., (© 2024 Wiley Periodicals LLC.)

Background: Fractional flow reserve (FFR) measured after percutaneous coronary intervention (PCI) carries prognostic information. Yet, myocardial mass subtended by a stenosis influences FFR. We hypothesized that a smaller coronary lumen volume and a large myocardial mass might be associated with lower post-PCI FFR., Aim: We sought to assess the relationship between vessel volume, myocardial mass, and post-PCI FFR., Methods: This was a subanalysis with an international prospective study of patients with significant lesions (FFR ≤ 0.80) undergoing PCI. Territory-specific myocardial mass was calculated from coronary computed tomography angiography (CCTA) using the Voronoi's algorithm. Vessel volume was extracted from quantitative CCTA analysis. Resting full-cycle ratio (RFR) and FFR were measured before and after PCI. We assessed the association between coronary lumen volume (V) and its related myocardial mass (M), and the percent of total myocardial mass (%M) with post-PCI FFR., Results: We studied 120 patients (123 vessels: 94 left anterior descending arteries, 13 left Circumflex arteries, 16 right coronary arteries). Mean vessel-specific mass was 61 ± 23.1 g (%M 39.6 ± 11.7%). The mean post-PCI FFR was 0.88 ± 0.06 FFR units. Post-PCI FFR values were lower in vessels subtending higher mass (0.87 ± 0.05 vs. 0.89 ± 0.07, p = 0.047), and with lower V/M ratio (0.87 ± 0.06 vs. 0.89 ± 0.07, p = 0.02). V/M ratio correlated significantly with post-PCI RFR and FFR (RFR r = 0.37, 95% CI: 0.21-0.52, p < 0.001 and FFR r = 0.41, 95% CI: 0.26-0.55, p < 0.001)., Conclusion: Post-PCI RFR and FFR are associated with the subtended myocardial mass and the coronary volume to mass ratio. Vessels with higher mass and lower V/M ratio have lower post-PCI RFR and FFR., (© 2023 Wiley Periodicals LLC.)

Aim: Microvascular resistance reserve (MRR) as derived from continuous intracoronary thermodilution specifically quantifies microvasculature function. As originally described, the technique necessitates reinstrumentation of the artery and manual reprogramming of the infusion pump when performing resting and hyperemic measurements. To simplify and to render this procedure operator-independent, we developed a fully automated method. The aim of the present study is to validate the automated procedure against the originally described one., Methods and Results: For the automated procedure, an infusion pump was preprogrammed to allow paired resting-hyperemic thermodilution assessment without interruption. To validate the accuracy of this new approach, 20 automated measurements were compared to those obtained in the same vessels with conventional paired resting-hyperemic thermodilution measurements (i.e., with a sensor pullback at each infusion rate and manual reprogramming of the infusion pump).  A close correlation between the conventional and the automated measuring technique was found for resting flow (Q rest : r = 0.89, mean bias = 2.52; SD = 15.47), hyperemic flow (Q hyper : r = 0.88, mean bias = -2.65; SD = 27.96), resting microvascular resistance (R μ-rest : r = 0.90, mean bias = 52.14; SD = 228.29), hyperemic microvascular resistance R μ-hyper : r = 0.92, mean bias = 12.95; SD = 57.80), and MRR (MRR: r = 0.89, mean bias = 0.04, SD = 0.59).  Procedural time was significantly shorter with the automated method (5'25″ ± 1'23″ vs. 4'36″ ± 0'33″, p = 0.013)., Conclusion: Continuous intracoronary thermodilution-derived measurements of absolute flow, absolute resistance, and MRR can be fully automated. This further shortens and simplifies the procedure when performing paired resting-hyperemic measurements., (© 2022 Wiley Periodicals LLC.)

Fractional flow reserve (FFR) pullbacks assess the location and magnitude of pressure drops along the coronary artery. The pullback pressure gradient (PPG) quantifies the FFR pullback curve and provides a numeric expression of focal versus diffuse coronary artery disease. This study aims (1) to validate the PPG using manual FFR pullbacks compared with motorized FFR pullbacks as a reference; and (2) to determine the intra- and interoperator reproducibility of the PPG derived from manual FFR pullbacks. Patients with stable coronary artery disease and an FFR ≤ 0.80 were included. All patients underwent FFR pullback evaluation either with a motorized device or manually, depending on the study cohort. The agreement of the PPG between repeated pullbacks was assessed using the Bland-Altman method. Overall, 116 FFR pullback maneuvers (96 manual and 20 motorized) were analyzed. There was excellent agreement between the PPG derived from manual and motorized pullbacks (mean difference -0.01 ± 0.07, 95% limits of agreement [LOA] -0.14 to 0.12). The intra- and interoperator reproducibility of PPG derived from manual pullbacks were excellent (mean difference <0.01, 95% LOA -0.11 to 0.12, and mean difference <0.01, 95% LOA -0.12 to 0.11, respectively). The duration of the pullback maneuver did not impact the reproducibility of the PPG (r = 0.12, 95% CI: -0.29 to 0.49, p = 0.567). Manual pullbacks allow for an accurate PPG calculation. The inter- and intraoperator reproducibility of PPG derived from manual pullbacks were excellent., (© 2022 Wiley Periodicals LLC.)

Objective: To investigate the impact of invasive functional guidance for coronary artery bypass graft surgery (CABG) on graft failure., Background: Data on the impact of fractional flow reserve (FFR) in guiding CABG are still limited., Methods: Systematic review and individual patient data meta-analysis were performed. Primary objective was the risk of graft failure, stratified by FFR. Risk estimates are reported as odds ratios (ORs) derived from the aggregated data using random-effects models. Individual patient data were analyzed using mixed effect model to assess relationship between FFR and graft failure. This meta-analysis is registered in PROSPERO (CRD42020180444)., Results: Four prospective studies comprising 503 patients referred for CABG, with 1471 coronaries, assessed by FFR were included. Graft status was available for 1039 conduits at median of 12.0 [IQR 6.6; 12.0] months. Risk of graft failure was higher in vessels with preserved FFR (OR 5.74, 95% CI 1.71-19.29). Every 0.10 FFR units decrease in the coronaries was associated with 56% risk reduction of graft failure (OR 0.44, 95% CI 0.34 to 0.59). FFR cut-off to predict graft failure was 0.79., Conclusion: Surgical grafting of coronaries with functionally nonsignificant stenoses was associated with higher risk of graft failure., (© 2021 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Objectives: To characterize hemodynamics of serial coronary stenoses using fractional flow reserve (FFR) pullbacks and the pullback pressure gradients (PPG) index., Background: The cross-talk between stenoses within the same coronary artery makes the prediction of the functional contribution of each lesion challenging., Methods and Results: One-hundred seventeen patients undergoing coronary angiography for stable angina were prospectively recruited. Serial lesions were defined as two or more narrowings with visual diameter stenosis >50% on conventional angiography. Motorized FFR pullback tracings were obtained at 1 mm/s. Pullbacks were visually adjudicated as presenting two, one, and no focal pressure drops. The pattern of disease (i.e., focal or diffuse) was quantified using the PPG index. Twenty-five vessels presented serial lesions (mean PPG 0.48 ± 0.17). Two, one or no focal pressure drops were observed in 40% (n = 10; PPG 0.59 ± 0.17), 52% (n = 13; PPG 0.44 ± 0.12) and 8% of cases (n = 2; PPG 0.27 ± 0.01; p-value = 0.01). Distal FFR was similar between vessels with two, one and no focal pressure drops in the pullback curve (p-value = 0.27). The PPG index independently predicted the presence of two focal pressure drops in the pullback curve (p = 0.04)., Conclusions: FFR pullbacks in serial coronary lesions exhibit three distinct functional patterns. High PPG was associated with pullback curves presenting two pressure drops. The PPG provides a quantitative assessment of the pattern of coronary artery disease in cases with serial lesions and might be useful to assess the appropriateness of percutaneous revascularization., (© 2021 Wiley Periodicals LLC.)

Objectives: The present study aimed at determining the accuracy and reproducibility of motorized FFR pullbacks in patients with stable coronary artery disease., Background: Fractional flow reserve (FFR) is recommended for decision making regarding myocardial revascularization. The distribution of epicardial resistance along coronary vessels can be assessed using FFR pullbacks., Methods: Duplicated FFR pullbacks were acquired using a motorized device at a speed of 1 mm/s in intermediate coronary stenosis. In addition, a single FFR value was measured at an anatomical landmark. The agreement between FFR measurements was assessed using the Bland-Altman method, Pearson's correlation coefficient and area under the pullback curve (AUPC)., Results: In 20 vessels, 37,326 FFR values were obtained. The mean FFR from the pullbacks was 0.91 ± 0.08 whereas the mean FFR at the distal location was 0.85 ± 0.09. The mean difference between pullbacks was -0.002 (LOA -0.058 to 0.054). The difference in AUPC between the two FFR pullbacks was 2.1 ± 1.6%. At pre-specified anatomical locations, the mean difference between the FFR derived from the pullback data and the measured FFR was 0 (LOA -0.040 to 0.039). The repeatability of the distal FFR measurement was high (bias -0.003, LOA -0.046 to 0.041)., Conclusion: A motorized FFR pullback was accurate to assess the distribution of epicardial resistance in patients with intermediate coronary artery disease. The reproducibility of the FFR pullback was high. Further studies are required to determine the potential usefulness of a hyperemic FFR pullback strategy for decision making and treatment planning., (© 2020 Wiley Periodicals, Inc.)

Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Intestinal malrotation results from failure of intestinal rotation and fixation during fetal life. We report two cases of esophageal reconstruction with free jejunal flaps following total laryngopharyngectomy of hypopharyngeal and cervical esophageal carcinoma in which intestinal malrotation was detected during the jejunal flap harvesting. In both cases, the ligament of Treitz was absent, and the laparotomy incision was thus extended to identify the jejunum. In case 1, harvesting an adequate length of the vascular pedicle of the flap was impossible because of the abnormal position of the pancreas; thus, a jejunal flap of maximal length was harvested for optimal pedicle positioning in the recipient site. In case 2, Ladd's ligament prohibited the release of the jejunum from the ascending colon and required its dissection. Both patients underwent successful reconstruction. When the ligament of Treitz is absent during jejunal flap harvesting, investing the whole bowel by extended laparotomy incision is recommended. When anatomical abnormality caused by intestinal malrotation is detected, releasing an adhesion of the jejunum from circumferential organs and identifying the adequate vascular pedicle of a jejunal flap are necessary. If harvesting the long vascular pedicle is impossible, a jejunal flap of maximal length should be harvested for optimal positioning for vascular anastomosis at the shortest distance in the recipient site., (© 2014 Wiley Periodicals, Inc.)

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥ 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes., (Copyright © 2011 UICC.)

In mammals, Sry, Sox9, and M33 act as regulators at a chromatin level and promote the maturation of embryonic gonads into testes. Recently, it was shown that transcriptional regulation by DNA methylation plays crucial roles in gene expression during the differentiation and development of various cell types. To determine the involvement of DNA methylation in sex determination of the gonad, we developed and performed organ culture of gonad with the DNA methyltransferase inhibitor 5-azacytidine to induce global DNA methylation status changes. In vitro treatment with 5-azacytidine specifically inhibited testicular cord formation in a dose-dependent manner; however, no appreciable defect was observed in ovarian explants. Inhibition of testicular cord was observed only in gonads from 11.5 days post-coitus embryos. These effects were not observed in 5-azacytidine-treated gonads from 12.0 days post-coitus embryos. To determine the effect of 5-azacytidine on Sertoli and Leydig cell differentiation in the testis, we performed whole mount in situ hybridization analysis. The Leydig and stromal cell marker genes Lhx9, Mfge8, and 3beta-Hsd were normally induced in 5-azaytidine-treated testicular explants. Sertoli cell marker genes, Sox9 and MIS were normally induced, but Col9a3, encoding an extracellular matrix component, was inhibited in 5-azacytidine-treated testicular explants. Thus, our data show that DNA methylation is involved in testicular cord formation and Sertoli cell differentiation, acting directly on the gonad at 11.5 days post-coitus.

Background: Attempts to analyze bone marrow aspirates have been reported with the use of several automated blood cell counters, but sufficient accuracy in examination is not acquired yet. Major problems have included difficulties in correctly differentiating various immature cells and interference by lipid in bone marrow aspirates. The goal of this study was to solve these problems to attain more accurate assessment of bone marrow aspirates with automated blood cell counters., Methods: We modified the XE-2100 Automated Hematology Analyzer (Sysmex Corporation, Kobe, Japan) to fit it for bone marrow aspirate measurement and evaluated its performance. Measurements were performed with the modified XE-2100 on 81 patient samples of bone marrow aspirates; as a reference, the manual visual method was used and flow cytometric analysis were carried out., Results: Good correlations between results with the modified XE-2100 and the manual visual method were obtained for total nucleated cell count (TNCC; r = 0.99), erythroblast/TNCC ratio (r = 0.93), and myeloid cell/TNCC ratio (r = 0.75)., Conclusions: When this device is used, bone marrow aspirate differentials can be determined quickly and easily. This device will be useful for preliminary examination to obtain a summary of various blood cell ratios in bone marrow aspirates before performance of microscopic examination., (Copyright 2004 Wiley-Liss, Inc.)

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in several RNA-related biological processes. We demonstrated hnRNP L as a candidate protein of DARP (duocarmycin-DNA adduct recognizing protein) by gel shift assay and amino acid sequencing. Stable transfectants of hnRNP L showed high sensitivity of the cells to the growth inhibitory effect of KW-2189, a duocarmycin derivative in vitro. Immunostaining of hnRNP L demonstrated differential intracellular localization of hnRNP L among human lung cancer cell lines. A transfection study using a series of deletion mutants of hnRNP L fused to indicated that the N-terminal portions of RRM(RNA recognition motif)1, RRM3 and RRM2 are involved in localization of hnRNP L. We identified sequences in these portions that have high homology with the sequences of known NLS (nuclear localization signal) and NES (nuclear export signal). hnRNP L is a factor that determines the sensitivities of cancer cells to the minor groove binder, and overexpression and differential intracellular localization of hnRNP L are involved in its function in lung cancer., (Copyright 2003 Wiley-Liss, Inc.)