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Background: Atrial cardiomyopathy (AtCM) has drawn attention as the pathophysiology related to cardiovascular events such as atrial tachyarrhythmia, congestive heart failure, and embolic stroke. As the concept of AtCM is relatively recent, the long-term clinical course of AtCM has not been reported., Case Summary: Here, we describe a 78-year-old patient diagnosed with end-stage AtCM. He had started to visit our hospital due to paroxysmal atrial fibrillation (AF) and hypertrophic cardiomyopathy over three decades since the age of 45. During follow-up, he experienced cardiogenic embolism and pacemaker implantation due to sick sinus syndrome. At this time, he complained of palpitation due to AF and underwent catheter ablation. Regardless of de novo ablation, left atrial voltage mapping showed ultimately extensive scar in left atrium and pulmonary vein, suggesting that conventional AF ablation strategy was ineffective. From this finding, he was diagnosed with end-stage AtCM. In the review of the previous 12-lead electrocardiogram, P-wave amplitude was decreased, and PR duration was prolonged gradually. We performed only cavotricuspid isthmus ablation and ended the ablation session. After six months, he complained of dyspnoea on effort due to pacing-induced cardiomyopathy. Furthermore, before the cardiac resynchronization therapy with a defibrillator (CRT-D) upgrade, left atrial appendage thrombus was detected even under the administration of apixaban. After thrombolysis with warfarin, CRT-D upgrade the left ventricular ejection fraction was improved., Discussion: In this case, the patient slowly developed end-stage AtCM and experienced multiple cardiovascular events related to severe AtCM. We should care for the disease progression of AtCM with vigilance., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The association between care needs level (CNL) at hospitalisation and postdischarge outcomes in older patients with acute heart failure (aHF) has been insufficiently investigated., Methods: This population-based cohort study was conducted using health insurance claims and CNL data of the Longevity Improvement & Fair Evidence study. Patients aged ≥65 years, discharged after hospitalisation for aHF between April 2014 and March 2022, were identified. CNLs at hospitalisation were classified as no care needs (NCN), support level (SL) and CNL1, CNL2-3 and CNL4-5 based on total estimated daily care time as defined by national standard criteria, and varied on an ordinal scale between SL&CNL1 (low level) to CNL4-5 (fully dependent). The primary outcomes were changes in CNL and death 1 year after discharge, assessed by CNL at hospitalisation using Cox proportional hazard models., Results: Of the 17 724 patients included, 7540 (42.5%), 4818 (27.2%), 3267 (18.4%) and 2099 (11.8%) had NCN, SL&CNL1, CNL2-3 and CNL4-5, respectively, at hospitalisation. One year after discharge, 4808 (27.1%), 3243 (18.3%), 2968 (16.7%), 2505 (14.1%) and 4200 (23.7%) patients had NCN, SL&CNL1, CNL2-3, CNL4-5 and death, respectively. Almost all patients' CNLs worsened after discharge. Compared to patients with NCN at hospitalisation, patients with SL&CNL1, CNL2-3 and CNL4-5 had an increased risk of all-cause death 1 year after discharge (hazard ratio [95% confidence interval]: 1.19 [1.09-1.31], 1.88 [1.71-2.06] and 2.56 [2.31-2.84], respectively)., Conclusions: Older patients with aHF and high CNL at hospitalisation had a high risk of all-cause mortality in the year following discharge., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear., Methods and Results: The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005)., Conclusion: Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves clinical outcomes in patients with heart failure (HF), but has limited evidence of SGLT2i use in early-phase acute coronary syndrome (ACS). We determined association of early SGLT2i use compared with either non-SGLT2i or dipeptidyl peptidase 4 inhibitor (DPP4i) use in hospitalized patients with ACS., Methods and Results: This retrospective cohort study that used the Japanese nationwide administrative claims database included patients hospitalized with ACS aged ≥20 years between April 2014 and March 2021. The primary outcome was a composite of all-cause mortality or HF/ACS rehospitalization. Using 1:1 propensity score matching, the association with outcomes of the early SGLT2i use (≤14 days after admission) compared with non-SGLT2i or DPP4i use was determined according to the HF treatment. Among 388 185 patients included 115 612 and 272 573 with and without severe HF, respectively. Compared to non-SGLT2i users, the SGLT2i users had a lower hazard ratio (HR) with the primary outcome [HR: 0.83, 95% confidence interval (CI): 0.76-0.91; P < 0.001] in the severe HF group; however, there was no significant difference in the non-severe HF group (HR: 0.92, 95% CI: 0.82-1.03; P = 0.16). SGLT2i use showed a lower risk of the outcome in patients with severe HF and diabetes compared with DPP4i use (HR: 0.83, 95% CI: 0.69-1.00; P = 0.049)., Conclusion: SGLT2i use in patients with early-phase ACS showed a lower risk of primary outcome in patients with severe HF, but the effect was not apparent in patients without severe HF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: In bradycardia patients treated with dual-chamber pacing, we aimed to evaluate whether pacing with atrioventricular (AV) delay management [AV hysteresis (AVH)], compared with standard pacing with fixed AV delays, reduces unnecessary ventricular pacing percentage (VPP) and is associated with better clinical outcomes. Main study endpoints were the incidence of heart failure hospitalizations (HFH), persistent atrial fibrillation (AF), and cardiac death., Methods and Results: Data from two identical prospective observational studies, BRADYCARE I in the USA and BRADYCARE II in Europe, Africa, and Asia, were pooled. Overall, 2592 patients (75 ± 10 years, 45.1% female, 50% with AVH) had complete clinical and device data at 1-year follow-up and were analysed. Primary pacing indication was sinus node disease (SND) in 1177 (45.4%), AV block (AVB) in 974 (37.6%), and other indications in 441 (17.0%) patients. Pacing with AVH, compared with standard pacing, was associated with a lower 1-year incidence of HFH [1.3% vs. 3.1%, relative risk reduction (RRR) 57.5%, P = 0.002] and of persistent AF (5.3% vs. 7.7%, RRR = 31.1%, P = 0.028). Cardiac mortality was not different between groups (1.0% vs. 1.4%, RRR = 27.8%, P = 0.366). Pacing with AVH, compared with standard pacing, was associated with a lower (P < 0.001) median VPP in all patients (7% vs. 75%), in SND (3% vs. 44%), in AVB (25% vs. 98%), and in patients with other pacing indications (3% vs. 47%)., Conclusion: Cardiac pacing with AV delay management via AVH is associated with reduced 1-year incidence of HFH and persistent AF, most likely due to a reduction in VPP compared to standard pacing., Competing Interests: Conflict of interest: M.A. participated in clinical trials sponsored by Abbott and Biotronik; he received speaker honoraria from Biotronik. A.A. participated in clinical trials sponsored by Boston Scientific, Medtronic, EPD Philips, and XSpline; he received consultant or speaker fees from Abbott, Boston Scientific, Cairdac, Corvia, EP Solution, Microport CRM, Philips, Radcliffe Publishers, and XSpline, and he has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. A.A. is the review editor of EP Europace and was not involved in the peer review process or publication decision. G.B. received speaker fees from Boston Scientific, Abbott, Daiichi, and Boehringer Ingelheim. A.P., W.L., and A.G. are Abbott employees. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Competing interests: None declared.

Aim: Although cardiac rehabilitation (CR) is a strongly recommended therapy, no large study has assessed the effects of outpatient CR in patients with heart failure (HF) in real-world settings. Therefore, this study aimed to investigate the multifactorial effects of outpatient CR in patients with HF using a nationwide database., Methods and Results: This nationwide retrospective cohort study was performed using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Patients with acute HF who underwent inpatient CR between April 2014 and March 2020 were included. The association between outpatient CR participation and all-cause mortality, rehospitalisation for HF, use of medical resources, and medical costs was analysed using propensity score matching analysis. Of 250,528 patients, 17,884 (7.1%) underwent outpatient CR. After propensity score matching, the CR (+) group was associated with a reduction in the risk of all-cause mortality (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.60-0.68, p < 0.001) and rehospitalisation for HF compared to the CR (-) group (HR: 0.87, 95% CI: 0.82-0.92, p < 0.001). The proportion of guideline-based medication use for HF at 1 year was higher in the CR (+) group than in the CR (-) group. The total medical costs from the index hospitalisation to 1.5 years after admission were similar between the groups., Conclusion: Outpatient CR participation after discharge from HF was associated with reduced mortality and rehospitalisation for HF without increasing medical costs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: None declared.

Background: Ramucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer., Materials and Methods: Patients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug., Results: Thirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%-41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed., Conclusion: Although the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported., Methods: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status., Results: Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%)., Conclusion: With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier: UMIN000007636., (© The Author(s) 2022. Published by Oxford University Press.)

Plants are often exposed not only to short-term (S) heat stress but also to long-term (L) heat stress over several consecutive days. A few Arabidopsis mutants defective in L-heat tolerance have been identified, but the molecular mechanisms involved are less well understood than those involved in S-heat tolerance. To elucidate the mechanisms, we isolated the new sensitive to long-term heat5 (sloh5) mutant from EMS-mutagenized seeds of L-heat-tolerant Col-0. The sloh5 mutant was hypersensitive to L-heat but not to S-heat, osmo-shock, salt-shock or oxidative stress. The causal gene, SLOH5, is identical to elongatedmitochondria1 (ELM1), which plays an important role in mitochondrial fission in conjunction with dynamin-related proteins DRP3A and DRP3B. Transcript levels of ELM1, DRP3A and DRP3B were time-dependently increased by L-heat stress, and drp3a drp3b double mutants were hypersensitive to L-heat stress. The sloh5 mutant contained massively elongated mitochondria. L-heat stress caused mitochondrial dysfunction and cell death in sloh5. Furthermore, WT plants treated with a mitochondrial myosin ATPase inhibitor were hypersensitive to L-heat stress. These findings suggest that mitochondrial fission and function are important in L-heat tolerance of Arabidopsis., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adjuvant treatment with Gliadel wafers may prolong overall survival (OS) for malignant glioma patients without increasing toxicity. In Japan, the long-term OS of these patients treated with Gliadel 7.7 mg implants has not been studied. We evaluated OS and prognostic factors that might affect OS in Japanese patients with malignant glioma who received the Gliadel 7.7 mg implant., Methods: This observational, long-term, postmarketing surveillance was an extension of a previous surveillance. Data were collected through case report forms at 2 and 3 years after Gliadel implant. Up to 8 Gliadel wafers (61.6 mg of carmustine) were placed over the tumor resection site. Primary endpoints were OS and prognostic factors that may influence OS., Results: Among the 506 patients analyzed, 62.6% had newly diagnosed disease, and 37.4% had recurrent disease; 79.1% had glioblastoma histological type and 79.6% had World Health Organization Grade IV disease. Patients received a median of 8 wafers. The median OS was 18.0 months; OS rates were 39.8% and 31.5% at 2 and 3 years, respectively. Age ≥65 years (hazard ratio [HR]: 1.456; P  = .002), lower resection rate (HR: 1.206; P  < .001), recurrence (HR: 2.418; P  < .001), and concomitant radiotherapy (HR: 0.588; P  < .001) were identified as significant prognostic factors., Conclusions: This study confirmed the 2- and 3-year OS of Japanese malignant glioma patients with varied backgrounds after Gliadel implant. With a careful interpretation of indirect comparisons with previously reported data, the results suggest that prognosis could be improved with Gliadel implants., Clinical Trial Registration: NCT02300506., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aims: Acute myocardial infarction complicated by cardiogenic shock (AMICS) is associated with substantial mortality, although there are limited data available on bleeding in this critical condition. This study sought to investigate the incidence and impact of major in-hospital bleeding on all-cause mortality in patients with AMICS who undergo percutaneous coronary intervention (PCI)., Methods and Results: Between 2015 and 2017, a total of 3411 patients hospitalized within 24 h after symptom onset were prospectively enrolled in the Japan Acute Myocardial Infarction Registry (JAMIR) and followed up for a median of 293 (interquartile range, 22-375) days. AMICS developed in 335 (9.8%) patients (mean age, 71.3 ± 13.6 years). Overall, the rate of major in-hospital bleeding (Bleeding Academic Research Consortium types 3 and 5) and in-hospital mortality was 14.6% and 28.7%, respectively. The majority of major in-hospital bleeding (73.5%) occurred within 48 h after PCI. Compared to patients without major in-hospital bleeding, those with it had higher rates of renal failure, left main coronary artery culprit lesion, and intra-aortic balloon pump or extracorporeal membrane oxygenation support, and had longer door-to-device time. The cumulative incidence of 1-year all-cause mortality was significantly higher in the major bleeding group compared to the non-major bleeding group (63.8% vs. 25.5%; log-rank P < 0.001). After adjusting for confounders, major in-hospital bleeding was independently associated with increased all-cause mortality (hazard ratio, 1.70; 95% confidence interval, 1.08-2.69)., Conclusions: These findings of JAMIR indicate that major in-hospital bleeding is associated with all-cause mortality in patients with AMICS who undergo PCI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Plants are often exposed not only to short-term (S-) heat stress but also to diurnal long-term (L-) heat stress over several consecutive days. To reveal the mechanisms underlying L-heat stress tolerance, we here used a forward genetic screen for sensitive to long-term heat (sloh) mutants and isolated sloh4. The mutant was hypersensitive to L-heat stress but not to S-heat stress. The causal gene of sloh4 was identical to MIP3 encoding a member of the MAIGO2 (MAG2) tethering complex, which is composed of the MAG2, MIP1, MIP2 and MIP3 subunits and is localized at the endoplasmic reticulum (ER) membrane. Although sloh4/mip3 was hypersensitive to L-heat stress, the sensitivity of the mag2-3 and mip1-1 mutants was similar to that of the wild type (WT). Under L-heat stress, the ER stress and the following unfolded protein response (UPR) were more pronounced in sloh4 than in the WT. Transcript levels of bZIP60-regulated UPR genes were strongly increased in sloh4 under L-heat stress. Two processes known to be mediated by INOSITOL REQUIRING ENZYME1 (IRE1) - accumulation of the spliced bZIP60 transcript and a decrease in the transcript levels of PR4 and PRX34, encoding secretory proteins - were observed in sloh4 in response to L-heat stress. These findings suggest that misfolded proteins generated in sloh4 under L-heat stress may be recognized by IRE1 but not by bZIP28, resulting in the initiation of the UPR via activated bZIP60. Therefore, it would be possible that only MIP3 in the MAG2 complex has an additional function in L-heat tolerance, which is not related to the ER-Golgi vesicle tethering., (� The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies., Methods and Results: Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10-2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199)., Conclusion: This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging provides prognostic information in patients with chronic heart failure (HF). However, there is little information available on the prognostic role of cardiac 123I-MIBG imaging in patients admitted for acute decompensated heart failure (ADHF), especially relating to reduced ejection fraction [HFrEF; left ventricular ejection fraction (LVEF) < 40%], mid-range ejection fraction (HFmrEF; 40% ≤ LVEF < 50%) and preserved ejection fraction (HFpEF; LVEF ≥ 50%)., Methods and Results: We studied 349 patients admitted for ADHF and discharged with survival. Cardiac 123I-MIBG imaging, echocardiography, and venous blood sampling were performed just before discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (late H/M) was measured on the chest anterior view images obtained at 200 min after the isotope injection. The endpoint was cardiac events defined as unplanned HF hospitalization and cardiac death. During a follow-up period of 2.1 ± 1.4 years, 128 patients had cardiac events (45/127 in HFrEF, 28/78 in HFmrEF, and 55/144 in HFpEF). On multivariable Cox analysis, late H/M was significantly associated with cardiac events in overall cohort (P = 0.0038), and in subgroup analysis of each LVEF subgroup (P = 0.0235 in HFrEF, P = 0.0119 in HFmEF and P = 0.0311 in HFpEF). Kaplan-Meier analysis showed that patients with low late H/M (defined by median) had significantly greater risk of cardiac events in overall cohort (49% vs. 25% P < 0.0001) and in each LVEF subgroup (HFrEF: 48% vs. 23% P = 0.0061, HFmrEF: 51% vs. 21% P = 0.0068 and HFpEF: 50% vs. 26% P = 0.0026)., Conclusion: Cardiac sympathetic nerve dysfunction was associated with poor outcome in ADHF patients irrespective of HFrEF, HFmrEF, or HFpEF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK)., Methods: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety., Results: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported., Conclusion: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns., Trial Registration: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch&#95;e.jsp, JapicCTI-142616., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Cell-to-cell communication is tightly regulated in response to environmental stimuli in plants. We previously used a photoconvertible fluorescent protein Dendra2 as a model reporter to study this process. This experiment revealed that macromolecular trafficking between protonemal cells in Physcomitrella patens is suppressed in response to abscisic acid (ABA). However, it remains unknown which ABA signaling components contribute to this suppression and how. Here, we show that ABA signaling components SUCROSE NON-FERMENTING 1-RELATED PROTEIN KINASE 2 (PpSnRK2) and ABA INSENSITIVE 3 (PpABI3) play roles as an essential and promotive factor, respectively, in regulating ABA-induced suppression of Dendra2 diffusion between cells (ASD). Our quantitative imaging analysis revealed that disruption of PpSnRK2 resulted in defective ASD onset itself, whereas disruption of PpABI3 caused an 81-min delay in the initiation of ASD. Live-cell imaging of callose deposition using aniline blue staining showed that, despite this onset delay, callose deposition on cross walls remained constant in the PpABI3 disruptant, suggesting that PpABI3 facilitates ASD in a callose-independent manner. Given that ABA is an important phytohormone to cope with abiotic stresses, we further explored cellular physiological responses. We found that the acquisition of salt stress tolerance is promoted by PpABI3 in a quantitative manner similar to ASD. Our results suggest that PpABI3-mediated ABA signaling may effectively coordinate cell-to-cell communication during the acquisition of salt stress tolerance. This study will accelerate the quantitative study for ABA signaling mechanism and function in response to various abiotic stresses., (� The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To improve outcome for ruptured aortic aneurysms (rAAs), centralization of treatment is potentially effective. However, there is no nationwide survey for the current managements and outcomes of rAA in Japan. The aim of this study was to assess the volume-outcome relationship for rAA treatment using the nationwide claim-based database., Methods: Using the Japanese Registry of All cardiac and vascular Diseases-Diagnostic Procedure Combination database, we identified patients admitted to 564 certified teaching hospitals with rAA between 1 April 2012 and 31 March 2015. Institutional case volume (cardiovascular surgeries per year) was categorized into quartiles (lowest, low, high and highest), and the odds ratios (ORs) for in-hospital mortality and neurological status at discharge were analysed for each quartile., Results: Of 7086 eligible patients, 3925 (55.4%) died in hospital. Mortality rates decreased from 69.4% in the lowest volume to 43.8% in the highest volume category (P < 0.001). The favourable impact of institutional case volume was sustained even after adjustment for covariates [low volume: OR 0.83, 95% confidence interval (CI) 0.65-1.07; P = 0.147; high volume: OR 0.69, 95% CI 0.54-0.89; P = 0.005; and highest volume: OR 0.55, 95% CI 0.42-0.72; P < 0.001 vs lowest volume]. Additionally, other 3 institutional parameters (increased aortic surgery volume, cardiovascular surgeons' volume and certified cardiologists' volume) were consistently associated with reduced in-hospital mortality. The rate of coma at discharge was the lowest in the highest volume group (P < 0.001). Increased institutional volume was associated with lower in-hospital mortality., Conclusion: Establishing regionally tailored systems to transfer patients to high-volume centres is needed to improve outcomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In multi-cellular organisms, cell-to-cell communication is crucial for adapting to changes in the surrounding environment. In plants, plasmodesmata (PD) provide a unique pathway for cell-to-cell communication. PD interconnect most cells and generate a cytoplasmic continuum, allowing the trafficking of various micro- and macromolecules between cells. This molecular trafficking through PD is dynamically regulated by altering PD permeability dependent on environmental changes, thereby leading to an appropriate response to various stresses; however, how PD permeability is dynamically regulated is still largely unknown. Moreover, studies on the regulation of PD permeability have been conducted primarily in a limited number of angiosperms. Here, we studied the regulation of PD permeability in the moss Physcomitrella patens and report that molecular trafficking through PD is rapidly and reversibly restricted by abscisic acid (ABA). Since ABA plays a key role in various stress responses in the moss, PD permeability can be controlled by ABA to adapt to surrounding environmental changes. This ABA-dependent restriction of PD trafficking correlates with a reduction in PD pore size. Furthermore, we also found that the rate of macromolecular trafficking is higher in an ABA-synthesis defective mutant, suggesting that the endogenous level of ABA is also important for PD-mediated macromolecular trafficking. Thus, our study provides compelling evidence that P. patens exploits ABA as one of the key regulators of PD function., (� The Author(s) 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The aim of the present study is to develop in vitro experimental analytical method for the electrophysiological properties of allogeneic induced pluripotent stem cell-derived cardiomyocytes (CMs) in cardiac conduction defect model., Methods and Results: Cardiomyocytes were derived from rat induced pluripotent stem cells CMs (riPSC-CMs) using an embryoid body-based differentiation method with the serial application of growth factors including activin-A, bone morphogenetic protein 4 (BMP-4), and inhibitor of wnt production 2 (IWP-2). Flow cytometry analysis showed that 74.0 ± 2.7% of riPSC-CMs expressed cardiac troponin-T (n = 3). Immunostaining analysis revealed organized sarcomeric structure in riPSC-CMs and the expression of connexin 43 between riPSC-CMs and neonatal rat ventricular CMs (NRVMs). Ca2+ transient recordings revealed the simultaneous excitement of riPSC-CMs and NRVMs, and prolonged Ca2+ transient duration of riPSC-CMs as compared with NRVMs (731 ± 15.9 vs. 610 ± 7.72 ms, P < 0.01, n = 3). Isolated NRVMs were cultured in two discrete regions to mimic cardiac conduction defects on multi-electrode array dish, and riPSC-CMs were seeded in the channel between the two discrete regions. Membrane potential imaging with di-8-ANEPPS discerned the propagation of the electrical impulse from one NRVM region to the other through a riPSC-CM pathway. This pathway had significantly longer action potential duration as compared with NRVMs. Electrophysiological studies using a multi-electrode array platform demonstrated the longer conduction time and functional refractory period of the riPSC-CM pathway compared with the NRVM pathway., Conclusion: Using an in vitro experimental system to mimic cardiac conduction defect, transplanted allogeneic riPSC-CMs showed electrical coupling between two discrete regions of NRVMs. Electrophysiological testing using our platform will enable electrophysiological screening prior to transplantation of stem cell-derived CMs.

Background and Aims: No reports have described the immunogenicity and boosting effect of the quadrivalent inactivated influenza vaccine (QIV) in adults with inflammatory bowel disease., Methods: Adults with Crohn's disease or ulcerative colitis were randomly assigned to a single vaccination group or booster group, and a QIV was administered subcutaneously. Serum samples were collected before vaccination, 4 weeks after vaccination, and after the influenza season in the single vaccination group. In the booster group, serum samples were taken before vaccination, 4 weeks after the first vaccination, 4 weeks after the second vaccination, and after the influenza season. We measured hemagglutination inhibition antibody (HAI) titer and calculated the geometric mean titer ratio (GMTR), seroprotection rate, and seroconversion rate., Results: In total, 132 patients were enrolled. Twenty-two patients received immunomodulatory monotherapy and 16 received anti-tumor necrosis factor-α (anti-TNF-α) single-agent therapy. Fifteen patients received combination therapy comprising an immunosuppressant and anti-TNF-α agent. Each vaccine strain showed immunogenicity satisfying the European Medicines Agency criteria with a single inoculation. The booster influenza vaccination did not induce additional response. In patients administered infliximab, the seroprotection rate and seroconversion rate tended to be lower in patients who maintained blood concentrations [seroprotection rate: H1N1: OR, 0.37 (95% CI, 0.11-1.21); H3N2: 0.22 (0.07-0.68); seroconversion rate: H1N1: 0.23 (0.06-0.91); H3N2: 0.19 (0.06-0.56)]., Conclusion: Single dose QIV showed sufficient immunogenicity in patients with inflammatory bowel disease, and a boost in immunization by additional vaccination was not obtained. Additionally, immunogenicity was low in patients receiving infliximab therapy.

Aims: Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients., Methods and Results: We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone., Conclusion: Rho-kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients.

Background: Patients with acute heart failure (AHF) commonly have multiple co-morbidities, and some of these patients die in the hospital from causes other than aggravated heart failure. However, limited information is available on the mode of death in patients with AHF. Therefore, the present study was performed to determine the incidence and predictors of in-hospital non-cardiac death in patients with AHF, using the Acute Decompensated Heart Failure Syndromes (ATTEND) registry Methods: The ATTEND registry included 4842 consecutive patients with AHF admitted between April 2007-September 2011. The primary endpoint of the present study was in-hospital non-cardiac death. A stepwise regression model was used to identify the predictors of in-hospital non-cardiac death., Results: The incidence of all-cause in-hospital mortality was 6.4% ( n=312), and the incidence was 1.9% ( n=93) and 4.5% ( n=219) for non-cardiac and cardiac causes, respectively. Old age was associated with in-hospital non-cardiac death, with a 42% increase in the risk per decade (odds 1.42, p=0.004). Additionally, co-morbidities including chronic obstructive pulmonary disease (odds 1.98, p=0.034) and anaemia (odds 1.17 (per 1.0 g/dl decrease), p=0.006) were strongly associated with in-hospital non-cardiac death. Moreover, other predictors included low serum sodium levels (odds 1.05 (per 1.0 mEq/l decrease), p=0.045), high C-reactive protein levels (odds 1.07, p<0.001) and no statin use (odds 0.40, p=0.024)., Conclusions: The incidence of in-hospital non-cardiac death was markedly high in patients with AHF, accounting for 30% of all in-hospital deaths in the ATTEND registry. Thus, the prevention and management of non-cardiac complications are vital to prevent acute-phase mortality in patients with AHF, especially those with predictors of in-hospital non-cardiac death.

Aims: The temporal changes and sex differences in post-traumatic stress disorder (PTSD) after natural disasters remain unclear. Therefore, we examined the prevalence, prognostic impacts, and determinant factors of PTSD after the Great East Japan Earthquake (GEJE) of 11 March 2011 in cardiovascular (CV) patients registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 Study (n = 10 219), with a special reference to sex., Methods and Results: By self-completion questionnaires of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J), the prevalence of PTSD, defined as IES-R-J score ≥25, was 14.8, 15.7, 7.4, and 7.5% in 2011, 2012, 2013, and 2014, respectively. The PTSD rate was higher in women than in men in all years (all P < 0.01). During a median 3.5-year follow-up period, the patients with PTSD in 2011 more frequently experienced a composite of all-cause death and hospitalization for acute myocardial infarction, stroke, and heart failure than those without PTSD [adjusted hazard ratio (aHR) 1.27, P < 0.01]. Importantly, the prognostic impacts of PTSD on all-cause death (aHR 2.10 vs. 0.87, P for interaction = 0.03) and CV death (aHR 3.43 vs. 0.90, P for interaction = 0.02) were significant in women but not in men. While insomnia medication was a prominent determinant factor of PTSD in both sexes during 2011-14, economic poverty was significantly associated with PTSD only in men., Conclusion: After the GEJE, marked sex differences existed in the prevalence, prognostic impacts, and determinant factors of PTSD, suggesting the importance of sex-sepcific mental stress care in disaster medicine., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: Although the importance of coronary microvascular dysfunction (CMD) has been emerging, reliable biomarkers for CMD remain to be developed. We examined the potential usefulness of plasma concentration of serotonin to diagnose CMD in patients with suspected angina and unobstructive coronary arteries., Methods and Results: We enrolled 198 consecutive patients (M/F 116/82, 60.2 ± 13.3 years old) who underwent acetylcholine provocation test and measured plasma serotonin concentration. Coronary microvascular dysfunction was defined as myocardial lactate production without or prior to the occurrence of epicardial coronary spasm during acetylcholine provocation test. Although no statistical difference in plasma concentration of serotonin [median (inter-quartile range) nmol/L] was noted between the vasospastic angina (VSA) and non-VSA groups [6.8 (3.8, 10.9) vs. 5.1 (3.7, 8.4), P = 0.135], it was significantly higher in patients with CMD compared with those without it [7.7 (4.5, 14.2) vs. 5.6 (3.7, 9.3), P = 0.008]. Among the four groups classified according to the presence or absence of VSA and CMD, serotonin concentration was highest in the VSA with CMD group. Importantly, there was a positive correlation between plasma serotonin concentration and baseline thrombolysis in myocardial infarction frame count (P = 0.001), a marker of coronary vascular resistance. The classification and regression trees analysis showed that plasma serotonin concentration of 9.55 nmol/L was the first discriminator to stratify the risk for the presence of CMD. In multivariable analysis, serotonin concentration greater than the cut-off value had the largest odds ratio in the prediction of CMD [odds ratio (95% confidence interval) 2.63 (1.28-5.49), P = 0.009]., Conclusions: Plasma concentration of serotonin may be a novel biomarker for CMD in patients with angina and unobstructive coronary arteries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.)

Aims: Neovascularization is closely associated with plaque progression in non-heart transplantation subjects; on the other hand, cardiac allograft vasculopathy causes unfavourable outcomes. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can provide microscopic assessment in vivo. The aim of this study was to investigate the impact of neovascularization on intimal proliferation., Methods and Results: Both IVUS and OCT were attempted in 45 consecutive patients during annual catheterization after heart transplantation. There were 115 vessels [28 vessels were catheterized within 8 weeks of heart transplantation (baseline)]. IVUS analysis assessed vessel, luminal, and intimal (vessel-lumen) volume using Simpson's method. Qualitative parameters including microchannel were assessed by OCT. A microchannel was defined as a no-signal tubuloluminal structure with a sharply delineated border considered to represent neovascularization. Microchannel was observed more often in patient who had their heart transplant more than a year prior to the imaging, compared with shorter periods (39.1 vs. 10.7%, P = 0.023). All microchannels were seen in thickness >0.5 mm, and intimal volume index (mm(3)/mm) correlated with frequency of microchannel (r = 0.54, P = 0.04). The risks for microchannels were donor age [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.22; P = 0.007], cytomegalovirus infection (OR 16.21; 95% CI 1.79-220.09; P = 0.012), diabetes (OR 9.5; 95% CI 1.21-116.10; P = 0.032), LDL-cholesterol (OR 1.07; 95% CI 1.01-1.13; P = 0.010), and intimal volume (OR 2.47; 95% CI 1.13-6.36; P = 0.023)., Conclusion: OCT-identified microchannels increased sharply within the first year and were correlated with intimal volume and coronary risks. This suggests that neovascularization may play an important role in the progression of cardiac allograft vasculopathy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: In aortic regurgitation (AR), energy loss (EL) produced by inefficient turbulent flow may be a burden to the heart predicting decompensation. We attempted to quantify EL in AR induced in an acute dog model and in patients with chronic AR using novel echocardiographic method vector flow mapping (VFM)., Methods and Results: In 11 anaesthetized open-chest dogs, AR was induced by distorting the aortic valve with a pigtail catheter, in totally 20 cases. Regurgitant fraction was determined using pulsed Doppler echocardiography, <30% considered mild to moderate (Group 1, n = 11) and ≥30% moderate to severe (Group 2, n = 9). The clinical study consisted of 22 patients with various degrees of AR; 11 mild to moderate (Group 1) and 11 moderate to severe (Group 2), and compared with 12 normals. VFM is based on continuity equation applied to colour Doppler and speckle tracking velocities, acquired from apical long-axis image. EL was calculated frame by frame, averaged from three beats. In the dog study, diastolic EL increased significantly with severity of AR (baseline vs. Group 1 vs. Group 2: 3.8 ± 1.6 vs. 13.0 ± 5.0 vs. 22.4 ± 14.0 [J/(m s)], ANOVA P = 0.0001). Similar to dogs, diastolic EL also increased in humans by the severity of AR (control vs. Group 1 vs. Group 2: 2.8 ± 1.5 vs. 14.3 ± 11.5 vs. 18.6 ± 2.3 [J/(m s)], ANOVA P = 0.001)., Conclusion: VFM provides a promising method to quantify diastolic EL in AR. Diastolic EL increases in AR proportional to its severity. EL may be useful to determine the severity of disease from the aspect of cardiac load., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3-weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety., (© The Author 2014. Published by Oxford University Press.)

Objective: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system., Methods: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy., Results: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days)., Conclusions: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients., (© The Author 2014. Published by Oxford University Press.)

Objective: Infusion reactions are common adverse reactions associated with antibody preparations. However, no studies have examined the time to onset of serious infusion reactions after administering cetuximab. We aimed to investigate the timing and severity of IRs affecting Japanese patients after administration of cetuximab., Methods: Study subjects were identified from a nationwide prospective registry of 2126 metastatic colorectal cancer patients scheduled to receive cetuximab. Infusion reactions were examined in 2006 patients with adequate safety data., Results: Infusion reactions of any grade occurred in 114 patients (5.7%), including Grade 3-4 infusion reactions in 22 patients (1.1%). Premedications were antihistamine plus corticosteroid (88.9% of patients with infusion reactions), antihistamine alone (9.2%) or corticosteroid alone (1.1%). In 95 patients (83.3%), infusion reactions occurred after the first dose. Twenty of the 22 Grade 3-4 infusion reactions occurred within 1 h of the first dose (the timing of the infusion reaction was unknown in one patient while another infusion reaction occurred after the fourth dose). Infusion reactions resolved in 111/114 patients (97.4%) while one patient recovered with sequelae, one patient died and one patient failed to recover within the follow-up period. Thirteen patients (15.7% of patients with infusion reactions) with Grade 1-2 infusion reactions showed recurrence after readministration of cetuximab; the recurrent infusion reactions were less severe than the initial reactions., Conclusions: Grade 3-4 infusion reactions occurred in 1.1% of colorectal cancer patients, and most occurred within 1 h of receiving the first dose of cetuximab. Therefore, patients should be carefully observed following cetuximab infusion, especially during the first hour after the first infusion., (© The Author 2014. Published by Oxford University Press.)

Aims: While previous studies reported a short-term increase in individual cardiovascular disease (CVD) after great earthquakes, mid-term occurrences of all types of CVDs after great earthquakes are unknown. We addressed this important issue in our experience with the Great East Japan Earthquake (11 March 2011)., Methods and Results: We retrospectively examined the impact of the Earthquake on the occurrences of CVDs and pneumonia by comparing the ambulance records made by doctors in our Miyagi Prefecture, the centre of the disaster area, during the periods of 2008-11 (n = 124,152). The weekly occurrences of CVDs, including heart failure (HF), acute coronary syndrome (ACS), stroke, cardiopulmonary arrest (CPA), and pneumonia were all significantly increased after the Earthquake compared with the previous 3 years. The occurrences of ACS and CPA showed the rapid increase followed by a sharp decline, whereas those of HF and pneumonia showed a prolonged increase for more than 6 weeks and those of stroke and CPA showed a second peak after the largest aftershock (7 April 2011). Furthermore, the occurrence of CPA was increased in the first 24 h after the Earthquake, followed by other diseases later on. These increases were independent of age, sex, or residence area (seacoast vs. inland)., Conclusion: These results indicate that the occurrences of all types of CVDs and pneumonia were increased in somewhat different time courses after the Earthquake, including the first observation of the marked and prolonged increase in HF, emphasizing the importance of intensive medical management of all types of CVDs after great earthquakes.

Aims: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex but increased left ventricular (LV) diastolic stiffness plays a key role. A load-independent, non-invasive, direct measure of diastolic stiffness is lacking. The diastolic wall strain (DWS) index is based on the linear elastic theory, which predicts that impaired diastolic wall thinning reflects resistance to deformation in diastole and thus, increased diastolic myocardial stiffness. The objectives of this community-based study were to determine the distribution of this novel index in consecutive HFpEF patients and healthy controls, define the relationship between DWS and cardiac structure and function and determine whether increased diastolic stiffness as assessed by DWS is predictive of the outcome in HFpEF., Methods and Results: Consecutive HFpEF patients (n = 327, EF ≥ 50%) and controls (n = 528) from the same community were studied. Diastolic wall strain was lower in HFpEF (0.33 ± 0.08) than in controls (0.40 ± 0.07, P < 0.001). Within HFpEF, those with DWS ≤ median (0.33) had higher LV mass index, relative wall thickness, E/e', Doppler-estimated LV end-diastolic pressure to LV end-diastolic volume ratio, left atrial volume index, and brain natriuretic peptide (BNP) levels than those with DWS > median. Heart failure with preserved ejection fraction patients with DWS ≤ median had higher rate of death or HF hospitalization than those with DWS > median (P = 0.003) even after the adjustment for age, gender, log BNP, LV geometry, or log E/e' (P < 0.01)., Conclusion: These data suggest that DWS, a simple index, is useful in assessing diastolic stiffness and that more advanced diastolic stiffness is associated with worse outcomes in HFpEF.

Aims: Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na(+)/K(+)-ATPase and activate the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF., Methods and Results: (i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague-Dawley rats. (iii) Ouabain elevated intracellular Ca(2+) concentration through the entry of extracellular Ca(2+), increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced (3)H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening., Conclusion: Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Objective: Cetuximab (Erbitux(®)) was approved for the treatment of metastatic colorectal cancer in Japan in 2008. To verify information on the safety in practical use of cetuximab, we conducted post-marketing surveillance in accordance with the conditions for approval., Methods: All patients to be treated with cetuximab were enrolled by the central enrolment method. Data on treatment status, and incidence and severity of adverse drug reactions were collected. The target number of patients was 1800., Results: A total of 2126 patients were enrolled from 637 institutions. Among 2006 patients analysed, 93.2% received cetuximab as third-line or later treatment. The median duration of treatment was 15.3 weeks, and 11.1% of patients received treatment for >48 weeks. The incidence of adverse drug reactions was 89.6%, of which ≥grade 3 was 21.5%. The incidence of infusion reactions was 5.7% (any grade), with 83.3% of them occurring at the first administration. The incidence of skin disorders was 83.7% (any grade), and the time to event varied for each skin disorder. The incidence of interstitial lung diseases was 1.2% (any grade). Diarrhoea and haematotoxicity scarcely occurred with cetuximab alone., Conclusions: In this surveillance, the incidence and categories of adverse drug reactions are not distinct from previous reports. Although most patients received cetuximab as third-line or later treatment, treatment was maintained with a median duration of 15 weeks. Cetuximab treatment in practical use is considered to be well tolerated and clinically useful in Japanese patients with metastatic colorectal cancer.

Objective: The actual condition of drug utilization and the adverse drug reactions profile of irinotecan hydrochloride hydrate (irinotecan), an antitumor drug, were examined on the basis of all the case survey results from April 1995 to January 2000., Methods: Drug utilization and the adverse drug reactions profile of irinotecan were figured out by checking of the patient conditions at the start of therapy and monitoring during on-therapy period in this survey., Results: Among the 13 935 patients investigated, 32% had non-small cell lung cancer, 16% had colorectal cancer, 15% had ovarian cancer and 14% had small cell lung cancer, all principal cancers in which irinotecan was domestically approved for use. Most frequent regimens of each cancer were concomitant use with cisplatin for non-small cell lung cancer and small cell lung cancer (38 and 46%, respectively), concomitant use with cisplatin or mitomycin for ovarian cancer (each 30%) and irinotecan alone for colorectal cancer (51%). The major (grade 3 or more) adverse drug reactions were myelosuppressions such as leukopenia (23.8 and 38.3% for lone and concomitant use, respectively) thrombocytopenia (6.5 and 14.3%) and gastrointestinal tract disorders such as diarrhea (10.2 and 10.0%)., Conclusions: It was reconfirmed that the incidences of serious leukopenia, thrombocytopenia and diarrhea were high among the patients with contraindication or careful administration of its use prescribed in the drug package insert. Therefore, for proper use of irinotecan, it is important to discriminate the patient on the basis of risk status.

Objective: After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice., Methods: All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate., Results: A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively., Conclusions: The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

A 42-year-old man was found to have an adenocarcinoma arising from ectopic gastric mucosa in Meckel's diverticulum, as diagnosed with surgical pathology. Recurrence was recognized with massive ascites at 1 year and 6 months after surgery. Chemotherapy in the first and second lines was not effective. In the third line of chemotherapy, pemetrexed and carboplatin were both administered and this resulted in a good response for massive ascites. This palliative therapy was effective and safe.

Objective: Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients., Methods: We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis., Results: The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T(3) and T(4)) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated., Conclusions: The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.

Many accessions (ecotypes) of Arabidopsis have been collected. Although few differences exist among their nucleotide sequences, these subtle differences induce large genetic variation in phenotypic traits such as stress tolerance and flowering time. To understand the natural variability in salt tolerance, large-scale soil pot experiments were performed to evaluate salt tolerance among 350 Arabidopsis thaliana accessions. The evaluation revealed a wide variation in the salt tolerance among accessions. Several accessions, including Bu-5, Bur-0, Ll-1, Wl-0, and Zu-0, exhibited marked stress tolerance compared with a salt-sensitive experimental accession, Col-0. The salt-tolerant accessions were also evaluated by agar plate assays. The data obtained by the large-scale assay correlated well with the results of a salt acclimation (SA) assay, in which plants were transferred to high-salinity medium following placement on moderate-salinity medium for 7 d. Genetic analyses indicated that the salt tolerance without SA is a quantitative trait under polygenic control, whereas salt tolerance with SA is regulated by a single gene located on chromosome 5 that is common among the markedly salt-tolerant accessions. These results provide important information for understanding the mechanisms underlying natural variation of salt tolerance in Arabidopsis.

Objective: Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. We evaluated the efficacy and safety of cetuximab in combination with irinotecan in patients with metastatic colorectal cancer (CRC) refractory to irinotecan, oxaliplatin and fluoropyrimidines., Methods: Cetuximab was administered initially at a dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Irinotecan was administered either weekly at a dose of 100 mg/m(2) or every 2 weeks at 150 mg/m(2)., Results: Between October 2005 and February 2006, 39 consecutive patients were enrolled. The response and disease control rates (complete or partial response, or stable disease) were 30.8% (95% CI, 17.0-47.6) and 64.1% (95% CI, 47.2-78.8), respectively. With a median follow-up of 14.4 months, median time to progression was 4.1 months (95% CI, 2.7-5.1) and median survival time was 8.8 months (95% CI, 5.9-12.8). Patients (5.1%) developed Grade 3 acne-like rash., Conclusions: Combination therapy of cetuximab and irinotecan is effective and well-tolerated in patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.

A 61-year-old female with surgically treated rectal cancer that had metastasized to lung and lymph nodes was treated with bevacizumab (BV) plus 5-fluorouracil (5-FU) and leucovorin (LV) as third-line chemotherapy after treatment failures with infusional 5-FU, LV and oxaliplatin (FOLFOX regimen); and infusional 5-FU, LV and irinotecan (FOLFIRI regimen). After four cycles of treatment, a computed tomography scan revealed reduced sizes of the lung and lymph node metastases. Tumor response has still been maintained after six cycles of treatment, and the chemotherapeutic response was evaluated as partial response according to the Response Evaluation Criteria In Solid Tumor guidelines. Manageable toxicity included grade 2 hypertension, grade 1 epistaxis and grade 1 stomatitis. Although there are no clinical trial results supporting the use of BV-containing therapy as third-line chemotherapy for advanced colorectal cancer, BV plus 5-FU and LV was effective and feasible in our patient with colon cancer that had progressed after treatment with 5-FU, irinotecan and oxaliplatin.

Aims: The aim of the study was to assess mechanisms and clinical backgrounds in order to determine residual platelet aggregability in dual antiplatelet therapy and to ascertain whether platelet aggregability is involved in systemic thrombogenicity., Methods and Results: A cross-sectional study was conducted in 85 consecutive patients who underwent dual antiplatelet therapy (aspirin and thienopyridine/cilostazol) after percutaneous coronary intervention (PCI). Although serum thromboxane B(2) and dephosphorylation of vasodilator-stimulated phosphoprotein were significantly abolished, the platelet aggregation tests showed inter-individual differences that could be partly explained by plasma glucose levels. Platelet aggregability was not related to other factors involved in thrombogenicity. Thrombin generation assessed by soluble fibrin was independently associated with total cholesterol (beta = 0.349, P < 0.001), brain natriuretic peptide (beta = 0.222, P = 0.018), and ankle-brachial index (beta = -0.330, P = 0.001). Plasminogen activator inhibitor-1 was associated with the apnea-hypopnea index (beta = 0.300, P = 0.006). E-selectin was correlated with diabetes mellitus (beta = 0.279, P = 0.008) and body mass index (beta = 0.323, P = 0.002)., Conclusion: Although dual antiplatelet therapy effectively inhibited its pharmacological targets, thrombin generation, inhibition of fibrinolytic activity, and endothelial dysfunction were determined by other clinical backgrounds. Our data suggested that some patients remain at risk of thrombotic complications after PCI and that these may benefit from anticoagulant treatment despite adequate dual antiplatelet therapy.

Ten anthocyanins, cyanidin 3-sambubioside, 3-glucoside and their acylated derivatives, cyanidin 3-lathyroside and cyanidin 3-galactoside, were isolated from red flowers of Camellia reticulata. Their structures were determined on the basis of spectroscopic analyses, and the chemotaxonomic distribution of the accumulated anthocyanins in the petals of wild Camellia reticulata and C. pitardii var. yunnanica is discussed.

There has been no previous report of oxaliplatin administration in patients undergoing hemodialysis. A 65-year-old female with end-stage renal disease who was undergoing hemodialysis presented with anemia in August 2005. She was diagnosed with colon cancer with multiple liver metastases. After colectomy, hepatic arterial infusion chemotherapy of 5-fluorouracil was initiated and systemic administration of irinotecan was later added. After 3 months of treatment, liver metastases were strikingly reduced in size, and the carcinoembryonic antigen level decreased from 336 to 14.2 ng/ml. Eight months after treatment initiation, liver metastases increased in size with higher levels of carcinoembryonic antigen, therefore hepatic arterial infusion of oxaliplatin 60 mg was initiated. Hepatic arterial infusion was performed biweekly during hemodialysis and blood platinum concentrations were assessed. At the first cycle, the area under the curve of total platinum was 19.39 microg h/ml and that of free platinum was 5.51 microg h/ml. After six treatment cycles, the carcinoembryonic antigen level declined from 335 to 123 ng/ml. After eight treatment cycles, she experienced transient fever and impaired consciousness as a result of cholangitis, which improved following administration of antibiotics. We propose that limited cycles of hepatic arterial infusion of oxaliplatin are feasible in patients undergoing hemodialysis and this may become a strategy for treating hepatic metastases from colon cancer in patients undergoing hemodialysis.