Changes of echocardiographic parameters in primary mitral regurgitation and determinants of symptom: an assessment from the Asian Valve Registry data.

Clinicians often have a difficulty in determining the presence of mitral regurgitation (MR)-related symptoms because of subjectivity. However, there are few actual measurement data for echocardiographic left ventricular (LV) and left atrial (LA) size related to the severity of MR and the relationship between MR-related symptoms and these echocardiographic parameters. Among patients enrolled in the Asian Valve Registry, we investigated 778 consecutive patients with primary MR showing sinus rhythm. Symptoms were determined by New York Heart Association grade (≤ II or ≥ III). MR severity was mild in 106, moderate in 285, and severe in 387 patients. LA volume index, LV end-diastolic diameter, and LV mass index increased with increasing MR grade [LA volume index: 47.9 (mild), 56.2 (moderate), and 64.9 ml/m2 (severe) (p < 0.001), LV end-diastolic diameter: 51.2, 54.5, 58.1 mm (p < 0.001), and LV mass index: 101, 109, 123 g/m2 (p < 0.001)]. Regarding moderate and severe MR, 70 patients (10.4%) were symptomatic. In multivariable analysis, for being symptomatic in moderate and severe MR patients, LV mass index (odds ratio [OR] per 10 g/m2 increment; 1.09; 95% confidence interval [CI]: 1.005-1.18, p = 0.040), ejection fraction (OR per 1% increment; 0.96, 95%CI: 0.93-0.98, p < 0.001), female gender (OR 2.28; 95% CI: 1.31-3.98, p = 0.004), and heart rate (OR per 1 bpm increment; 1.03; 95%CI: 1.01-1.05, p = 0.007) were independent factors. LV and LA parameters on echocardiography worsened as MR severity progressed. Larger LV mass index and lower ejection fraction were independent determinant factors for MR-related symptoms. We should also pay attention to LV hypertrophy in patients with primary MR.

Relations of Augmented Systolic Annular Expansion and Leaflet/Papillary Muscle Dynamics in Late-Systolic Mitral Valve Prolapse Evaluated by Echocardiography with a Speckle Tracking Analysis.

The mechanism of systolic annular expansion in mitral valve prolapse (MVP) is not clarified. Since annular expansion is systolic outward shift of MV leaflet/chorda tissue complex at superior and outer ends, annular expansion could be related to inward (superior) shift of the complex at another inferior and inner end of the papillary muscle (PM) tip and/or systolic lengthening of the tissue complex, especially MV leaflets.MV annulus systolic expansion, PMs' systolic superior shift, and MV leaflets' systolic lengthening were evaluated by echocardiography with a speckle tracking analysis in 25 normal subjects, 25 subjects with holo-systolic MVP and 20 subjects with late-systolic MVP.PMs' superior shift, MV leaflets' lengthening, MV annular area at the onset of systole and subsequent MV annulus expansion were significantly greater in late-systolic MVP than in holo-systolic MVP (4.6 ± 1.6 versus 1.5 ± 0.7 mm/m2, 2.5 ± 1.4 versus 0.6 ± 2.0 mm/m2, 6.8 ± 2.5 versus 5.7 ± 1.0 cm2/m2 and 1.6 ± 0.8 versus 0.1 ± 0.5 cm2/m2, P < 0.001, respectively). Multivariate analysis identified MV leaflets' lengthening and PMs' superior shift as independent factors associated with MV annular expansion.Conclusions: These results suggest that systolic MV annular expansion in MVP is related to abnormal MV leaflets' lengthening and PMs' superior shift.

Insights into the mechanism of paradoxical low-flow, low-pressure gradient severe aortic stenosis: association with reduced O2 consumption by the whole body.

The mechanism of reduced stroke volume index (SVi) in paradoxical low-flow, low-pressure gradient (PLFLPG) aortic stenosis (AS) remains unclarified. Guyton et al. ( 21 ) demonstrated that SVi is determined by whole body O2 consumption (V̇o2) in many subjects, including patients with heart disease. We hypothesized that reduced SVi in PLFLPG AS is associated with reduced V̇o2 by the whole body. This study investigated the relationship between V̇o2, SVi, and AS severity in patients with AS to examine the association between reduced V̇o2 and PLFLPG AS. In 59 patients (24 men and 35 women, mean age: 78 ± 7 yr old) with severe AS, SVi, AS severity, and type were evaluated by echocardiography, and V̇o2 was measured by the fraction of O2 in expired gases. SVi and V̇o2 were significantly decreased in 20 patients with PLFLPG AS compared with 39 patients with non-PLFLPG AS (30 ± 4 vs. 41 ± 7 ml/m2 and 2.4 ± 0.5 vs. 3.0 ± 0.5 ml·min-1·kg-1, respectively, P < 0.01). The SVi-to-V̇o2 ratio was not different between the two groups (13.1 ± 2.6 vs. 13.6 ± 2.1, not significant). SVi was independently correlated with V̇o2 ( r = 0.74, P < 0.01) but not with the aortic valve area index. Categorized PLFLPG AS was also significantly associated with reduced V̇o2 ( P < 0.001). PLFLPG AS is associated with reduced V̇o2 by the whole body, which may offer insights into the mechanism of PLFLPG AS. NEW & NOTEWORTHY Paradoxical low-flow, low-pressure gradient severe aortic stenosis (PLFLPG AS) is an important and problematic subtype, and its central pathophysiology with reduced stroke volume is yet to be clarified. We hypothesized and subsequently clarified that reduced stroke volume in PLFLPG AS is associated with reduced O2 consumption by the whole body. This study suggests important insights into the mechanism of PLFLPG AS and may further promote studies to investigate further mechanisms and novel treatment.

Possible mechanism of late systolic mitral valve prolapse: systolic superior shift of leaflets secondary to annular dilatation that causes papillary muscle traction.

Progressive superior shift of the mitral valve (MV) during systole is associated with abnormal papillary muscle (PM) superior shift in late systolic MV prolapse (MVP). The causal relation of these superior shifts remains unclarified. We hypothesized that the MV superior shift is related to augmented MV superiorly pushing force by systolic left ventricular pressure due to MV annular dilatation, which can be corrected by surgical MV plasty, leading to postoperative disappearance of these superior shifts. In 35 controls, 28 patients with holosystolic MVP, and 28 patients with late systolic MVP, the MV coaptation depth from the MV annulus was measured at early and late systole by two-dimensional echocardiography. The PM tip superior shift was monitored by echocardiographic speckle tracking. MV superiorly pushing force was obtained as MV annular area × (systolic blood pressure - 10). Measurements were repeated after MV plasty in 14 patients with late systolic MVP. Compared with controls and patients with holosystolic MVP, MV and PM superior shifts and MV superiorly pushing force were greater in patients with late systolic MVP [1.3 (0.5) vs. 0.9 (0.6) vs. 3.9 (1.0) mm/m2, 1.3 (0.5) vs. 1.2 (1.0) vs. 3.3 (1.3) mm/m2, and 487 (90) vs. 606 (167) vs. 742 (177) mmHg·cm2·m-2, respectively, means (SD), P < 0.001]. MV superior shift was correlated with PM superior shift ( P < 0.001), which was further related to augmented MV superiorly pushing force ( P < 0.001). MV and PM superior shift disappeared after surgical MV plasty for late systolic MVP. These data suggest that MV annulus dilatation augmenting MV superiorly pushing force may promote secondary superior shift of the MV (equal to late systolic MVP) that causes subvalvular PM traction in patients with late systolic MVP. NEW & NOTEWORTHY Late systolic mitral valve prolapse (MVP) is associated with mitral valve (MV) and papillary muscle (PM) abnormal superior shifts during systole, but the causal relation remains unclarified. MV and PM superior shifts were correlated with augmented MV superiorly pushing force by annular dilatation and disappeared after surgical MV plasty with annulus size and MV superiorly pushing force reduction. This suggests that MV annulus dilatation may promote secondary superior shifts of the MV (late systolic MVP) that cause subvalvular PM traction.

Comparison between characteristics of severe and very severe aortic stenosis.

OBJECTIVES: Patients with very severe aortic stenosis (AS) have extremely poor clinical outcomes even if they are asymptomatic compared to those with severe AS, but the clinical and echocardiographic characteristics of patients with very severe AS remain unclear. METHODS: The Asian Valve Registry is a prospective, multicenter, multinational registry for the study and identification of the incidence, natural course, clinical outcomes, and prognostic factors for patients with significant AS at 9 centers in Asian countries. Severe AS was observed in 367 of 1066 patients with AS, and 212 were classified as very severe AS, defined as a peak aortic valve velocity ≥5.0 m/s or a mean aortic valve gradient ≥60 mm Hg. RESULTS: The prevalence of NYHA functional class II-IV among patients with very severe AS was significantly higher than that among patients with severe AS (67.9% vs 51.5%, P < .001). As for echocardiographic parameters, it was noteworthy that left ventricular mass index (LVMI) and left atrial volume index (LAVI) for patients with very severe AS were significantly larger than those for patients with severe AS (LVMI: 145.1 ± 36.4 g/m2 vs 119.2 ± 32.1 g/m2 , P < .0001; LAVI: 56.1 ± 24.6 mL/m2 vs 49.8 ± 22.6 mL/m2 , P = .002). Moreover, multivariate logistic regression analysis showed that LVMI was the only independently associated with NYHA functional class II-IV in patients with very severe AS. CONCLUSIONS: Our findings may well have clinical implications for better management of patients with AS and lead to better understanding of poor outcomes for patients with very severe AS.

Cellular force assay detects altered contractility caused by a nephritis-associated mutation in nonmuscle myosin IIA.

Recent progress in understanding the essential roles of mechanical forces in regulating various cellular processes expands the field of biology to one where interdisciplinary approaches with engineering techniques become indispensable. Contractile forces or contractility-inherently present in proliferative cells due to the activity of ubiquitous nonmuscle myosin II (NMII)-are one of such mechano-regulators, but because NMII works downstream of diverse signaling pathways, it is often difficult to predict how the inherent cellular forces change upon perturbations to particular molecules. Here, we determine whether the contractility of individual cells is upregulated or downregulated based on an assay analyzing specific deformations of silicone gel substrates. We focus on the effect of mutations in the human MYH9 gene that encodes NMIIA, which have been implicated in the pathogenesis of various diseases including nephritis. Our assay equipped with a high-throughput data analysis capability reveals that a point mutation of E1841K but not I1816V significantly reduces the magnitude of the endogenous forces of human embryonic kidney (HEK293) cells. Given the increasingly recognized roles of the endogenous forces as a critical mechano-regulator as well as that no apparent morphological changes were induced to cells even by introducing the mutations, our findings suggest a possibility that the detected reduction in the force magnitude at the individual cellular level may underlie the pathogenesis of the kidney disease.

High-sensitive cardiac troponin T as a novel predictor for recurrence of atrial fibrillation after radiofrequency catheter ablation.

AIMS: We aimed to determine whether elevated serum high-sensitive cardiac troponin T (hs-TnT) levels predict atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). METHODS AND RESULTS: We included 125 consecutive patients with AF (paroxysmal, n = 79; persistent, n = 46) who underwent first-time PVI. Serum hs-TnT, high-sensitive C-reactive protein (hs-CRP), atrial natriuretic peptide, and plasma B-type natriuretic peptide levels were measured in venous samples collected before PVI. Elevated hs-TnT was diagnosed in patients with levels ≥0.014 µg/L. All patients underwent multidetector computed tomographic examinations before PVI to measure left atrial volume (LAV) and left ventricular (LV) mass, which were indexed to body surface area. Arrhythmia recurrence was defined as AF/atrial tachycardia episodes lasting for ≥30 s after a 2-month blanking period from the PVI procedure. Elevated hs-TnT levels were observed in 22 (17.6%) patients. Age, diabetes mellitus, LV mass index, estimated glomerular filtration rate, and hs-CRP were independently associated with serum hs-TnT levels (all P < 0.05). During a mean follow-up of 12.9 ± 8.5 months after a single PVI procedure, the clinical recurrence rate was 33% (n = 41). Multivariate Cox proportional hazard analysis revealed that a greater LAV index (P = 0.01) and elevated serum hs-TnT level (P = 0.01) were significant predictors of AF recurrence after PVI. CONCLUSION: This study demonstrated that elevated serum hs-TnT levels are associated with AF recurrence independent of traditional risk factors and left atrial enlargement.

Epicardial Adipose Tissue Accumulation Is Associated With Renal Dysfunction and Coronary Plaque Morphology on Multidetector Computed Tomography.

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with coronary artery disease (CAD), although the underlying pathophysiological mechanism remains unclear. Epicardial adipose tissue (EAT) has recently been recognized as an important source of various pro-inflammatory cytokines causing coronary atherosclerosis. This study investigated the relationship between CKD and EAT volume in association with high-risk plaque. METHODS AND RESULTS: The study included 275 patients with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m(2)who underwent multidetector computed tomography (MDCT) for the evaluation of CAD. Patients were classified, according to eGFR, into a CKD group (30≤eGFR<60 ml/min/1.73 m(2)) or a non-CKD group (eGFR ≥60 ml/min/1.73 m(2)). MDCT was used to assess coronary plaque morphology and EAT volume. One hundred and ten patients with CKD were more likely to be older, have higher prevalence of hypertension, lower serum HDL-C, higher serum CRP, and larger EAT volume, than those without CKD (all P<0.01). On multivariate analysis age, hypertension, and EAT volume were significantly associated with eGFR (all P<0.01). EAT volume was associated with the presence of high-risk plaque, independent of traditional CAD risk factors (P=0.003). CONCLUSIONS: Patients with CKD had significantly increased EAT volume, which could be associated with the presence of high-risk plaque.

Pacing From the Right Ventricular Septum and Development of New Atrial Fibrillation in Paced Patients With Atrioventricular Block and Preserved Left Ventricular Function.

BACKGROUND: Whether pacing from the right ventricular (RV) septum improves prognosis is unclear. Furthermore, the clinical characteristics of patients who develop atrial fibrillation (AF) and cardiovascular events during long-term RV septal pacing have not been described.Methods and Results:We retrospectively evaluated the incidence of AF and cardiovascular events, including cardiac death, heart failure requiring hospitalization, or stroke, for a median of 4.0 years in 123 recipients of dual-chamber pacemakers implanted for atrioventricular block with preserved left ventricular function, who were free from AF before device implantation. AF developed in 30 patients (24%), and multivariable analysis suggested that the cumulative percentage of RV pacing was the only independent predictor of newly developed AF (hazard ratio: 1.19 for each 10% increment; 95% confidence interval: 1.04-1.41; P=0.01). Furthermore, older age, newly developed AF and a paced QRS duration ≥155 ms at pacemaker implantation were significant predictors of cardiovascular events. CONCLUSIONS: RV septum pacing may induce AF in up to one-quarter of patients paced for atrioventricular block, according to the frequency of pacing. More importantly, in such patients, AF induced by RV pacing and a paced QRS duration ≥155 ms at pacemaker implantation are significantly associated with poor prognosis. Therefore, we recommend pacing from sites producing a paced QRS duration <155 ms and avoiding unnecessary RV pacing. (Circ J 2016; 80: 2302-2309).

Left Atrial Remodeling in Segmental vs. Global Mitral Valve Prolapse　- Three-Dimensional Echocardiography.

BACKGROUND: Segmental and global mitral valve prolapse (MVP) comprise 2 representative phenotypes in this syndrome. While mitral regurgitation (MR) severity is a major factor causing left atrial (LA) remodeling in MVP, prominent mitral valve (MV) annulus dilatation in global MVP may specifically cause inferiorly predominant LA remodeling. We compared MV annulus and LA geometry in patients with segmental and global MVP.Methods and Results:LA volume as well as inferior, middle, and superior LA cross-sectional areas (CSA) were measured on 3-D echocardiography in 20 controls, in 40 patients with segmental MVP, and in 18 with global MVP. On multivariate analysis, MR severity was primarily associated with LA dilatation in segmental MVP (P<0.001), while MV annular dilatation was primarily associated with LA dilatation in global MVP (P<0.001). Although there was no regional predominance in LA dilatation in segmental MVP, inferior predominance of LA dilatation was significant in global MVP (increase in inferior, middle, and superior LA-CSA relative to mean of the controls: +220±70% vs. +171±55% vs. +137±37%, P<0.001). CONCLUSIONS: LA remodeling in segmental and global MVP is considerably different regarding its association with MR volume or MV annular dilatation and its regional predominance. While MR volume may mainly contribute to LA remodeling in segmental MVP, MV annular dilatation seems to have an important role in LA remodeling in global MVP. (Circ J 2016; 80: 2533-2540).

Comparison of effects of sitagliptin and voglibose on left ventricular diastolic dysfunction in patients with type 2 diabetes: results of the 3D trial.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is frequently observed in patients with type 2 diabetes. Dipeptidyl peptidase-4 inhibitor (DPP-4i) attenuates postprandial hyperglycemia (PPH) and may have cardio-protective effects. It remains unclear whether DPP-4i improves LV diastolic function in patients with type 2 diabetes, and, if so, it is attributable to the attenuation of PPH or to a direct cardiac effect of DPP-4i. We compared the effects of the DPP-4i, sitagliptin, and the alpha-glucosidase inhibitor, voglibose, on LV diastolic function in patients with type 2 diabetes. METHODS: We conducted a prospective, randomized, open-label, multicenter study of 100 diabetic patients with LV diastolic dysfunction. Patients received sitagliptin (50 mg/day) or voglibose (0.6 mg/day). The primary endpoints were changes in the e' velocity and E/e' ratio from baseline to 24 weeks later. The secondary efficacy measures included HbA1c, GLP-1, lipid profiles, oxidative stress markers and inflammatory markers. RESULTS: The study was completed with 40 patients in the sitagliptin group and 40 patients in the voglibose group. There were no significant changes in the e' velocity and E/e' ratio from baseline to 24 weeks later in both groups. However, analysis of covariance demonstrated that pioglitazone use is an independent factor associated with changes in the e' and E/e' ratio. Among patients not using pioglitazone, e' increased and the E/e' ratio decreased in both the sitagliptin and voglibose groups. GLP-1 level increased from baseline to 24 weeks later only in the sitagliptin group (4.8 ± 4.7 vs. 7.3 ± 5.5 pmol/L, p < 0.05). The reductions in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group (-0.7 ± 0.6 % vs. -0.3 ± 0.4, p < 0.005; -1.3 ± 3.2 kg vs. 0.4 ± 2.8 kg, p < 0.05, respectively). There were no changes in lipid profiles and inflammatory markers in both groups. CONCLUSIONS: Our trial showed that sitagliptin reduces HbA1c levels more greatly than voglibose does, but that neither was associated with improvement in the echocardiographic parameters of LV diastolic function in patients with diabetes. TRIAL REGISTRATION: Registered at http://www.umin.ac.jp under UMIN000003784.

Multicenter investigations of the prevalence of abdominal aortic aneurysm in elderly Japanese patients with hypertension.

BACKGROUND: Physical examination as an initial screening tool to diagnose abdominal aortic aneurysm (AAA) has lost favor over the past 20 years. This multicenter cohort study aimed to determine the prevalence of AAA in elderly Japanese patients with hypertension (HT) and to clarify the diagnostic accuracy of physical examination using a pocket-sized ultrasound imaging device (the "pocket-echo"). METHODS AND RESULTS: A total of 1,731 patients with HT aged >60 years from 20 collaborating institutions were enrolled in this study. Abdominal palpation was performed on physical examination, and the pocket-echo was used to confirm the diagnosis of AAA. The abdominal aorta was well visualized in 1,692 patients (98%). AAA was discovered in 69 patients (4.1%), with advanced age and male sex identified as independent risk factors. The prevalence of AAA increased according to age regardless of sex, and reached 9.2% and 5.7%, respectively, in males and females ≥80 years. Overall, 33 cases of AAA were missed on abdominal palpation (sensitivity, 52%), whereas for AAAs >40 mm, the sensitivity was 75%. CONCLUSIONS: We assessed the utility of the pocket-echo and physical examination for diagnosing AAA in Japanese patients with HT aged over 60 years. Our findings highlight the importance of AAA screening programs in high-risk Japanese populations, and confirm the ability of physical examination to detect large, but not small, AAAs.

DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study.

BACKGROUND: Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes. METHODS: We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events. RESULTS: ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1). CONCLUSIONS: Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events. TRIAL REGISTRATION: registered at http://www.umin.ac.jp/ctrj/ under UMIN000003951.

Chromosome interior observation by focused ion beam/scanning electron microscopy (FIB/SEM) using ionic liquid technique.

Attempts to elucidate chromosome structure have long remained elusive. Electron microscopy is useful for chromosome structure research because of its high resolution and magnification. However, biological samples such as chromosomes need to be subjected to various preparation steps, including dehydration, drying, and metal/carbon coating, which may induce shrinkage and artifacts. The ionic liquid technique has recently been developed and it enables sample preparation without dehydration, drying, or coating, providing a sample that is closer to the native condition. Concurrently, focused ion beam/scanning electron microscopy (FIB/SEM) has been developed, allowing the investigation and direct analysis of chromosome interiors. In this study, we investigated chromosome interiors by FIB/SEM using plant and human chromosomes prepared by the ionic liquid technique. As a result, two types of chromosomes, with and without cavities, were visualized, both for barley and human chromosomes prepared by critical point drying. However, chromosome interiors were revealed only as a solid structure, lacking cavities, when prepared by the ionic liquid technique. Our results suggest that the existence and size of cavities depend on the preparation procedures. We conclude that combination of the ionic liquid technique and FIB/SEM is a powerful tool for chromosome study.

A case of late-onset bleeding from an intercostal artery pseudoaneurysm after hemostasis using soft coagulation.

BACKGROUND: The use of soft coagulation is becoming common in thoracic surgery. Soft coagulation provides rapid hemostasis from small vessels during surgery by dehydrating tissue and denaturing proteins, without burning the tissue. CASE PRESENTATION: A 68-year-old man, with a history of right lower lobectomy 3 years prior, underwent a partial resection of the right upper lobe for a pulmonary nodule suspicious for secondary lung cancer. During the surgery, dissection of the adhesion caused a bleeding from the 6th intercostal artery, and hemostasis was achieved using soft coagulation (some degree of tissue carbonization was noticed at later mortality and morbidity conference). He experienced hemoptysis at postoperative day 18 and was transferred to our hospital. Contrast-enhanced CT scan revealed bleeding from the pseudoaneurysm of the 6th intercostal artery. Embolization was performed by angiography to stop the bleeding. CONCLUSIONS: We experienced a case of late-onset bleeding from a pseudoaneurysm related to soft coagulation hemostasis. Lessons learned from this patient are that additional hemostasis, such as ligation, would be considered for small arteries after hemostasis has been achieved by soft coagulation, especially when some degree of tissue carbonization is suspected.

Secondary Mutations of the EGFR Gene That Confer Resistance to Mobocertinib in EGFR Exon 20 Insertion.

INTRODUCTION: Approximately 10% of mutations in the EGFR gene in NSCLC are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR tyrosine kinase inhibitors (TKIs). Several novel EGFR TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the U.S. Food and Drug Administration. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR TKIs of earlier generations. METHODS: We chronically exposed murine pro-B-cell line cells transduced with the five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH, and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib exhibited good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Recent Advances in Perioperative Immunotherapies in Lung Cancer.

Several clinical trials have been revolutionizing the perioperative treatment of early-stage non-small cell lung cancer (NSCLC). Many of these clinical trials involve cancer immunotherapies with antibody drugs that block the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand PD-L1. While these new treatments are expected to improve the treatment outcome of NSCLC patients after pulmonary resection, several major clinical questions remain, including the appropriate timing of immunotherapy (neoadjuvant, adjuvant, or both) and the identification of patients who should be treated with neoadjuvant and/or adjuvant immunotherapies, because some early-stage NSCLC patients are cured by surgical resection alone. In addition, immunotherapy may induce immune-related adverse events that will require permanent treatment in some patients. Based on this fact as well, it is desirable to select appropriate patients for neoadjuvant/adjuvant immunotherapies. So far, data from several important trials have been published, with findings demonstrating the efficacy of adjuvant atezolizumab (IMpower010 trial), neoadjuvant nivolumab plus platinum-doublet chemotherapy (CheckMate816 trial), and several perioperative (neoadjuvant plus adjuvant) immunotherapies (AEGEAN, KEYNOTE-671, NADIM II, and Neotorch trials). In addition to these key trials, numerous clinical trials have reported a wealth of data, although most of the above clinical questions have not been completely answered yet. Because there are so many ongoing clinical trials in this field, a comprehensive understanding of the results and/or contents of these trials is necessary to explore answers to the clinical questions above as well as to plan a new clinical trial. In this review, we comprehensively summarize the recent data obtained from clinical trials addressing such questions.

Passive exercise using whole-body periodic acceleration enhances blood supply to ischemic hindlimb.

OBJECTIVE: Whole-body periodic acceleration (WBPA) has been developed as a passive exercise technique to improve endothelial function by increasing shear stress through repetitive movements in spinal axis direction. We investigated the effects of WBPA on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease. METHODS AND RESULTS: After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice, suggesting that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease. CONCLUSIONS: WBPA increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle. WBPA is a potentially suitable noninvasive intervention to facilitate therapeutic angiogenesis.

Impaired coronary flow reserve as a marker of microvascular dysfunction to predict long-term cardiovascular outcomes, acute coronary syndrome and the development of heart failure.

BACKGROUND: In the absence of obstructive coronary narrowing, impaired coronary flow reserve (CFR) represents coronary microvascular dysfunction. Transthoracic Doppler echocardiography (TTDE) allows non-invasive measurement of CFR in the left anterior descending (LAD) artery. This study aimed to assess the prognostic value of TTDE-derived CFR (as a marker of microvascular function) in predicting long-term cardiovascular events, acute coronary syndrome (ACS) events, and the development of heart failure (HF). METHODS AND RESULTS: This study consisted of 272 patients with coronary artery disease not involving obstructive narrowing (≥50%) in the LAD. Patients underwent TTDE examination for CFR measurement in the LAD. During the follow-up period of 4.0±1.9 years, 32 patients (12%) had cardiovascular events. Cox proportional hazard analysis identified lower CFR as an independent risk factor of cardiovascular events (P<0.001), ACS events (P=0.008), and HF development (P=0.003). A CFR less than 2.4 was the best cut-off value for predicting all events (area under the curve=0.82). CFR excellently predicted the development of HF (area under the curve=0.95), but not ACS events (area under the curve=0.67). CONCLUSIONS: This TTDE study demonstrated that CFR was a significant and independent determinant of long-term cardiovascular events, ACS events and HF in patients with coronary artery disease. A CFR greater than 2.0 was not suitable to predict a favorable long-term outcome, even in the absence of obstructive coronary narrowing.