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Abstract Inflammatory microenvironments often become acidic (pH

Background Hypertension is a risk factor for bleeding events and is included in the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/Alcohol concomitantly)score. However, the effects of blood pressure (BP) and changes in BP on bleeding events in patients undergoing percutaneous coronary intervention (PCI) remain poorly understood. This study is aimed to investigate the relationship between systolic BP (SBP) changes during hospitalisation and bleeding events in patients undergoing PCI.Methods From the Clinical Deep Data Accumulation System database, a multicentre database encompassing seven tertiary medical hospitals in Japan that includes data for patient characteristics, medications, laboratory tests, physiological tests, cardiac catheterisation and PCI treatment, data for 6351 patients undergoing PCI between April 2013 and March 2019 were obtained. The study population was categorised into three groups based on the changes in SBP during hospitalisation: (1) elevated BP (≥20 mm Hg), (2) no change (≥−20 to

Abstract Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought to clarify the formation process of SLT and thrombogenicity during the perioperative period of TAVI. This multicenter, prospective, single-arm interventional study enrolled 26 patients treated with edoxaban for atrial fibrillation and who underwent TAVI for severe aortic stenosis between September 2018 and September 2022. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI in 18 patients and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD) (n = 11). SLT was observed in 16.7% (3/18) at 1 week, but decreased to 5.9% (1/17) at 3 months after TAVI. Patients with SLT at 1 week had a significantly decreased maximal leaflet thickness compared to those without SLT. Thrombogenicity assessed by T-TAS decreased markedly at 1 week and tended to increase at 3 months. The stagnation volume assessed by CFD was positively associated with a higher maximum leaflet thickness. This study showed the course of leaflet thrombus formation and visualization of stagnation in neo-sinus of THV in the acute phase after TAVI.

Background Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor‐κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti‐inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti‐inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. Methods and Results Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory‐related gene expression, and elevated serum interleukin‐6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage‐like cell line RAW264.7 cells demonstrated that esaxerenone‐ and spironolactone‐attenuated lipopolysaccharide‐induced interleukin‐6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65–STAT3 interaction, leading to a subsequent increase in interleukin‐6 promoter activity, which was reversed by esaxerenone. Conclusions Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti‐inflammatory properties exerted by modulating the transcriptional activity of the MR–p65–STAT3 complex. These results suggest that the MR–p65–STAT3 complex can be a novel therapeutic target for treating MI.

Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2 R172K and TP53 R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2 R172K and TP53 R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Abstract We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

Objective This study aimed to investigate the association between heart failure (HF) severity measured based on brain natriuretic peptide (BNP) levels and future bleeding events after percutaneous coronary intervention (PCI).Background The Academic Research Consortium for High Bleeding Risk presents a bleeding risk assessment for antithrombotic therapy in patients after PCI. HF is a risk factor for bleeding in Japanese patients.Methods Using an electronic medical record-based database with seven tertiary hospitals in Japan, this retrospective study included 7160 patients who underwent PCI between April 2014 and March 2020 and who completed a 3-year follow-up and were divided into three groups: no HF, HF with high BNP level and HF with low BNP level. The primary outcome was bleeding events according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. The secondary outcome was major adverse cardiovascular events (MACE). Furthermore, thrombogenicity was measured using the Total Thrombus-Formation Analysis System (T-TAS) in 536 consecutive patients undergoing PCI between August 2013 and March 2017 at Kumamoto University Hospital.Results Multivariate Cox regression showed that HF with high BNP level was significantly associated with bleeding events, MACE and all-cause death. In the T-TAS measurement, the thrombogenicity was lower in patients with HF with high BNP levels than in those without HF and with HF with low BNP levels.Conclusions HF with high BNP level is associated with future bleeding events, suggesting that bleeding risk might differ depending on HF severity.

Background: Heart failure (HF) is associated with a high bleeding risk after percutaneous coronary intervention (PCI). Additionally, major bleeding events increase the risk of subsequent major adverse cardiac events (MACE). However, whether brain natriuretic peptide (BNP) levels and major bleeding events following PCI are associated with MACE and all-cause death remains unknown. This study aimed to investigate the impact of HF severity or bleeding on subsequent MACE and all-cause death. Methods: The Clinical Deep Data Accumulation System (CLIDAS), a multicenter database involving seven hospitals in Japan, was developed to collect data from electronic medical records. This retrospective analysis included 7160 patients who underwent PCI between April 2014 and March 2020 and completed a three-year follow-up. Patients were divided according to the presence of HF with high BNP (HFhBNP) (>100 pg/ml) and major bleeding events within 30 days post-PCI (30-day bleeding): HFhBNP with bleeding (n = 14), HFhBNP without bleeding (n = 370), non-HFhBNP with bleeding (n = 74), and non-HFhBNP without bleeding (n = 6702). Results: In patients without 30-day bleeding, HFhBNP was a risk factor for MACE (hazard ratio, 2.19; 95% confidence interval, 1.56–3.07) and all-cause death (hazard ratio, 1.60; 95% confidence interval, 1.60–2.23). Among HFhBNP patients, MACE incidence was higher in patients with 30-day bleeding than in those without bleeding, but the difference was not significant (p = 0.075). The incidence of all-cause death was higher in patients with bleeding (p = 0.001). Conclusions: HF with high BNP and bleeding events in the early stage after PCI might be associated with subsequent MACE and all-cause death.

BackgroundThe causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE).MethodsThis was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups.ResultsIn total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23–1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69–2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results.ConclusionCLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

Abstract Background Heart failure (HF)‐related congestive hepatopathy is a well‐recognized problem in management of HF. The fibrosis‐4 (FIB4) index calculated by [age × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)] is useful for evaluating liver stiffness. We aimed to investigate the impact of the FIB4 index on prognosis in patients with HF. Methods and results Consecutive HF patients referred for hospitalization at Kumamoto University Hospital, Japan, were registered between 2006 and 2015. We observed cardiovascular outcomes in each type of HF [HF with reduced left ventricular ejection fraction (LVEF) (HFrEF), HF with mid‐range LVEF (HFmrEF) and with preserved LVEF (HFpEF)] according to their FIB4 index; Group 1 (FIB4 index 2.67). This study enrolled 83 HFrEF patients, 117 HFmrEF patients, and 504 HFpEF patients. In HFpEF patients, the Kaplan–Meier curve revealed that Group 3 had a significantly higher rate of total cardiovascular events compared with the other two groups. By contrast, the occurrences of total cardiovascular events were not different among three groups in HFrEF and HFmrEF patients. Multivariate Cox proportional hazard analysis with significant factors in univariate analysis identified that the FIB4 index as an independent and significant predictor for future total cardiovascular events in HFpEF patients (hazard ratio: 1.09, 95% confidence interval: 1.03–1.15, P = 0.001). Conclusions The FIB4 index was a significant predictor for total cardiovascular events in HFpEF.

Abstract Falling is a representative incident in hospitalization and can cause serious complications. In this study, we constructed an algorithm that nurses can use to easily recognize essential fall risk factors and appropriately perform an assessment. A total of 56,911 inpatients (non-fall, 56,673; fall; 238) hospitalized between October 2017 and September 2018 were used for the training dataset. Correlation coefficients, multivariable logistic regression analysis, and decision tree analysis were performed using 36 fall risk factors identified from inpatients. An algorithm was generated combining nine essential fall risk factors (delirium, fall history, use of a walking aid, stagger, impaired judgment/comprehension, muscle weakness of the lower limbs, night urination, use of sleeping drug, and presence of infusion route/tube). Moreover, fall risk level was conveniently classified into four groups (extra-high, high, moderate, and low) according to the priority of fall risk. Finally, we confirmed the reliability of the algorithm using a validation dataset that comprised 57,929 inpatients (non-fall, 57,695; fall, 234) hospitalized between October 2018 and September 2019. Using the newly created algorithm, clinical staff including nurses may be able to appropriately evaluate fall risk level and provide preventive interventions for individual inpatients.

Background: Although the Khorana venous thromboembolism (VTE) risk score (KRS) is well recognized as a simple VTE risk assessment method in patients with cancer, whether it is suitable for Asian populations is unclear. Objectives: This study validated KRS for the prediction of VTE and investigated the value of the KRS in predicting mortality in Japanese patients with cancer. Methods: A body mass index value of 25 kg/m2 or more was defined as obesity according to World Health Organization consensus. A total of 27,687 patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups by the KRS. The primary and secondary endpoints were VTE and all-cause mortality, respectively. Results: The prevalence of VTE was 1.7%, 7.3%, and 11.0% for low-, intermediate-, and high-score patients, respectively. Receiver operating characteristic (ROC) analysis showed that the KRS significantly predicted VTE (area under the curve, 0.679; 95% confidence interval [CI] 0.666-0.692; P < 0.001). The cutoff value for the KRS was 1.0. Logistic regression analysis demonstrated that the KRS was an independent predictor of VTE (odds ratio 1.766; 95% CI 1.673-1.865; P < 0.01). The cutoff value of the KRS for all-cause mortality determined by ROC analysis was 2.0. Kaplan–Meier analysis demonstrated a significantly higher incidence of mortality in the KRS ≥2 group than in the KRS 0-1 group (log-rank: P < 0.01). Conclusions: The KRS was useful in Japanese patients with cancer and might be a potentially useful marker for the prediction of mortality. Establishing optimal scores for Japanese subjects is mandatory because of its low diagnostic ability. (KUMAMON Cancer registry; UMIN000047554)

Introduction: Vertebral artery injury (VAI) due to blunt cervical spine injury (BCSI) can cause severe cerebral infarction. This study aimed to evaluate the risks of cerebral infarction and to develop a brain screening algorithm in patients with BCSI. Methods: We examined the characteristics of 37 consecutive patients diagnosed with BCSI at our institute between January 2017 and April 2021 and retrospectively analyzed the risk factors for post-trauma cerebral infarction, such as patient background characteristics, fracture side and level, vertebral artery (VA) status, details of treatment, and complications. Results: A total of 12 patients (32.4%) had VAI, of whom six were treated with intravascular coil embolization to prevent cerebral infarction after cervical spine surgery. Of the five patients (13.5%) with cerebral infarction, four had VAI and one had intact VAs but with a fracture of the intervertebral foramen on the dominant side of the VA (illustrative case). Only the presence of VAI showed a significant difference in the risk of cerebral infarction onset (p = 0.015). Coil embolization did not increase the risk of postoperative cerebral infarction (p = 0.12). Conclusion: VAI was the only risk factor for the development of cerebral infarction in patients with BCSI, suggesting that head magnetic resonance imaging (MRI) screening is recommended for those with VAI. In patients without VAI, vertebral fractures on the dominant side of the VA might be a risk for cerebral infarction, indicating that head MRI screening should also be considered in these patients.

Abstract Aims The focus on wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM) is increasing because of novel treatment options. There is currently no report on a large number of Japanese patients with ATTRwt‐CM. The study aimed to examine the characteristics and prognosis of ATTRwt‐CM in Japan. Methods and results Consecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt‐CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Data, including demographic characteristics, co‐morbidities, clinical manifestations at diagnosis, laboratory results, electrocardiographic and echocardiographic data, imaging and pathological findings, and treatment were obtained. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2–75) months. Heart failure was the most common clinical manifestation leading to diagnosis (61%) and initial manifestations (49%). Of 106 patients, carpal tunnel syndrome was observed in 57 patients (54%), and the median period from initial symptom onset to diagnosis was 96 (48–120) months. Histopathological confirmation of transthyretin amyloid was achieved in 94 patients (73%), including 66 (51%) and 28 cases (22%) with endomyocardial and extracardiac biopsies. During the observation period (median 15.0 [inter‐quartile range, 5.4–33.2] months after diagnosis), 34 patients (26%) died. Of these, 27 patients (79%) had cardiovascular deaths (heart failure, 25; sudden death, two). The median survival duration was 58.9 months and the 5 years' survival rate was 48%. According to a multivariate Cox hazard analysis, age [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05–1.23, P = 0.002] and low serum sodium levels (HR, 0.89; 95% CI, 0.79–0.996; P = 0.04) contributed to all‐cause mortality, and low serum sodium levels contributed to hospitalization for heart failure (HR, 0.86; 95% CI, 0.77–0.96; P = 0.005). Conclusions Clinical characteristics and prognosis of ATTRwt‐CM patients in Japan were examined. Carpal tunnel syndrome can be considered an indication for diagnosis of ATTRwt‐CM. Age and low serum sodium level were significant predictive factors of all survival outcomes. The clinical features of ATTRwt‐CM should be recognized to provide appropriate treatment.

Abstract Aims The prediction of future heart failure (HF) in stable outpatients is often difficult for general practitioners and cardiologists. Recently, the H2FPEF score (0–9 points) has been proposed for the discrimination of HF with preserved ejection fraction from non‐cardiac causes of dyspnoea. The six clinical and echocardiographic variables that constitute the H2FPEF score include the following: (i) obesity (H); (ii) the use of ≥2 antihypertensive drugs (H); (iii) atrial fibrillation (F); (iv) pulmonary hypertension (P); (v) an age > 60 years (E); and (vi) E/e' > 9 (F). We performed an external validation study that investigated whether the H2FPEF score could predict future HF‐related events in stable outpatients with cardiovascular risk factor(s) in Japan. Methods and results In this prospective cohort study, after exclusion of 195 from 551 consecutive, stable Japanese outpatients with at least one cardiovascular risk factor who were enrolled between September 2010 and July 2013, the remaining 356 outpatients (171 men, 185 women, mean age 73.2 years) were eligible for the analysis. We calculated the H2FPEF score (0–9 points), and followed up the patients for an average of 517 days. In all of the 356 patients, the mean H2FPEF score was 3.1 ± 1.8, and 15 developed HF‐related events during the follow‐up period, including cardiovascular death (n = 2) and hospitalization for HF decompensation (n = 13). Multivariate Cox proportional hazards analysis showed that the H2FPEF score was an independent predictor of future HF‐related events (P < 0.001 for all three models). Kaplan–Meier survival curves showed a significantly higher probability of HF‐related events in the outpatients with a high H2FPEF score (P < 0.001). In receiver operating characteristic (ROC) curve analysis, the H2FPEF score was significantly associated with the occurrence of future HF‐related events (P < 0.001). In ROC curve analysis, the sensitivity, specificity, and positive likelihood ratio of a H2FPEF score of 7 points to predict HF‐related events were 47%, 96%, and 11.4%, respectively. Conclusions The H2FPEF score could provide useful information for future HF‐related events in stable outpatients with cardiovascular risk factor(s) in Japan.

Background The clinical implication of vascular endothelial dysfunction in patients with atrial fibrillation (AF) remains unclear. This study aimed to elucidate the correlation between changes in vascular endothelial function assessed by reactive hyperemia‐peripheral arterial tonometry and the effect of sinus rhythm restoration after catheter ablation (CA) for AF. Methods and Results Consecutive 214 patients who underwent CA for AF were included in this single center, retrospective study. The natural logarithmic transformed reactive hyperemia‐peripheral arterial tonometry index (LnRHI) of all patients was measured before CA as well as 3 and 6 months after CA. LnRHI in sinus rhythm was significantly higher than that in AF before CA. Multivariate logistic regression analysis revealed that the presence of AF was an independent risk factor for lowering of LnRHI (odds ratio, 4.092; P=0.002) before CA. The LnRHI was significantly improved 3 and 6 months after CA in patients without AF recurrence. Multivariate Cox hazard analysis revealed that changes in LnRHI from before to 3 months after CA independently correlated with recurrence of AF (hazard ratio, 0.106; P=0.001). Receiver operating characteristic analysis showed the decrease in LnRHI levels from before to 3 months after CA as a significant marker that suspects AF recurrence (area under the curve, 0.792; log‐rank test, P

Background Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. Methods and Results We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P

Background We investigated the clinical significance of derivatives of reactive oxygen metabolites (DROMs), a new marker of reactive oxygen species, in patients with nonischemic heart failure (HF) and compared them among new categories of HF. Methods and Results We recruited 201 consecutively hospitalized patients with HF and measured DROM under stable conditions. Then, we divided them according to new categories of HF (HF with reduced ejection fraction [EF], HF with midrangeEF, and HF with preserved EF) without coronary artery disease. In subgroup analysis, we followed EF changes in patients with HF with reduced EF and classified them into HF with recovered EF or nonrecovered EF according to whether EF had improved to >40%. DROMs are significantly and independently associated with HF‐related events in patients with NIHF. There were no significant differences in DROM and the probability of HF‐related events among HF categories in Kaplan–Meier analysis. However, patients with HF with reduced EF and HF with preserved EF but not HF with midrange EF with HF‐related events had higher DROM than those without HF‐related events. In subgroup analysis, Kaplan–Meier analysis demonstrated that the probabilities of HF‐related events in HF with recovered EF were dramatically decreased. DROM were significantly higher in patients with HF with nonrecovered EF than in HF with recovered EF. In receiver operating characteristic analysis, the cutoff level of DROM for predicting improvements in HF with recovered EF was 347 Carratelli units. Furthermore, the C‐statistic value for predicting EF improvement for the DROM levels was 0.703. In multivariable logistic regression analysis, DROM was independently and significantly associated with the prediction of HF with recovered EF. Conclusions DROM measurements can provide important prognostic information for risk stratification in any category of NIHF. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000035827.

Abstract Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.

Background Meningiomas are often embolized preoperatively to reduce intraoperative blood loss and facilitate tumor resection. However, the procedure is controversial and its effects have not yet been reported. We evaluated preoperative embolization for meningiomas and its effect on postoperative outcome and recurrence. Methods We retrospectively reviewed the medical records of 186 patients with WHO grade I meningiomas who underwent surgical treatment at our hospital between January 2010 and December 2020. We used propensity score matching to generate embolization and no-embolization groups (42 patients each) to examine embolization effects. Results Preoperative embolization was performed in 71 patients (38.2%). In the propensity-matched analysis, the embolization group showed favorable recurrence-free survival (RFS) (mean 49.4 vs 24.1 months; Wilcoxon p=0.049). The embolization group had significantly less intraoperative blood loss (178±203 mL vs 221±165 mL; p=0.009) and shorter operation time (5.6±2.0 hours vs 6.8±2.8 hours; p=0.036). There were no significant differences in Simpson grade IV resection (33.3% vs 28.6%; p=0.637) or overall perioperative complications (21.4% vs 11.9%; p=0.241). Tumor embolization prolonged RFS in a subanalysis of cases who experienced recurrence (n=39) among the overall cases before variable control (mean RFS 33.2 vs 16.0 months; log-rank p=0.003). Conclusions After controlling for variables, preoperative embolization for meningioma did not improve the Simpson grade or patient outcomes. However, it might have effects outside of surgical outcomes by prolonging RFS without increasing complications. [ABSTRACT FROM AUTHOR]