Teikyo University Hospital

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomere and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implying contributions to atherogenesis. However, whether senescent vascular cells are present in the vasculature and contribute to the pathogenesis of atherosclerosis remains unclear. METHODS AND RESULTS: Senescence-associated beta-galactosidase (beta-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had had ischemic heart diseases. Strong beta-gal stainings were observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. An immunohistochemical analysis using anti-factor VIII antibody demonstrated that beta-gal stained cells are vascular endothelial cells. To determine whether endothelial cell senescence causes endothelial dysfunction, we induced senescence in human aortic endothelial cells (HAECs) by inhibiting telomere function and examined the expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) activity. Senescent HAECs exhibited increased ICAM-1 expression and decreased eNOS activity, both of which are alterations implicated in atherogenesis. In contrast, introduction of telomerase catalytic component significantly extended the life span and inhibited the functional alterations associated with senescence in HAECs. CONCLUSIONS: Vascular endothelial cells with senescence-associated phenotypes are present in human atherosclerotic lesions, and endothelial cell senescence induced by telomere shortening may contribute to atherogenesis.

Importance: Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option. Objective: To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events. Design, Setting, and Participants: Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019. Interventions: Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522). Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. Results: Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). Conclusions and Relevance: Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02619760.

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.

BACKGROUND: Prasugrel is an antiplatelet agent that shows more prompt, potent, and consistent platelet inhibition than clopidogrel. The objective of this study was to confirm the efficacy and safety of prasugrel at loading/maintenance doses of 20/3.75 mg. METHODS AND RESULTS: Japanese patients (n=1,363) with acute coronary syndrome undergoing percutaneous coronary intervention were randomized to either prasugrel (20/3.75 mg) or clopidogrel (300/75 mg), both in combination with aspirin (81-330 mg for the first dose and 81-100 mg/day thereafter), for 24-48 weeks. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) at 24 weeks, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke. We compared the incidence of MACE between the 2 groups using point estimates. Safety outcomes included the incidence of bleeding events until 2 weeks after the last dose. The incidence of MACE at 24 weeks was 9.4% in the prasugrel group and 11.8% in the clopidogrel group (risk reduction 23%, hazard ratio 0.77, 95% confidence interval 0.56-1.07). The incidence of non-coronary artery bypass graft-related major bleeding was similar in both groups (1.9% vs. 2.2%). CONCLUSIONS: Prasugrel 20/3.75 mg was associated with a low incidence of ischemic events, similar to the results of TRITON-TIMI 38, and with a low risk of clinically serious bleeding in Japanese ACS patients.

BACKGROUND: The value of pancreatoduodenectomy (PD) with extended lymphadenectomy for pancreatic cancer has been evaluated by many retrospective studies and 3 randomized controlled trials (RCT). However, the protocols used and the results found in the 3 RCTs were diverse. Therefore, a multicenter RCT was proposed in 1998 to evaluate the primary end point of long-term survival and the secondary end points of morbidity, mortality and quality of life of patients undergoing standard versus extended lymphadenectomy in radical PD for pancreatic cancer. METHODS: From March 2000 to May 2003, 112 patients with potentially curable pancreatic head cancer were enrolled and intraoperatively randomized to a standard or extended lymphadenectomy group. No resected patients received any adjuvant treatments. RESULTS: A hundred and one eligible patients were analyzed. Demographic and histopathological characteristics of the two groups were similar. The mean operating time, intraoperative blood loss and number of retrieved lymph nodes were greater in the extended group, but the other operative results were comparable. CONCLUSIONS: Although this multicenter RCT was conducted in a strict setting, extended lymphadenectomy in radical PD did not benefit long-term survival in patients with resectable pancreatic head cancer and led to levels of morbidity, mortality and quality of life comparable to those found after standard lymphadenectomy.

AIMS: Theoretically, bioresorbable vascular scaffolds (BVSs) may provide superior long-term results compared with permanent metallic drug-eluting stents (DESs). However, whether BVSs are as safe and effective as metallic DESs prior to complete bioresorption is unknown. METHODS AND RESULTS: ABSORB Japan was a single-blind, multicentre, active-controlled, randomized trial designed to support regulatory approval of the Absorb BVS in Japan. Eligible patients with one or two de novo lesions in different epicardial vessels were randomized at 38 Japanese sites in a 2:1 ratio to Absorb BVS vs. cobalt-chromium everolimus-eluting stents (CoCr-EESs). The primary endpoint was target lesion failure [TLF: a composite of cardiac death, myocardial infarction attributable to target vessel, or ischaemia-driven target lesion revascularization (ID-TLR)] at 12 months, powered for non-inferiority. The major secondary endpoint was angiographic in-segment late lumen loss (LLL) at 13 months. A total of 400 patients were randomized to BVSs (266 patients and 275 lesions) or CoCr-EESs (134 patients and 137 lesions). TLF through 12 months was 4.2% with BVSs and 3.8% with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.39% (3.95%); Pnon-inferiority < 0.0001]. Definite/probable stent/scaffold thrombosis at 12 months occurred in 1.5% of the patients with both devices (P = 1.0), and ID-TLR for restenosis was infrequent (1.1% with BVSs and 1.5% with CoCr-EESs, P = 1.0). With 96.0% angiographic follow-up, in-segment LLL at 13 months was 0.13 ± 0.30 mm with BVSs and 0.12 ± 0.32 mm with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.01 (0.07); Pnon-inferiority < 0.0001). CONCLUSION: In the ABSORB Japan randomized trial, 12-month clinical and 13-month angiographic outcomes of BVSs were comparable to CoCr-EESs. CLINICAL REGISTRATION: ClinicalTrials.gov, number NCT01844284.

Background: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous “more versus less statins” trials. However, no clear evidence for more versus less statins has been established in an Asian population. Methods: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) &lt;120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. Results: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P &lt;0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69–0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73–0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (&lt;95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. Conclusions: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01042730.

BACKGROUND: Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence. METHODS AND RESULTS: The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent-associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent-associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age <65 years. For LST versus VLST, they were hemodialysis, heart failure, insulin-dependent diabetes mellitus, and low body mass index. Patients with LST had a significantly higher rate of Thrombolysis in Myocardial Infarction grade 2/3 flow (36%) at the time of ST than those with EST (13%) (P<0.0001) and VLST (17%; P<0.0001). Mortality rate at 1 year after ST was significantly lower in patients with VLST (10.5%) compared with those with EST (22.4%; P=0.003) or LST (23.5%; P=0.009). CONCLUSIONS: ST timing-dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

AIMS: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. METHODS: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status. RESULTS: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively. CONCLUSION: In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

OBJECTIVES: NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) was designed for evaluating the noninferiority of a biolimus-eluting stent (BES) relative to an everolimus-eluting stent (EES) in terms of target lesion revascularization (TLR) at 1 year. BACKGROUND: Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited. METHODS: The NEXT trial is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BES with EES. Between May and October 2011, 3,235 patients were randomly assigned to receive either BES (n = 1,617) or EES (n = 1,618). RESULTS: At 1 year, the primary efficacy endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group, demonstrating noninferiority of BES relative to EES (p for noninferiority <0.0001, and p for superiority = 0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% vs. 0.06%, p = 0.18). An angiographic substudy enrolling 528 patients (BES: n = 263, and EES: n = 265) demonstrated noninferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03 ± 0.39 mm vs. 0.06 ± 0.45 mm, p for noninferiority <0.0001, and p for superiority = 0.52) at 266 ± 43 days after stent implantation. CONCLUSIONS: One-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and extremely low rate of stent thrombosis.

1 Current status of non‐pharmacotherapies in Japan Pacemaker treatment for bradyarrhythmia was first approved for national health insurance coverage in Japan in 1974, and its use rapidly became widespread thereafter. Approximately 40 years later, in 2017, the number of patients treated with this technology has increased to 60 137 (41 895 new cases and approximately 18 242 replacements). 5 Capsule‐shaped leadless pacemaker also became available in 2016, and this technology is being established as a new option. Non‐pharmacological treatment of tachy‐arrhythmia began in 1969 from when Will C. Sealy performed surgery in patients with Wolff‐Parkinson‐White (WPW) syndrome (Figure 1). Since then, the application of surgical treatment has expanded to conditions such as ventricular tachycardia (VT) and atrial fibrillation (AF), and surgery has been the pioneer of radical therapy for tachyarrhythmias. At the present time, many surgical methods have been replaced by catheter ablation; however, surgical treatment still remains an indispensable option for patients with a tachycardia resistant to other medical treatments. Open in a separate window FIGURE 1 History of non‐pharmacotherapy of cardiac arrhythmia

Background Prediction of thrombotic and bleeding risk is important to optimize antithrombotic therapy after percutaneous coronary intervention. Methods and Results We developed the prediction rules for thrombotic and bleeding events separately in Japanese patients. Derivation and validation cohorts consisted of 4778 patients from CREDO ‐Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) registry cohort 2 and 4669 patients from RESET (Randomized Evaluation of Sirolimus‐Eluting Versus Everolimus‐Eluting Stent Trial) and NEXT (Nobori Biolimus‐Eluting Versus Xience/Promus Everolimus‐Eluting Stent Trial). Primary thrombotic and bleeding events were a composite of myocardial infarction, definite or probable stent thrombosis or ischemic stroke, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding. The prediction rule for thrombosis assigned 2 points for severe chronic kidney disease, atrial fibrillation, peripheral vascular disease, and anemia and 1 point for age ≥75 years, heart failure, diabetes mellitus, and chronic total occlusion. The prediction rule for bleeding assigned 2 points for thrombocytopenia, severe chronic kidney disease, peripheral vascular disease, and heart failure and 1 point for prior myocardial infarction, malignancy, and atrial fibrillation. In derivation and validation cohorts, area under the curve was 0.68 and 0.64, respectively, for thrombosis and 0.66 and 0.66, respectively, for bleeding. In the validation cohort, a high thrombosis risk score (≥4, n=682) was associated with higher 3‐year incidence of thrombotic events than a score that was intermediate (2–3, n=1178) or low (0–1, n=2809) (7.6%, 3.7%, versus 2.4%, respectively; P &lt;0.0001). A high bleeding risk score (≥3, n=666) was associated with higher incidence of bleeding than scores that were intermediate (1–2, n=1802) or low (0, n=2201) (8.8%, 4.1%, versus 2.3%, respectively; P &lt;0.0001). Among 682 patients at high thrombotic risk, only 39 (5.7%) had low bleeding risk, whereas 401 (58.8%) had high bleeding risk with very high incidence of bleeding (11.6%). Conclusions CREDO ‐Kyoto thrombotic and bleeding risk scores demonstrated modest accuracy in stratifying thrombotic and bleeding risks; however, a large proportion of patients at high thrombotic risk also had high bleeding risk.

BACKGROUND: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. METHODS: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. RESULTS: score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79-1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71-1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. CONCLUSIONS: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the frequency, possible predictive factors, and prognosis of deteriorating ischemic stroke in 4 clinical categories according to the classification of the Oxfordshire Community Stroke Project (OCSP). METHODS: A total of 350 patients with first-ever ischemic stroke who presented within 24 hours of onset were enrolled. Based on the OCSP criteria, cerebral infarctions were divided into the following 4 clinical categories: total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar infarcts (LACI), and posterior circulation infarcts (POCI). Clinical deterioration was defined as a decrease of >/=1 points in the Canadian Neurological Scale (CNS) (in TACI, PACI, and LACI) or Rankin Scale (RS) (in POCI) during 7 days from the onset. In each clinical category, deteriorating (D) and nondeteriorating (ND) patients were compared in terms of their background characteristics, risk factors, vital signs, laboratory data, and cranial CT at the time of hospitalization. The acute-phase mortality and functional outcome were also compared. RESULTS: The subjects comprised 86 patients (24.6%) with TACI, 63 (18.0%) with PACI, 141 (40.3%) with LACI, and 60 (17.1%) with POCI. Overall, 90 patients (25.7%) deteriorated. The frequency was very high in TACI (41.9%), followed by LACI (26.2%) and POCI (21.7%), whereas it was very low in PACI (6. 3%). There were some clinical variables that differed significantly between D and ND groups. In the patients with TACI, early abnormalities of the cranial CT and significant stenoses in corresponding arteries were more frequent in the D than the ND group. In those with LACI, the CNS and hematocrit were lower in the D than the ND group. In those with POCI, cerebral atrophy was more severe and significant stenoses in vertebrobasilar arteries were more frequent in the D than ND group. The mortality of the D groups of patients with TACI and POCI exceeded 35%, and the functional outcome was worse in the D group than in the ND group of patients with TACI, LACI, and POCI. CONCLUSIONS: The frequency of deterioration in acute ischemic stroke significantly differed among the OCSP subgroups, and deterioration worsened the prognosis. There were some factors that could predict deterioration: early CT findings in TACI, large-artery atherosclerosis in TACI and POCI, and stroke severity in LACI. Further research to find sophisticated radiological and chemical markers appears to be needed.

OBJECTIVES: The purpose of this study was to clarify the incidence of (CS)-associated osteonecrosis among different underlying diseases and to evaluate the risk factors for steroid-associated osteonecrosis in a prospective MRI study. METHODS: We prospectively used MRI to study 337 eligible underlying disease patients requiring CS therapy and succeeded in examining 1199 joints (hips and knees) in 302 patients with MRI for at least 1 year starting immediately after the onset of CS therapy (1-year follow-up rate of 90%). The underlying diseases included SLE in 687 joints (173 patients) and a variety of other rheumatological disorders in 512 joints (129 patients). RESULTS: The incidence of osteonecrosis was significantly higher in SLE patients than in non-SLE patients (37 vs 21%, P = 0.001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk of osteonecrosis compared with paediatric patients [odds ratio (OR) = 13.2], that high daily CS dosage (>40 mg/day) entailed a significantly higher risk of osteonecrosis compared with the dosage of <40 mg/day (OR = 4.2), that SLE patients had a significantly higher risk of osteonecrosis compared with non-SLE patients (OR = 2.6) and that male patients had a significantly higher risk of osteonecrosis compared with female patients (OR = 1.6). CONCLUSION: These findings suggest that the incidence of CS-associated osteonecrosis varies among different underlying diseases.

The original guideline for non-pharmacological treatments (cardiac implantable electronic device, catheter ablation, and arrhythmia surgery) of arrhythmias (Japanese Circulation Society [JCS] Guideline on Non-pharmacotherapy of Cardiac Arrhythmias) was first published in 2001, and there have been two revisions thereafter (2006 and 2011). The “JCS Guideline on Indications and Procedures for Catheter Ablation” was published in 2012 to cover the rapid development and expansion of catheter ablation techniques. Advances in non-pharmacological treatment of arrhythmia have further accelerated since then, with the succeeding emergence of new functions, usefulness, and evidence. Against the background of these remarkable developments, the guidelines needed to undergo many changes and revisions. Therefore, the format has been revised again to include cardiac implantable electronic devices and catheter ablation therapies. Since 2011, there has been a succession of innovative devices and treatment methods, such as (1) implantable cardiac monitoring, (2) subcutaneous implantable cardioverter-defibrillators, (3) wearable cardioverter-defibrillators, (4) remote monitoring, (5) magnetic resonance imaging-compatible devices, (6) leadless pacemakers, (7) balloon technology for pulmonary vein isolation, (8) percutaneous lead extraction, and (9) left atrial appendage closure devices. Thus, this revision needed to add new sections to accommodate these developments. In addition, new content on existing treatment methods has been added as much as possible, including hardware improvements, new evidence, and the challenge of reducing radiation exposure. Selecting and summarizing suitable information from the vast amount of available data within a limited space could have been a daunting task for all team members; however, our efforts have culminated in this guideline revision containing carefully selected and essential information, thanks to everyone who collaborated on this project. Two related guidelines (JCS Guideline on Treatment of Acute and Chronic Heart Failure, and JCS Guideline on Treatment of Genetic Arrhythmia) were each revised in 2018.1, 2 Some working group members participated in the revision of both guidelines, as team members or observers, thus ensuring consistency between the guidelines. Non-pharmacotherapy in the broad sense includes external cardioversion for atrial fibrillation and sustained ventricular tachyarrhythmias, temporary intravenous pacing, and percutaneous pacing. However, for details of these therapies, refer to the JCS Guidelines on Pharmacotherapy of Atrial Fibrillation3 and the Japan Resuscitation Council Guidelines.4 Pacemaker treatment for bradyarrhythmia was first approved for national health insurance coverage in Japan in 1974, and its use rapidly became widespread thereafter. Approximately 40 years later, in 2017, the number of patients treated with this technology has increased to 60 137 (41 895 new cases and approximately 18 242 replacements).5 Capsule-shaped leadless pacemaker also became available in 2016, and this technology is being established as a new option. Non-pharmacological treatment of tachy-arrhythmia began in 1969 from when Will C. Sealy performed surgery in patients with Wolff-Parkinson-White (WPW) syndrome (Figure 1). Since then, the application of surgical treatment has expanded to conditions such as ventricular tachycardia (VT) and atrial fibrillation (AF), and surgery has been the pioneer of radical therapy for tachyarrhythmias. At the present time, many surgical methods have been replaced by catheter ablation; however, surgical treatment still remains an indispensable option for patients with a tachycardia resistant to other medical treatments. As with surgical treatment, catheter ablation was initially performed for supraventricular tachycardias such as WPW syndrome. However, the revolutionary discovery of pulmonary vein isolation (PVI) for AF and the advent of three-dimensional (3D) navigation systems have subsequently resulted in a tremendous increase in the number of cases treated with catheter ablation. In 2016, >74 000 catheter ablation procedures were performed in Japan, of which >45 000 were implemented for AF.6 In 2015, a PVI method using cryoballoon ablation was introduced in Japan. Later, new techniques such as hot balloon or laser balloon (endoscopic systems using laser irradiation) ablation technologies entered the market, and safer and easier treatment methods are currently being established. In addition, prevention of systemic embolism using a left atrial appendage closure (LAAC) device is being established as a breakthrough treatment for AF patients who have difficulty in continuing anticoagulation therapy. Because early implantable cardioverter-defibrillators (ICDs) were highly invasive owing to the requirement for a thoracotomy, the indications for this treatment were highly limited. However, the development of transvenous leads, the discovery of the biphasic shock method, and a reduction in both the size and weight of the generator have now enabled implantation using the same technique as for pacemakers, which has contributed to expanding the application of ICDs to primary prevention. In 2017, approximately 6691 devices (4288 new cases, 2403 replacements) were implanted in Japan.5 The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed in 2015, and its clinical usage is progressing. In 2004, cardiac resynchronization therapy (CRT) became available for patients with impaired cardiac function, and the usefulness of this treatment has been verified. especially in heart failure patients with complete left bundle branch block in Japan. Because patients with heart failure have a high risk of sudden death, an ICD with a biventricular pacing function (CRT defibrillator [CRT-D]) was also developed and approved in 2006. In 2017, CRT was newly administered in 3321 patients in Japan, 2399 of whom (72%) received the CRT-D, demonstrating that the treatment has been actively applied to prevent sudden death.5 A wearable cardioverter-defibrillator (WCD) was introduced in Japan in 2015, which can be used for candidates for ICD therapy as a bridge treatment until application of an ICD is possible. Many devices are also equipped with a remote monitoring function, which sends most of the biological information and device data to the medical facility while the patient is staying at home by enabling the early detection of abnormal findings. As described above, there have been remarkable developments in the non-pharmacotherapy of arrhythmias. However, problems still remain, including (1) the risk of complications associated with aging of patients, (2) the requirement for high-quality training of specialists and medical staff to enable them to handle the expanding indications and diversifying treatment methods, (3) the overflow of information and increasing complexity of management because of the sophisticated and multiple functionalities of the devices, and (4) the impact of the expanding indications of expensive devices in the setting of limited medical resources. In the future, it will be necessary to formulate evidence unique to Japan on the extent to which cutting-edge non-pharmacological treatments for arrhythmias improve the prognosis of patients. This guideline recommends indications for non-pharmacotherapy of arrhythmia based on the latest findings and evidence. There is an increasing variety of non-pharmacotherapies, and extensive progress is being made in this field. This guideline contains information on conventional cardiac implantable electronic devices (CIEDs), such as pacemakers, ICDs, and ICDs with biventricular pacing function, as well as new information on remote monitoring, magnetic resonance imaging-conditional CIEDs, leadless pacemakers, percutaneous lead extraction, implantable monitors, S-ICDs, and WCDs. Information on catheter ablation includes radiation exposure, new 3D mapping systems, balloon ablation for AF, bipolar ablation, and chemical ablation. In addition, this guideline discusses the LAAC device for the first time, which is not a treatment for arrhythmia itself but for preventing thromboembolism – a serious problem associated with AF. Non-pharmacotherapy of arrhythmia is expected to increase in the future, so there is a need to standardize all non-pharmacotherapy processes, including not only treatment indications but also their theoretical background, recommended procedures, necessary equipment and implementation system, and precautions that have to be taken before and after the procedure. The indications of non-pharmacological treatments of tachyarrhythmia in children differ from those in adults, so there are many cautionary points to note. Therefore, CIEDs and catheter ablation for children are described under independent chapters, as in previous guidelines. The information on surgical treatment for arrhythmia mainly focuses on surgical treatment for AF and VT. Surgery for supraventricular tachycardia has been omitted from this guideline because the number of surgical procedures has dramatically decreased in recent years. Nevertheless, surgery is still indicated for some patients with supraventricular tachycardias, including those with unsuccessful ablation. The aim of this guideline is to clarify the indications, results, and complications of non-pharmacological treatments for arrhythmias such as bradyarrhythmia, supraventricular tachycardia, AF, premature ventricular contractions, VT, and ventricular fibrillation, as well as treatment for the associated heart failure and thromboembolism. We are striving for standardized treatment by explicitly describing the procedures. Specific information on the procedures is also included, such as the knowledge, equipment, and doctor/facility conditions required to perform the procedure. The guideline has been created based on evidence and consensus at the time of publication and should be updated over time. This guideline describes the recommended indications and procedures as of 2018. Future technological advances will further expand the indications for non-pharmacotherapy of arrhythmia and make the procedures more reliable and convenient. This guideline is designed to be used as a reference by doctors diagnosing and treating diseases in clinical practice, and the final decision should be made by the attending physicians after ascertaining the patient's condition. Even when selecting a diagnosis or treatment that does not follow the guideline, the decision of the attending physicians should be prioritized in consideration of the individual patient's situation. In actual clinical settings, it is most important for the attending physicians to make the judgment after fully considering the clinical background and social situation of each patient while complying with the guideline. For this guideline, we first surveyed materials based on evidence from the USA and Europe, then further critically examined the level of evidence, collected information available in Japan, and examined all materials based on the experiences and opinions of members and collaborators in the joint working group. The recommendation classes and evidence levels used in this guideline conform to those of the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) guidelines.7 The recommendation class of indications for each diagnosis and treatment method is classified as I, IIa, IIb, and III, and the level of evidence is classified into levels A, B, and C (Tables 1,2). The guideline also states the class of recommendation and level of evidence based on the “MINDS Handbook for Clinical Practice Guideline Development 2007”,8 published by the Medical Information Network Distribution Service (MINDS) Evidence-based Medicine dissemination promotion project as a guideline preparation method (Tables 3,4). The MINDS grades of recommendation are comprehensively determined, taking into account the following factors: (1) level of evidence, (2) amount and variation of evidence, (3) extent of clinical effectiveness, (4) clinical applicability (physician ability, regional characteristics, medical resources, insurance system, etc), and (5) evidence on harm and cost. Not recommended as evidence indicates that the treatment is ineffective or even harmful The MINDS level of evidence (levels of evidence in literature on treatment) is a classification based on research design, and the highest level was adopted when multiple papers were considered. This guideline describes both the conventional AHA/ACC/HRS guideline classifications and the MINDS classification, whenever possible, for the content of each diagnosis and treatment. However, the MINDS grade of recommendation and level of evidence should be used only as a reference, as this system regards the evidence level in a fundamentally different manner. This revision adds new knowledge acquired from advances in diagnostic techniques and treatment methods, or recently reported important evidence, while considering consistency with each of the previously reported guidelines published by the JCS Joint Working Group. Pacemaker therapy for bradyarrhythmia became covered by insurance in Japan in 1974. Initially, pacemakers only had ventricular pacing function; however, at present, pacemakers with functions such as maintaining atrioventricular synchrony with dual-chamber pacing modes, as well as monitoring atrioventricular conductivity to suppress right ventricular pacing, have been developed, which has contributed to improving patients’ prognosis. In 2017, a capsule-type leadless pacemaker appeared on the market, and its clinical application is progressing. An implantable cardioverter-defibrillator (ICD) was introduced in Japan in 1996 to treat fatal arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]). Early ICDs were a highly invasive treatment requiring a thoracotomy, severely limiting their indications. However, the subsequent development of transvenous leads, discovery of the biphasic shock method, and reduction in the size and weight of the generator enabled use of the same technique as that for pacemaker implantation, which has greatly contributed to the expansion of indications for improving life prognosis and for primary prevention. The year 2000 saw the appearance of the dual-chamber ICD, which contributed to a dramatic improvement in pacing function during bradycardia, equivalent to that of a pacemaker for bradycardia, and a diagnostic algorithm based on atrial signal detection. Furthermore, the subcutaneous ICD (S-ICD) was introduced in 2015 and has been actively used for patients without venous access and/or those who do not require pacing functions. In 2004, biventricular pacing, or cardiac resynchronized therapy (CRT), became available for patients with impaired cardiac function, and its utility has been confirmed, especially in patients with heart failure who have desynchronous contractions due to complete left bundle branch block (CLBBB). As patients with heart failure are at a high risk of sudden death, an ICD with a biventricular pacing function (CRT-D) was developed and approved in 2006. Improved pacing-site selectivity with quadrupolar left ventricular leads, functions utilizing self-right bundle conduction, and multipoint left ventricular pacing have been applied in clinical practice and may reduce the number of non-responders. As of 2017, CRT-D has been indicated for 72% of new cardiac resynchronization therapy (CRT) cases in Japan; thus, aggressive prevention of sudden death is ongoing.5 ICDs have limited effectiveness after an acute myocardial infarction and at the early stage after the diagnosis of heart failure. In 2015, wearable cardioverter-defibrillators (WCDs) came into use to prevent sudden death during the waiting period while the indications for ICD are being determined. WCD is also used as a bridging treatment until the next implantation for patients whose ICD has been removed because of infection or other reasons. Many devices are equipped with a remote monitoring function, which now enables the early detection of abnormal findings related to device functions and biological characteristics. Furthermore, although their use is conditional, magnetic resonance imaging (MRI)-compatible devices has become to be recognized as ordinary function, which is particularly useful in Japan where the rate of installation and using MRI are high. Non-pharmacological treatment of arrhythmia requires advanced medical technology, and progress is rapid in this field. Physician and facility requirements are extremely important for the application of this guideline. This section describes the current facility standards and practitioner standards; however, as these may be revised in the future, refer to the Japanese Circulation Society or Japanese Heart Rhythm Society (HRS) websites to obtain the latest information. Each non-pharmacotherapy must be applied effectively and safely, and a system for responding to emergencies (human resource development, establishment of a team medical system, use of fully maintained equipment) is required. The following institutional standards and practitioner standards were proposed by the Japanese HRS in 2017, considering the novelty of the leadless pacemaker and that this procedure requires cardiac access via the femoral vein using a large sheath9 (see “3.7 Leadless pacemakers” in this chapter). Facility standards Practitioner standards The following practitioner standards were proposed by the Japanese HRS in 2016 for S-ICD implantation.11 Practitioner standards Clinical use of a WCD requires appropriate selection of cases and understanding of the equipment, and the following practitioner standards were proposed by the Japanese HRS in 2017.12 Practitioner standards ICMs may be implanted in any facility that satisfies the facility standards for pacemakers, ICD, or CRT-P/CRT-D as a condition for insurance application (based on the 2015 Medical Fee Points Table). When deciding on the indications for treatments that require advanced medical technology such as CIEDs, it is essential that the patient provides voluntary consent after receiving sufficient information. The information should be provided using words that the patient can understand, pursuant to the provisions of Chapter 1, Article 1-4, paragraph 2 of the Medical Care Act: “In the delivery of medical care, a physician, dentist, pharmacist, nurse, or other medical care professional shall give appropriate explanations and endeavor to foster understanding in the recipients of medical care.” The content of the explanation is based on the judgment according to the knowledge and experience of each doctor; however, it is necessary to provide the following information to the patient: (1) information on the disease (type and severity of arrhythmia, underlying heart disease, etc); (2) aim and details of the treatment (including device model and manufacturer name), therapeutic effect and success rate, complications (types, severity, and incidence) during the acute phase and during long-term follow-up (requires not only general information but also information on the performance in the facility in question), and the reason for selecting the treatment; (3) treatments other than the treatment in question (pharmacotherapies, other non-pharmacotherapies [including treatment available at other facilities]) and the therapeutic effect of those treatments; (4) expected results with monitoring alone without the treatment in question (predicted outcome and probability thereof); (5) positioning of the treatment in question for various arrythmias and possible unexpected complications (short-term and long-term); (6) cost of the treatment (including the cost of this treatment and other treatments); and (7) assurance that consent can be withdrawn before and during treatment. After the provision of the above information, if the patient requests opinions from other doctors or medical institutions (second opinion), then it is essential to respond to the request. The patient is the main person in the decision-making process, and the right of self-determination of the patient is the most important factor when deciding on indications for non-pharmacotherapy. Basically, the consent of the patient and/or the family is required, based on their understanding of the explanation provided by the medical staff involved in testing and treatment. If the patient is unable to express their intention or is a minor, a family representative or legal representative will act on their behalf. Ultimately, the signatures of all attendees, including the medical staff, are obtained. Normally, 2 copies of the information sheet are prepared. The original copy is generally kept in the patient's medical record and another copy is given to the patient. Physicians must be fully cognizant that informed consent is an important opportunity for the patients to compare and consider the benefits and disadvantages of the treatment, and to enable selection of treatment that is truly beneficial for them. The information must also be specific and easy to understand for the patients and their families. Complications with CIED implantation are due to the device itself (generators and/or leads), or the implantation procedure. Generator complications include malfunctions such as recalls and resets due to electromagnetic interference. Lead complications include malfunctions such as recalls, lead dislodgement and aging, pacing and venous and implantation techniques can reduce complications lead lead and from lead There are in the of CIED infection which is reported to from to of the ICD and CRT-D indications has resulted in increased implantation of the devices in patients patients with heart or and patients taking and/or as well as an increased number of due to long-term which the of is important to that implantation of a CIED is a surgical thus, it is necessary to fully understand the of infection and the and surgical and surgical and use of The Japanese Society of and the Japan Society for have proposed Guidelines for of for of particularly with to the use of As is also an infection complete is The of the the CIED is also The is created above the of the not in the subcutaneous to prevent of the If the subcutaneous containing the subcutaneous is it is recommended to a under the for lead can complications such as and Therefore, methods such as before and have been recommended to vein is over vein to prevent lead by the and the method is recommended not only to reduce the complications but also to prevent lead prevent to the and improve lead When the care should be taken to of the venous and myocardial The rate is reported to be and is by the use of on the of the lead after lead and lead is also important to understand the of the lead or including the condition of of the implanted pacing and should be As an early has a high who are taking or due to atrial fibrillation (AF), or disease are a and is particularly important in these patients. not only but can also device infection at a remote phase because it to and When is it is important to the of If there is of the and of or the is and can be with using However, and should be if the because of or if of by is performed because it the risk of There is in the of device and risk include heart of and other pulmonary disease, external pacemaker device and early device infection has it is necessary to the system, which a consideration is required and after and left to lead and and monitoring to early failure are also The and of the may after is necessary to the pacing and the of the before and the as is also recommended to before of patients who on life after should also be can which can pacing in pacemakers and therapy in A of electromagnetic has been published by the Japan can generally be used if the is not on and however, patients must be to a of from electromagnetic and from than home use of therapy equipment, is is needed when using rapid electronic equipment, and electronic The patient should be to from the if experience and have been reported to have an and medical care may be required to prevent interference. There are conditions to be for and patients with are required by to have a (see Chapter for patients with an The recent emergence of new devices has made management more There is also a that the of understanding of device functions will as patients become is important to provide patient using and to information on appropriate for possible CIED management is performed with device using the is necessary to not only the information of the device but also the general condition of the patient using various Specific information (1) (2) lead (3) pacing (4) and pacing (5) arrhythmia detection and treatment and (6) heart rate and information, The patient management is by at this information. In recent it has become possible to perform remote monitoring in most monitoring has been to be as as conventional and to enable the diagnosis of arrhythmia and Furthermore, and life prognosis have also been Therefore, remote monitoring for patients with CIEDs is highly and it is recommended to it as a management however, there are increased for There has been an increase in the number of patients implanted with CIEDs and in the aging to patients with CIEDs is required.

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.

BACKGROUND: The present study analyzed biliary tract cancer patients registered from 2008 to 2013 in Japan and evaluated the outcomes of biliary tract cancer. METHODS: A total of 18,606 patients were registered from 2008 to 2013. Cases were analyzed with regard to patient survival according to contiguous extent of the primary tumor (T), node metastasis, and tumor stage using the 3rd English edition of the Japanese classification of the biliary tract cancers. RESULTS: Five-year survival rates were 39.8% for gallbladder cancer, 24.2% for perihilar bile duct cancer, 39.1% for distal bile duct cancer, and 61.3% for ampullary region cancer. Significant differences were observed between newly introduced subdivisions in the new Japanese classification for all tumoral sites except gallbladder cancer. The survival rate in patients with #13a metastasis was significantly higher than in patients with distant lymph node metastasis. CONCLUSIONS: The new Japanese classification adopted the 7th edition of staging system developed by the Union for International Cancer Control staging system. However, numerous aspects of these classification systems remain unvalidated. The present analysis demonstrated the significance of a proportion of T factor subdivisions and classifications of regional lymph nodes in cases of gallbladder cancer in the new Japanese classification.

Although recent findings of cancer biology research indicate that prognostic power arises from genes expressed by stromal cells rather than epithelial cells, desmoplastic reaction (DR) has not been completely examined as a prognostic marker for colorectal cancer. A pathologic review of 821 stage II and III patients who underwent R0 resection for colorectal cancer at 4 independent institutions was conducted. DR was classified as mature, intermediate, or immature based on the existence of hyalinized keloid-like collagen and myxoid stroma at the extramural desmoplastic front. Totally, 325, 282, and 214 patients were classified as having mature, intermediate, and immature DR, respectively. DR significantly influenced the recurrence rate in the liver, lung, and peritoneum (P≤0.0001 to 0.01). Five-year relapse-free survival (RFS) rate was the highest in the mature group (85.7%), followed by the intermediate (77.3%) and immature (50.4%) groups. A significant adverse impact of immature stroma on RFS was observed in subset analyses of the 4 institutions. Multivariate analysis revealed that DR, along with T and N stages, is an independent prognostic factor. On the basis of Harrell's concordance index, the prognostic power of DR categorization (0.67) in stratifying RFS was greater than any other conventional prognostic factors, including TNM (0.64), N (0.62) and T stages (0.59), venous invasion (0.59), and tumor grade (0.54). Characterizing DR based on the histologic products of activated fibroblasts is valuable for evaluating prognostic outcomes. To our knowledge, this is the first study reporting a greater prognostic power of histology of the fibrotic stroma than that of tumor factors.