Search

Examines the treatment of notoedres cati infestitation in cats with selamectin. Identification of other ectoparasites; Observation of cats for general and local adverse reactions after treatment; Evaluation of microscopic skin scrapings.

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H 2 S) in HFpEF., Objectives: This study evaluated H 2 S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H 2 S on HFpEF severity through alterations in endogenous H 2 S production and pharmacological supplementation. We also evaluated the effects of the H 2 S donor, diallyl trisulfide (DATS) in combination with the GLP-1/glucagon receptor agonist, survodutide, in HFpEF., Methods: HFpEF patients and two rodent models of HFpEF ("two-hit" L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H 2 S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H 2 S donor, JK-1, supplementation. DATS and survodutide combination therapy was tested in ZSF1 obese rats., Results: H 2 S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H 2 S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e' ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H 2 S supplementation restored H 2 S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype. DATS synergized with survodutide to attenuate obesity, improve diastolic function, exercise capacity, and reduce oxidative stress and cardiac fibrosis., Conclusions: H 2 S deficiency is evident in HFpEF patients and conserved across multiple preclinical HFpEF models. Increasing H 2 S bioavailability improved cardiovascular function, while knockout of endogenous H 2 S production exacerbated HFpEF pathology and mortality. These results suggest H 2 S dysregulation contributes to HFpEF and increasing H 2 S bioavailability may represent a novel therapeutic strategy for HFpEF. Furthermore, our data demonstrate that combining H 2 S supplementation with GLP-1/glucagon receptor agonist may provide synergistic benefits in improving HFpEF outcomes., Highlights: H 2 S deficiency is evident in both human HFpEF patients and two clinically relevant models. Reduced H 2 S production by CSE and increased metabolism by SQR impair H 2 S bioavailability in HFpEF. Pharmacological H 2 S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models. Targeting H 2 S dysregulation presents a novel therapeutic strategy for managing HFpEF. H 2 S synergizes with GLP-1/glucagon agonist and ameliorates HFpEF.

[Purpose] Rehabilitation can improve physical function and quality of life in patients with advanced cancer. However, relevant studies on advanced lung cancers are limited. Differences in physical function and symptoms based on the treatment phase should be considered. This study investigated the relationship between physical function and quality of life during the treatment phase in patients with advanced lung cancer. [Participants and Methods] Patients with stage IV non-small-cell lung cancer and postoperative recurrence who were hospitalized between May 2018 and October 2021 were selected. Data, including age, histological type of lung cancer, treatment details, functional independence measures, and European Organization for Research and Treatment of Cancer QLQ-C30, were collected from medical records. Patients were categorized into groups based on the treatment phase: the initial, subsequent, and best supportive care (BSC) groups comprised patients admitted for initial treatment, receiving second or subsequent treatments, and receiving best supportive care, respectively. The relationship between physical function and quality of life during each treatment phase was examined. [Results] Physical function in the subsequent group was associated with physical functioning, role functioning, cognitive functioning, social functioning, and fatigue. Meanwhile, the BSC group had fewer associated items than the other groups. [Conclusion] Rehabilitation during the ongoing treatment phase improves physical function and quality of life., Competing Interests: The authors declare no conflicts of interest., (2025©by the Society of Physical Therapy Science. Published by IPEC Inc.)

The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on mesenchymal-epithelial transition factor (MET) inhibitor-induced edema remain unclear. In a patient with tepotinib-induced edema and an N-terminal pro-brain natriuretic peptide (NTproBNP) level ≥ 300 pg/mL, the addition of empagliflozin to loop diuretics reduced the edema. This suggests that empagliflozin may be a treatment option for MET inhibitor-induced edema., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Recent reports suggest increased myocardial iNOS expression leads to excessive protein s -nitrosylation, contributing to the pathophysiology of HFpEF. However, the relationship between NO bioavailability, dynamic regulation of protein s -nitrosylation by trans- and de-nitrosylases, and HFpEF pathophysiology has not been elucidated. Here, we provide novel insights into the delicate interplay between NO bioavailability and protein s -nitrosylation in HFpEF., Methods: Plasma nitrite, nitrosothiols (RsNO), and 3-nitrotyrosine (3-NT) were measured in HFpEF patients and in controls. Studies in WKY or ZSF1 obese rats were performed to evaluate HFpEF severity, NO signaling, and total nitroso-species (Rx(s)NO) levels. snRNA sequencing was performed to identify key genes involved in NO signaling and s -nitrosylation regulation., Results: In HFpEF patients, circulating RsNO and 3-NT were significantly elevated while nitrite, a biomarker for NO bioavailability, remained unchanged. In ZSF1 obese rats, NO bioavailability was significantly reduced while Rx(s)NO levels exhibited an age-dependent increase as HFpEF progressed. snRNA seq highlighted significant upregulation of a trans-nitrosylase, hemoglobin-beta subunit (HBb), which was corroborated in human HFpEF hearts 1 . Subsequent experiments confirmed HBb upregulation and revealed significant reductions in enzyme activity of two major de-nitrosylases, Trx2 and GSNOR in ZSF1 obese hearts. Further, elevated RxNO levels, increased HBb expression, and reduced activity of Trx2 and GSNOR were identified in the kidney and liver of the ZSF1 obese rats., Conclusions: Our data reveal circulating markers of nitrosative stress (RsNO and 3-NT) are significantly elevated in HFpEF patients. Data from the ZSF1 obese rat model mirror the results from HFpEF patients and reveal that pathological accumulation of RxNO/nitrosative stress in HFpEF may be in part, due to the upregulation of the trans-nitrosylase, HBb, and impaired activity of the de-nitrosylases, Trx2 and GSNOR. Our data suggest that dysregulated protein nitrosylation dynamics in the heart, liver, and kidney contribute to the pathogenesis of cardiometabolic HFpEF., Translational Perspective: Our findings describe for the first time that circulating RsNO and 3-NT are significantly upregulated in HFpEF patients suggesting systemic nitrosative stress in HFpEF, and demonstrate a profound disconnect between insufficient physiological NO signaling and pathological nitrosative stress in HFpEF, which is in stark contrast to HFrEF in which both NO bioavailability and protein s -nitrosylation are attenuated. Further, this study provides novel mechanistic insights into a critical molecular feature of HFpEF in humans and animal models: nitrosative stress arises predominantly from imbalance of trans-nitrosylases and de-nitrosylases, thereby leading to impaired NO bioavailability concomitant with increased protein s -nitrosylation. Importantly, these perturbations extend beyond the heart to the kidney and liver, suggesting HFpEF is characterized by a systemic derangement in trans- and de-nitrosylase activity and providing a unifying molecular lesion for the systemic presentation of HFpEF pathophysiology. These findings have direct clinical implications for the modulation of NO levels in the HFpEF patient, and indicate that restoring the balance between trans- and denitrosylases may be novel therapeutic targets to ameliorate disease symptoms in HFpEF patients.

Background: The ONCO DVT study (Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis) revealed superiority of 12-month relative to 3-month edoxaban treatment for the thrombotic risk in cancer-associated isolated distal deep vein thrombosis. However, it is unknown whether the superiority could be common in different modified Ottawa score subgroups., Objectives: To identify more preferable candidates for extended anticoagulation in patients with cancer-associated isolated distal deep vein thrombosis using the modified Ottawa score., Methods: In this post-hoc subgroup analysis of the ONCO DVT study, we stratified 601 patients into the low (≤-1, N = 126), intermediate (0, N = 323), and high (≥1, N = 152) modified Ottawa score subgroups and compared clinical outcomes between the 12-month and 3-month edoxaban treatment groups., Results: The cumulative incidence of symptomatic recurrent venous thromboembolism or venous thromboembolism-related death was not different between the 12-month and 3-month edoxaban treatment groups in the low score subgroup (0.0% vs 2.2%), whereas it was lower in the 12-month than in the 3-month edoxaban treatment group in the intermediate (0.8% vs 7.6%) and high (3.1% vs 15.6%) score subgroups. There were no significant differences in the cumulative incidences of the major bleeding between the 12-month and 3-month edoxaban treatment groups in the low (10.1% vs 7.6%), intermediate (8.8% vs 5.0%), and high (13.9% vs 12.6%) score subgroups., Conclusion: A 12-month compared with 3-month edoxaban treatment showed a lower risk of thrombotic events in patients with cancer-associated isolated distal deep vein thrombosis in the intermediate and high modified Ottawa score subgroups but not in the low score subgroup, suggesting a limited benefit of extended anticoagulation therapy beyond 3 months in patients with low modified Ottawa score., Competing Interests: Declaration of competing interests Y.Y. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo and grant support from Bayer Healthcare and Daiichi Sankyo. T.M. reports lecturer's fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; manuscript fees from Bristol-Myers Squibb and Pfizer; and advisory board for Novartis and Teijin. Y.N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Y.O. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo and research funds from Bayer Healthcare and Daiichi Sankyo. N.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. Y.T. received lecture fees from AstraZeneca, Chugai Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and Daiichi Sankyo and grant support from Daiichi Sankyo, AstraZeneca, and Ono Pharmaceutical. S.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the incidence and characteristics of ischemic cardiac events, specifically major adverse cardiac events (MACE), in patients undergoing long-term treatment with multikinase inhibitors (MKIs) such as lenvatinib and sorafenib., Methods: A single-center retrospective analysis was conducted on 41 patients treated with lenvatinib or sorafenib for more than one year at our institution from 2015 to 2022. Patient records were reviewed to collect data on demographics, cancer type, cardiovascular risk factors, MKI treatment duration, and MACE incidence. MACE events, defined as acute heart failure, fatal arrhythmia, acute myocardial infarction, and coronary revascularization, were analyzed to determine potential correlations with MKI therapy., Results: Among the 41 patients, three (7.3%) developed MACE, presenting as acute heart failure, fatal arrhythmia, and acute myocardial infarction, all associated with significant coronary artery stenosis. Notably, none of these patients had a prior history of cardiovascular disease. Despite variations in clinical presentation, all cases suggested a link between long-term MKI administration and accelerated coronary atherosclerosis. Factors involved in atherosclerosis were significantly older and tended to be more hypertensive in the non-MACE group., Conclusions: Long-term MKI therapy may increase the risk of severe ischemic cardiac events, likely due to accelerated atherosclerosis. Clinicians and oncology nurses should monitor patients closely for early signs of angina, especially in an outpatient setting, to prevent acute cardiac events. Further large-scale studies are warranted to establish a clearer causal relationship between MKI therapy and cardiovascular risks., Competing Interests: Dr. Kenmotsu received research funding from Ono Pharmaceutical Co, Ltd., Novartis Pharma K.K., Eli Lilly K.K, AstraZeneca K.K., Loxo Oncology, and speakers bureau from Amgen inc., AstraZeneca K.K., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Merck, MSD, Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Pfizer, Taiho Pharma, Takeda Pharmaceutical Co., Ltd., (© 2024 The Author(s).)

Background: The optimal duration of anticoagulation therapy for patients with cancer and acute low-risk pulmonary embolism (PE) is clinically relevant, but evidence is lacking. Prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding., Methods: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 32 institutions in Japan, we randomly assigned patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, in a 1:1 ratio, to receive either an 18-month or a 6-month rivaroxaban treatment. The primary end point was recurrent venous thromboembolism (VTE) at 18 months. The major secondary end point was major bleeding at 18 months according to the criteria of the International Society on Thrombosis and Hemostasis. The primary hypothesis was that an 18-month treatment was superior to a 6-month treatment in terms of the primary end point., Results: From February 2021 to March 2023, 179 patients were randomized, and after the exclusion of one patient who withdrew consent, 178 were included in the intention-to-treat population: 89 patients in the 18-month rivaroxaban group and 89 in the 6-month rivaroxaban group. The mean age was 65.7 years; 47% of the patients were men, and 12% had symptoms of PE at baseline. The primary end point of recurrent VTE occurred in 5 of the 89 patients (5.6%) in the 18-month rivaroxaban group and in 17 of the 89 (19.1%) in the 6-month rivaroxaban group (odds ratio, 0.25 [95% CI, 0.09-0.72]; P =0.01). Among 22 recurrent VTE, 5 patients presented with a symptomatic recurrent VTE; recurrent PE occurred in 11 patients, including 2 with main and 4 with lobar PEs; and recurrent deep vein thrombosis was seen in 11 patients, including 3 with proximal deep vein thromboses. The major secondary end point of major bleeding occurred in 7 of the 89 patients (7.8 %) in the 18-month rivaroxaban group and in 5 of the 89 patients (5.6%) in the 6-month rivaroxaban group (odds ratio, 1.43 [95% CI, 0.44-4.70]; P =0.55)., Conclusions: In patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, the 18-month rivaroxaban treatment was superior to the 6-month rivaroxaban treatment with respect to recurrent VTE events.

Background: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood., Methods: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31 P nuclear magnetic resonance (NMR) spectroscopy and substrate oxidation profile was assessed by 13 C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes., Results: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes., Conclusions: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation., Competing Interests: None.

Competing Interests: This study was funded by Daiichi Sankyo Co, Ltd, which had no role in the study design, data collection, analysis, interpretation, or writing of the report. Dr Nishimoto has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Dr Yamashita has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo; and has received grant support from Bayer Healthcare and Daiichi Sankyo. Dr Morimoto has received lecturer fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; has received manuscript fees from Bristol-Myers Squibb and Pfizer; and serves on the Advisory Boards of Novartis and Teijin. Dr Ogihara has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo; and has received research funds from Bayer Healthcare and Daiichi Sankyo. Dr Ikeda has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Objective: The European Cardio-Oncology Guidelines recommend regular electrocardiography and troponin testing during immune checkpoint inhibitors (ICIs) treatment, but their efficacy for monitoring ICI treatment remains unclear. This study aimed to evaluate the effectiveness of a surveillance protocol for early detection of ICI-induced myocarditis., Methods: Between May 2014 and May 2024, patients who began treatment with ICIs at our hospital and developed ICI-induced myocarditis were included in this study. We created a straightforward management flowchart for myocarditis. The protocol was based on monitoring troponin T levels. We confirmed the efficacy of our surveillance protocol using a case series of ICI-induced myocarditis., Results: During the observation period, 3481 patients were newly started on ICIs at our hospital. Five patients were previously diagnosed with myocarditis, and five patients were diagnosed with myocarditis after the implementation of the surveillance protocol. The manual enabled the early detection of myocarditis, and the mortality rate for myocarditis at our hospital improved from 60% to 0%. The incidence of conduction system disorders significantly reduced from 100% to 0% ( P  < 0.01). After the surveillance protocol was initiated, there were no cases of myocarditis requiring immunosuppressive drugs beyond steroids., Conclusions: This study confirmed the relevance of a troponin-based surveillance protocol for the early detection of ICI-induced myocarditis. The implementation of the surveillance protocol reduced mortality from myocarditis and significantly reduced serious complications of conduction system disorders. Although this study is a small case series of patients who developed myocarditis, we confirm the effectiveness of surveillance for myocarditis., Competing Interests: Takuya Oyakawa received honoraria from Pfizer, Daiichi Sankyo, TOA EIYO, Novartis, AstraZeneca, and Bristol-Myers Squibb. Nao Muraoka has no conflict of interest. Kei Iida has no conflict of interest. Ayano Fujita has no conflict of interest. Yokoyama Koichi has no conflict of interest. Ishikawa Hiroshi has no conflict of interest. Haruyasu Murakami reports grants from Chugaipharma, AstraZeneca, Abbvie, Daiichi Sankyo, IQvia, and Taiho Pharmaceutical, Bayer, and received honoraria from Chugai pharma, Daiichi Sankyo, AtraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb Japan, MSD, Pfizer, Novartis Lilly Japan, Taiho pharmaceutical, and Eisai, Nihonkayaku, as well as participation on a data safety monitoring board or advisory board, outside the submitted work., (© 2024 The Authors.)

Background: The ONCO DVT study demonstrated potential benefits of extended edoxaban treatment in patients with isolated distal deep vein thrombosis in terms of thrombotic risk. However, the risk-benefit balance in patients with anemia remains unclear., Methods and Results: This prespecified subgroup analysis included 601 patients, divided into anemia (n=402) and no-anemia (n=199) groups. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) or VTE-related death. Anemia was defined as hemoglobin <12 g/dL for women and <13 g/dL for men. In the anemia subgroup, the primary endpoint occurred in 3 (1.5%) and 17 (8.4%) patients in the 12- and 3-month edoxaban treatment groups, respectively (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05-0.58), compared with 0 and 5 (4.9%) patients, respectively, in the no-anemia subgroup (P interaction=0.997). Major bleeding occurred in 26 (13.1%) and 17 (8.4%) patients with anemia in the 12- and 3-month edoxaban treatment groups, respectively (OR 1.64; 95% CI 0.86-3.14), compared with 2 (2.1%) and 5 (4.9%) patients without anemia (OR 0.67; 95% CI 0.26-1.73; P interaction=0.13)., Conclusions: Regardless of the presence of anemia, edoxaban treatment for 12 months was superior to treatment for 3 months in reducing thrombotic events, whereas the risk of major bleeding did not differ significantly between the 2 treatment groups.

Background: The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk., Methods and Results: In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N = 151) and those with a reduced edoxaban dose (30 mg/day; N = 450) and evaluated the clinical outcomes for the 12- and 3-month treatments. The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P = 0.02; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P = 0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P = 0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than in the 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P = 0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P = 0.89; OR, 0.97; 95% CI, 0.49-1.91), signalling there was a potential interaction (P = 0.07)., Conclusions: A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy., Trial Registration Number: NCT03895502 (ONCO DVT Trial): https://classic.clinicaltrials.gov/ct2/show/NCT03895502., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events., Conclusions: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Background: The multicenter, open-label, randomized clinical trial ONCO DVT compared 3-month and 12-month edoxaban treatment regimens for isolated distal deep vein thrombosis (DVT) and suggested potential benefits of prolonged edoxaban treatment in terms of thrombotic risk. However, the risk-benefit balance of prolonged edoxaban treatment in patients with renal function remains unclear., Objectives: To compare the safety and efficacy of 3-month and 12-month edoxaban treatment regimens in patients with cancer-associated isolated distal DVT and different renal functions., Methods: This pre-specified subgroup analysis of the ONCO DVT study included 601 patients divided into subgroups according to renal function using a 50 mL/min creatinine clearance (Ccr) cutoff. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) and VTE-related death at 12 months and the major secondary endpoint was major bleeding at 12 months., Results: Among the 601 patients, 131 (21.8 %) comprised the renal dysfunction subgroup. The primary endpoint occurred in 6 (9.7 %) and 1 (1.4 %) patients in the 3-month and 12-month edoxaban groups in the renal dysfunction subgroup, respectively, and in 16 (6.6 %) and 2 (0.9 %) patients in the no renal dysfunction subgroup, respectively. The major secondary endpoint occurred in 9 (14.5 %) and 7 (10.1 %) patients in the 12-month and 3-month edoxaban groups in the renal dysfunction subgroup, and in 13 (5.3 %) and 21 (9.3 %) patients in the no renal dysfunction subgroup, respectively., Conclusions: A 12-month edoxaban regiment was superior to a 3-month treatment in terms of thrombotic risk irrespective of renal function. A higher bleeding risk was not identified in patients with renal dysfunction who received prolonged edoxaban treatment., Competing Interests: Declaration of competing interest Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Morimoto reports lecturer's fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer and Tsumura; manuscript fees from Bristol-Myers Squibb and Pfizer; advisory board for Novartis and Teijin. Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Dr. Ogihara received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Bayer Healthcare and Daiichi Sankyo. Dr. Dohi received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Daiichi Sankyo. Dr. Ikeda N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. Dr. Tsubata received lecture fees from AstraZeneca, Chugai Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical and Daiichi Sankyo, and grant support from Daiichi Sankyo, AstraZeneca and Ono Pharmaceutical. Dr. Ikeda S. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb and Daiichi Sankyo. Dr. Mo received lecture fees from Bayer Healthcare. Dr. Tsujita received significant research grant from AMI Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., MOCHIDA PHARMACEUTICAL CO., LTD., and scholarship fund from AMI Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., ONO PHARMACEUTICAL CO., LTD., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and honoraria from Amgen K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and belongs to the endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO CORPORATION, TERUMO Co, Ltd., Abbott Medical Co., Ltd., Cardinal Health Japan, Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., Medtoronic Japan Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: It remains controversial whether a cancer history increases the risk of cardiovascular (CV) events among patients with myocardial infarction (MI) who undergo revascularization., Methods and results: Patients who were confirmed as type 1 acute MI (AMI) by coronary angiography were retrospectively analyzed. Patients who died in hospital or those not undergoing revascularization were excluded. Patients with a cancer history were compared with those without it. A cancer history was examined in the in-hospital cancer registry. The primary outcome was a composite of cardiac death, recurrent type 1 MI, post-discharge coronary revascularization, heart failure hospitalization, and stroke. Among 551 AMI patients, 55 had a cancer history (cancer group) and 496 did not (non-cancer group). Cox proportional hazards model revealed that the risk of composite endpoint was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.13-2.82). Among the cancer group, patients who were diagnosed as AMI within 6 months after the cancer diagnosis had a higher risk of the composite endpoint than those who were diagnosed as AMI 6 months or later after the cancer diagnosis (adjusted HR: 5.43; 95% CI: 1.55-19.07)., Conclusions: A cancer history increased the risk of CV events after discharge among AMI patients after revascularization.

Background  Although the close relationship between cancer and venous thromboembolism (VTE) has been identified, risk stratification for VTE in Japanese patients with cancer remains unclear. Objectives  This study aimed to validate the Khorana VTE risk assessment score (KRS) for VTE diagnosis and establish an optimal predictive model for VTE in Japanese patients with cancer. Methods  A total of 7,955 Japanese patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups according to the KRS. Using 37 explanatory variables, a total of 2,833 patients with cancer were divided into derivation and validation cohorts (5:5). A risk model for Japanese participants was developed using the derivation cohort data. Results  The prevalence of VTE in low-, intermediate-, and high-score patients was 1.2, 2.5, and 4.3%, respectively. Logistic regression analysis demonstrated that cancer stage (III-IV) and KRS ≥ 2 were independent and significant predictors of VTE onset. The risk model for VTE assigned 1 point to body mass index ≥25 kg/m 2 and 2 points each to the prevalence of osteochondral cancer and D-dimer level ≥1.47 µg/mL. The areas under the curve of the risk model were 0.763 and 0.656 in the derivation and validation cohorts, respectively. Conclusion  The KRS was useful in Japanese patients, and our new predictive model may be helpful for the diagnosis of VTE in Japanese patients with cancer., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding., Methods: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point., Results: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point., Conclusions: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502., Competing Interests: Disclosures Dr Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr Morimoto reports lecturer’s fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; article fees from Bristol Myers Squibb and Pfizer; and membership on advisory boards for Novartis and Teijin. Dr Nishimoto received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo. Dr Ogihara received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Bayer Healthcare and Daiichi Sankyo. Dr Dohi received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Daiichi Sankyo. Dr N. Ikeda received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. Dr Tsubata received lecture fees from AstraZeneca, Chugai Pharmaceutical, Bristol Myers Squibb, Kyowa Kirin, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and Daiichi Sankyo, and grant support from Daiichi Sankyo, AstraZeneca, and Ono Pharmaceutical. Dr S. Ikeda received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. Dr Mo received lecture fees from Bayer Healthcare. The other authors report no conflicts.

Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation., Competing Interests: Conflict of interests M.I. holds a patent related to this work: U.S. Patent 9,517,250 entitled “Methods for Generating Cardiomyocytes,” issued on October 19, 2012., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

We herein report the outcomes of rehabilitation intervention for a patient in his 80s with chronic obstructive pulmonary disease on prolonged mechanical ventilation after COVID-19 infection. The patient was forced to be long-term bedridden due to respirator dependence, showing notable muscle weakness and needing full assistance for all of his activities of daily living (ADL). We implemented rehabilitation for the purposes of withdrawal from mechanical ventilation and improvement of his physical function. We provided a combination program of range of motion exercise, resistance training, and gradual mobilization, such as sitting on the edge of the bed, moving between the bed and wheelchair, sitting on the wheelchair, standing and walking. After rehabilitation for 24 days, the patient was withdrawn from mechanical ventilation, his muscle strength recovered to a level of 4 (Good) on manual muscle testing (MMT) and he became able to walk using a walker. A follow-up survey one year later confirmed that he performed ADL without assistance and returned to work.

Objectives: To determine the incidence and location of lower extremity deep vein thrombosis in patients undergoing radical cystectomy., Methods: We performed radical cystectomy in 137 patients with bladder cancer between August 2014 and February 2020. Since 2014, we have had a policy to screen for deep vein thrombosis using lower extremity ultrasonography both before and after radical cystectomy. We determined the incidence and location of deep vein thrombosis and classified it as either proximal or distal type. Furthermore, we explored the incidence of pulmonary embolism within 3 months after radical cystectomy., Results: After excluding six patients with a lack of ultrasonographic data, we evaluated 131 patients. Preoperative deep vein thrombosis (one proximal and 17 distal) was diagnosed in 18 patients (14%) with no symptoms. Postoperative deep vein thrombosis was diagnosed in 41 patients (31%; three proximal and 38 distal), of whom 26 (63%) had new-onset deep vein thrombosis after cystectomy. Three patients, two with proximal and one with distal type deep vein thrombosis, developed nonfatal pulmonary embolism postoperatively. Multivariate analysis showed that preoperative D-dimer levels (odds ratio 5.35, 95% confidence interval 1.74-16.50; P < 0.003), type of urinary diversion (ileal neobladder; odds ratio 11.15, 95% confidence interval 2.16-57.55; P = 0.004), and preoperative deep vein thrombosis (odds ratio 15.93, 95% confidence interval 3.82-66.30; P < 0.001) were significant risk factors for postoperative deep vein thrombosis., Conclusions: Pre- and post-radical cystectomy whole-leg ultrasonography can lead to an early perioperative diagnosis and immediate treatment of proximal deep vein thrombosis, thereby potentially preventing fatal pulmonary embolism., (© 2021 The Japanese Urological Association.)

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

OBJECTIVE. The purpose of this study was to clarify the natural history of unruptured visceral artery aneurysms due to segmental arterial mediolysis and the efficacy of transcatheter arterial embolization. MATERIALS AND METHODS. Patients with a pathologic or clinical diagnosis of visceral artery aneurysms due to segmental arterial mediolysis between 2005 and 2015 were enrolled. For patients with clinical diagnoses, images were collected and assessed by central radiologic review. To clarify the natural history of unruptured aneurysms, the morphologic changes were assessed. The efficacy and safety of transcatheter arterial embolization for aneurysms due to segmental arterial mediolysis were evaluated. RESULTS. Forty-five patients with 123 aneurysms due to segmental arterial mediolysis were enrolled. Among the 123 aneurysms, 70 unruptured aneurysms were evaluated for natural history. Forty-five of the 70 (64%) aneurysms had no change in morphology. Among the other 25 aneurysms, nine (13% of the 70) were reduced in size, 13 (19%) disappeared, and three (4%) were newly found at follow-up. Aneurysms of the middle colic artery were ruptured in 10 of 11 (91%) cases. Transcatheter arterial embolization was performed on 45 aneurysms and was successful in all cases but caused slight arterial injury in three cases (6.7%). CONCLUSION. At initial diagnosis, unruptured aneurysms due to segmental arterial mediolysis are likely to be stable or to resolve, but the risk of rupture of aneurysms of the middle colic artery appears high. Transcatheter arterial embolization is a useful treatment, but careful manipulation is necessary.

Implantation of subdural electrodes on the brain surface is still widely performed as one of the "gold standard methods" for the presurgical evaluation of epilepsy. Stereotactic insertion of depth electrodes to the brain can be added to detect brain activities in deep-seated lesions to which surface electrodes are insensitive. This study tried to clarify the efficacy and limitations of combined implantation of subdural and depth electrodes in intractable epilepsy patients. Fifty-three patients with drug-resistant epilepsy underwent combined implantation of subdural and depth electrodes for long-term intracranial electroencephalography (iEEG) before epilepsy surgery. The detectability of early ictal iEEG change (EIIC) were compared between the subdural and depth electrodes. We also examined clinical factors including resection of MRI lesion and EIIC with seizure freedom. Detectability of EIIC showed no significant difference between subdural and depth electrodes. However, the additional depth electrode was useful for detecting EIIC from apparently deep locations, such as the insula and mesial temporal structures, but not in detecting EIIC in patients with ulegyria (glial scar). Total removal of MRI lesion was associated with seizure freedom. Depth electrodes should be carefully used after consideration of the suspected etiology to avoid injudicious usage.