94 results on '"M, Kokubo"'
Search Results
2. Stroke Care during the COVID-19 Pandemic: International Expert Panel Review
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Venketasubramanian, N. Anderson, C. Ay, H. Aybek, S. Brinjikji, W. De Freitas, G.R. Del Brutto, O.H. Fassbender, K. Fujimura, M. Goldstein, L.B. Haberl, R.L. Hankey, G.J. Heiss, W.-D. Lestro Henriques, I. Kase, C.S. Kim, J.S. Koga, M. Kokubo, Y. Kuroda, S. Lee, K. Lee, T.-H. Liebeskind, D.S. Lip, G.Y.H. Meairs, S. Medvedev, R. Mehndiratta, M.M. Mohr, J.P. Nagayama, M. Pantoni, L. Papanagiotou, P. Parrilla, G. Pastori, D. Pendlebury, S.T. Pettigrew, L.C. Renjen, P.N. Rundek, T. Schminke, U. Shinohara, Y. Tang, W.K. Toyoda, K. Wartenberg, K.E. Wasay, M. Hennerici, M.G.
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Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. Summary: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced. © 2021 S. Karger AG, Basel. Copyright: All rights reserved.
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- 2021
3. P103 Heart failure with preserved ejection fruction defines the progression of abnormal brain aging: a prospective study of young-old hypertensive patients
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Toyoaki Murohara, K Nomoto, K Kawashima, A Shimizu, M Kokubo, K Toba, H Arai, and Akihiro Hirashiki
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Geriatrics ,medicine.medical_specialty ,business.industry ,Atrial fibrillation ,medicine.disease ,White matter ,medicine.anatomical_structure ,Atrophy ,Heart failure ,Internal medicine ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,Heart failure with preserved ejection fraction ,business ,Prospective cohort study ,Brain aging - Abstract
Funding Acknowledgements Ministry of Health, Labor and Welfare (MHLW) Geriatrics and Gelontorogy sponsored research funds Background & purpose: Recently, many longitudinal studies have shown that heart failure with reduced ejection fraction (HFrEF) is associated with various types of brain abnormalities: cerebral micro-bleeding, atrophy, or pathologic degeneration (white matter hyperintensity; WMH). These brain abnormalities are known to increase with aging and to be closely associated with cognitive impairment. Heart failure with preserved ejection fraction (HFpEF) also increases with aging, but there have been few longitudinal studies to address the relationship between HFpEF and brain abnormalities. Thus, this longitudinal study aimed to clarify this relationship by focusing on WMH volume. METHODS The participants were 111 well-controlled hypertensive patients aged between 65 and 75 years with normal LV contraction and no history of symptomatic heart failure, ischemic heart disease, atrial fibrillation, stroke, or cognitive dysfunction. The participants were classified into 3 groups: Low E/e", E/e" < 8; Middle E/e", 8≤ E/e" ≤ 15; and High E/e", E/e" > 15. WMH volume was quantified on brain magnetic resonance imaging using analytical software. RESULTS During the mean 2.6 ± 1.0-year follow-up period, the rate of increase of WMH volume was significantly higher in the high E/e" group (1.1 ± 1.2 mL/year) than in the low E/e" group (0.30 ± 0.78 mL/year; P = 0.0238). Linear regression analysis including other confounders showed that the only positive association was between the rate of increase of WMH volume and the E/e" ratio (beta- coefficient = 0.225, P = 0.018). CONCLUSION The severity of LV diastolic dysfunction is positively correlated with increasing WMH volume. Abstract P103 Figure. The rates of increase of WMH volumes
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- 2020
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4. P768Cardiopulmonary exercise testing for assessing frailty status in stable elderly patients with heart failure
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A Shimizu, K Kawashima, H Arai, Akihiro Hirashiki, K Nomoto, and M Kokubo
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medicine.medical_specialty ,Ejection fraction ,Rehabilitation ,business.industry ,medicine.medical_treatment ,medicine.disease ,Brain natriuretic peptide ,Internal medicine ,Heart failure ,medicine ,Cardiology ,Frail elderly ,Cardiology and Cardiovascular Medicine ,business - Abstract
Introduction Frailty is a syndrome associated with aging that produces subclinical dysfunction across multiple organ systems and leads to increased risk of mortality. The Kihon Checklist (KCL) was developed by the Japanese Ministry of Health, Labor and Welfare to identify older persons in need of care; it is a reliable tool for predicting general frailty in older adults. There is little information about the relationship between frailty status and exercise capacity. Purpose To investigate whether cardiopulmonary exercise testing (CPX) parameters are associated with frailty in stable elderly patients with heart failure (HF). Methods Ninety-two stable elderly patients with HF were evaluated by using CPX and the total KCL (t-KCL). A t-KCL score of 0–3 was classified as robust, 4–7 as pre-frail, and ≥8 as frail. Diagnostic performance (DP) -plot analysis was used to assess the utility of CPX parameters to distinguish between the presence and absence of frailty. Results Mean age, left ventricular ejection fraction, plasma brain natriuretic peptide, peak work rate (WR), peak VO2, and t-KCL score were 81.7 years, 57.8%, 182 pg/mL, 49.6 W, 13.2 mL/kg/min, and 10.7, respectively. t-KCL score was significantly correlated with peak VO2 (r=−0.53, p Cut-off value for peak WR Conclusions Frailty status was significantly associated with peak WR in stable elderly patients with HF. CPX may be useful for assessing frailty status in stable elderly patients with HF.
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- 2019
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5. Long-term follow up in type A insulin resistant syndrome treated by insulin-like growth factor I
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A Kawakita, H Ishihama, M Nagai, Y Nishimura, H Shiraya, M Kokubo, M Kobayashi, T Imamura, K Muramatsu, and Y Suzuki
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Blood Glucose ,medicine.medical_specialty ,Erythrocytes ,Side effect ,medicine.medical_treatment ,Lymphocyte Activation ,Insulin-like growth factor ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Insulin ,Testosterone ,Acanthosis Nigricans ,Lymphocytes ,Insulin-Like Growth Factor I ,Child ,biology ,business.industry ,Growth factor ,Hyperandrogenism ,Syndrome ,Fibroblasts ,medicine.disease ,Polycystic ovary ,Receptor, Insulin ,Insulin receptor ,Endocrinology ,Pediatrics, Perinatology and Child Health ,biology.protein ,Female ,Insulin Resistance ,business ,Follow-Up Studies ,Polycystic Ovary Syndrome ,Research Article - Abstract
Insulin-like growth factor I (IGF-I) is a useful therapeutic agent in insulin resistant diabetes mellitus due to insulin receptor disease because of its hypoglycaemic effects through the IGF-I receptor. A girl with typical type A insulin resistant syndrome was treated with IGF-I for two years and the treatment was effective in ameliorating hyperglycaemia. Overproduction of testosterone in polycystic ovaries was aggravated with this treatment, however. Therefore, IGF-I treatment may be used for glycaemic control but with caution because of its possible side effect of aggravating hyperandrogenism in these patients.
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- 1994
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6. Clinical studies of long-term behavior of Dacron arterial substitutes
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M. Kokubo
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medicine.medical_specialty ,business.industry ,medicine ,Long term behavior ,business ,Surgery - Published
- 1990
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7. A case of idiopathic musical hallucination with increasing repertoire
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Masayuki Satoh, M Kokubo, and Shigeki Kuzuhara
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Auditory hallucination ,media_common.quotation_subject ,Repertoire ,Cognition ,Musical ,medicine.disease ,behavioral disciplines and activities ,humanities ,Psychiatry and Mental health ,Schizophrenia ,Perception ,medicine ,Musical hallucinations ,Surgery ,Letters ,Neurology (clinical) ,medicine.symptom ,Psychology ,Timbre ,Cognitive psychology ,media_common - Abstract
A musical hallucination is defined as a type of auditory hallucination characterised by the perception of music without an external source.1 Reports in the literature state that musical hallucinations are common in women, and are associated with ageing, deafness,2,3 brain diseases (epilepsy, tumour, stroke, meningitis and neurosyphilis),3,4 psychiatric diseases (schizophrenia and manic depression),3,4 toxic states (alcohol)2 and drugs (antidepressants,1 salicylate,5 quinine and aspirin4). Some authors proposed that, when listening to music, the auditory input is processed by three stages, operating in a hierarchical fashion: perception of individual sounds, perception or imagery of pattern in segmented sound, and encoding or recognition of patterned segmented sound.6 It is supposed that musical hallucinations are caused by abnormal autonomous activity in the auditory brain systems responsible for normal musical imagery.7 It seems reasonable to say that, in acquired peripheral deafness, there is impoverished auditory input that allows spontaneous activity between perception or imagery and encoding or recognition of pattern in segmented sound.6 Regarding lesions in the central nervous system, these lesions may alter the threshold of spontaneous activity within the network for the perception and imagery of music.6 We describe a patient with musical hallucination who experienced an increase in the repertoire of musical hallucinations as she sang various songs, and discuss some of the undetermined problems related to cognitive processing of music: melody, accompaniment and timbre. In July 2002, a 75-year-old, right-handed woman was visiting a hospital on a daily …
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- 2007
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8. Immunohistochemical localization of ornithine aminotransferase in normal rat tissues by Fab'-horseradish peroxidase conjugates
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K Tashiro, T Koide, M Kokubo, T Matsuzawa, N Katunuma, H Watanabe, M Kasahara, and Y Gushiken
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Histology ,Ornithine aminotransferase ,Eye ,Kidney ,Horseradish peroxidase ,Immunoenzyme Techniques ,Immunoglobulin Fab Fragments ,Ciliary body ,medicine ,Animals ,Horseradish Peroxidase ,Transaminases ,Ornithine-Oxo-Acid Transaminase ,biology ,Immunoperoxidase ,Histocytochemistry ,Brain ,Rats, Inbred Strains ,Molecular biology ,Epithelium ,Rats ,medicine.anatomical_structure ,Liver ,Peroxidases ,Biochemistry ,biology.protein ,Immunohistochemistry ,Choroid plexus ,sense organs ,Anatomy ,Digestive System ,Peroxidase - Abstract
Immunohistochemical localization of ornithine aminotransferase (L-ornithine: 2-oxo-acid aminotransferase, EC 2.6.1.13), a mitochondrial enzyme whose hereditary absence induces gyrate atrophy of the choroid and retina, was elucidated by a direct immunoperoxidase method using Fab'-horseradish peroxidase conjugates. In immunodiffusion studies, the antibodies raised with the re-crystallized enzyme were highly specific to ornithine aminotransferase. To show localization of ornithine aminotransferase in normal rat tissues, clear immunohistochemical staining of this enzyme through the inner mitochondrial membrane in paraffin sections was achieved with Fab'-horseradish peroxidase conjugates. Strong immunoreactivity was present in cerebral neurons, hepatocytes, and epithelial cells of renal tubuli, gut mucous membranes, and ocular tissues. Specific distribution of ornithine aminotransferase was found in ependymal cell groups: namely, epithelial cells of the choroid plexus, pigmented and nonpigmented epithelial cells of the ciliary body. and Müller cells and pigment epithelium of the retina.
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- 1986
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9. Effect of the centrally acting antitussives on ascites tumor cells
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S, Kigoshi, M, Nishio, and M, Kokubo
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Antitussive Agents ,Mice ,Thebaine ,Morphinans ,Cell Survival ,Codeine ,Animals ,Antineoplastic Agents ,Female ,Carcinoma, Ehrlich Tumor ,Sarcoma 180 ,Dextromethorphan ,Cells, Cultured - Abstract
Dextromethorphan, dimemorfan, dihydrocodeine and oxymethebanol, centrally acting antitussives, were examined for their effect on Ehrlich carcinoma cells and sarcoma-180 cells in vitro or in vivo. The tumor cells were suspended in Hanks balanced salt solution (pH 7.4) supplemented with 2% bovine albumin, and they were incubated with and without 1 mM drugs at 37 degrees C for 120 min. The incubation of the tumor cells with dextromethorphan or dimemorfan resulted in a decrease in the proportion of the viable cells (less than 25% after 120 min). However, no significant change was observed in the proportion of the viable tumor cells during the incubation with and without the other drugs (80-83% after 120 min). In addition, mice given the tumor cells i.p. were injected intraperitoneally with drugs (20-80 mg/kg/day) once daily for 5 successive days, and their survival time was observed. There was a slight difference in the survival time between mice treated with and without dextromethorphan or dimemorfan. However, a significant difference was found in the survival time between mice treated with and without dextromethorphan when mice given Ehrlich carcinoma cells were injected with the drug (40 mg/kg/time) twice a day for 5 days (about 18 days and 29 days). These results indicate that dextromethorphan and dimemorfan are cytotoxic to the tumor cells in vitro and in vivo.
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- 1983
10. Influence of flow disturbance on an anastomotic intimal hyperplasia
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M. Kokubo
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medicine.medical_specialty ,Intimal hyperplasia ,Disturbance (geology) ,Flow (mathematics) ,business.industry ,Internal medicine ,medicine ,Cardiology ,Anastomosis ,medicine.disease ,business - Published
- 1989
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11. Study for late graft failure
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M. Kokubo
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medicine.medical_specialty ,Graft failure ,business.industry ,medicine ,business ,Surgery - Published
- 1986
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12. Prospective external validation of radiomics-based predictive model of distant metastasis after dynamic tumor tracking stereotactic body radiation therapy in patients with non-small-cell lung cancer: A multi-institutional analysis.
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Adachi T, Nakamura M, Matsuo Y, Karasawa K, Kokubo M, Sakamoto T, Hiraoka M, and Mizowaki T
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- Humans, Male, Female, Prospective Studies, Aged, Middle Aged, Retrospective Studies, Radiotherapy Planning, Computer-Assisted methods, Radiotherapy, Intensity-Modulated methods, Aged, 80 and over, Prognosis, Neoplasm Metastasis, Adult, Image Processing, Computer-Assisted methods, Radiomics, Carcinoma, Non-Small-Cell Lung diagnostic imaging, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Non-Small-Cell Lung pathology, Radiosurgery methods, Lung Neoplasms diagnostic imaging, Lung Neoplasms radiotherapy, Lung Neoplasms pathology, Radiotherapy Dosage, Tomography, X-Ray Computed methods
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Background and Purpose: This study aims to externally validate a predictive model for distant metastasis (DM) with computed tomography (CT)-based radiomics features in prospectively enrolled non-small-cell lung cancer patients undergoing dynamic tumor-tracking stereotactic body radiation therapy (DTT-SBRT)., Materials and Methods: The study collected retrospective data from 567 patients across 11 institutions as the training dataset and prospectively enrolled 42 patients from four institutions as the external test dataset. Four clinical features were collected, and 944 CT-based radiomic features were extracted from gross tumor volumes. After standardization and feature selection, DM predictive models were developed using fine and gray regression (FG) and random survival forest (RSF), incorporating clinical and radiomic features, and their combinations within the training dataset. Then, the model was applied to the test dataset, dividing patients into high- and low-risk groups based on medians of risk scores. Model performance was assessed using the concordance index (C-index), and the statistical significance between groups was evaluated using Gray's test., Results: In the training dataset, 122 of 567 patients (21.5%) developed DM, compared to 9 of 42 patients (21.4%) in the test dataset. In the test dataset, the C-indices of the clinical, radiomics, and hybrid models with FG were 0.559, 0.544, and 0.560, respectively, whereas those with RSF were 0.576, 0.604, and 0.627, respectively. The hybrid model with RSF, which exhibited the best predictive performance of all models, identified 7 of 23 patients (30.4%) as high risk and 2 of 19 patients (10.5%) as low risk for DM incidence in the test dataset (p = 0.116)., Conclusion: Although predictive models for DM lack significance when applied to prospectively enrolled cases undergoing DTT-lung SBRT, the model with RSF exhibits a consistent capacity to effectively classify patients at a high risk of developing DM., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)
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- 2024
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13. Exploratory bibliometric analysis and text mining to reveal research trends in cardiac aging.
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Kamihara T, Tanaka K, Omura T, Kaneko S, Hirashiki A, Kokubo M, and Shimizu A
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Objectives: We conducted a text mining analysis of 40 years of literature on cardiac aging from PubMed to investigate the current understanding on cardiac aging and its mechanisms. This study aimed to embody what most researchers consider cardiac aging to be., Methods: We used multiple text mining and machine learning tools to extract important information from a large amount of text., Results: Analysis revealed that the terms most frequently associated with cardiac aging include "diastolic," "hypertrophy," "fibrosis," "apoptosis," "mitochondrial," "oxidative," and "autophagy." These terms suggest that cardiac aging is characterized by mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. We also revealed an increase in the frequency of occurrence of "autophagy" in recent years, suggesting that research on autophagy has made a breakthrough in the field of cardiac aging. Additionally, the frequency of occurrence of "mitophagy" has increased significantly since 2019, suggesting that mitophagy is an important factor in cardiac aging., Conclusions: Cardiac aging is a complex process that involves mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. Further research is warranted to elucidate the mechanisms of cardiac aging and develop strategies to mitigate its detrimental effects., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s). Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)
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- 2024
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14. Prognostic Significance of Serum Uric Acid and Exercise Capacity in Older Adults Hospitalized for Worsening Cardiovascular Disease.
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Hirashiki A, Shimizu A, Kamihara T, Kokubo M, Hashimoto K, Ueda I, and Murohara T
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Elevated serum uric acid (sUA) is associated with the risk of developing cardiovascular disease (CVD). Here, we examined the prognostic significance of sUA and exercise capacity in 411 Japanese adults (age, ≥65; mean, 81 years) hospitalized for worsening CVD. When the patients were stratified by sUA into three groups (<5.3, 5.4-6.9, >7.0 mg/dL), the high-sUA group had a significantly worse peak VO
2 and composite endpoint (rehospitalization due to worsening CVD and all-cause mortality) compared with low- and moderate-sUA groups ( p < 0.001). When the patients were stratified by sUA into five groups (sUA < 3.9, 4.0-5.9, 6.0-7.9, 8.0-8.9, and >10.0 mg/dL), the incidence of the composite endpoint was significantly higher in the highest sUA group compared with that in the reference group, but only in women. Univariate Cox regression analysis, but not a multivariate analysis, indicated that sUA was significantly associated with the composite endpoint. Although sUA and exercise capacity may have some degree of prognostic significance in older patients with CVD, this significance may differ between men and women.- Published
- 2024
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15. Randomized Controlled Trial of Cardiac Rehabilitation Using the Balance Exercise Assist Robot in Older Adults with Cardiovascular Disease.
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Hirashiki A, Shimizu A, Kamihara T, Kokubo M, Hashimoto K, Ueda I, Sato K, Kawamura K, Itoh N, Murohara T, Kagaya H, and Kondo I
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Background: Recent studies have investigated the effects of exercise on the functional capacity of older adults; training with a balance exercise assist robot (BEAR) effectively improves posture. This study compared the clinical safety and efficacy of training using BEAR video games to conventional resistance training in older adults with cardiovascular disease (CVD)., Methods: Ninety patients (mean age: 78 years) hospitalized due to worsening CVD were randomized to cardiac rehabilitation (CR) Group R (conventional resistance training) or Group B (training using BEAR). After appropriate therapy, patients underwent laboratory testing and functional evaluation using the timed up-and-go test (TUG), short physical performance battery (SPPB), and functional independence measure (FIM) just before discharge and 4 months after CR. The rates of CVD readmission, cardiac death, and fall-related fractures were monitored., Results: BEAR had no adverse effects during exercise. At 4 months, TUG and SPPB improved significantly in both groups, with no significant difference between them. FIM motor and the Geriatric Nutritional Risk Index were significantly improved in Group B versus Group R. There was no significant difference in cardiac events and fall-related fractures between the two groups., Conclusion: CR with BEAR is safe and comparable to conventional resistance training for improving balance in older adults with CVD.
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- 2024
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16. Evolution of a Large Language Model for Preoperative Assessment Based on the Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery.
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Kamihara T, Tabuchi M, Omura T, Suzuki Y, Aritake T, Hirashiki A, Kokubo M, and Shimizu A
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Background: The Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery standardizes preoperative cardiovascular assessments. The present study investigated the efficacy of a large language model (LLM) in providing accurate responses meeting the JCS 2022 Guideline. Methods and Results: Data on consultation requests, physicians' cardiovascular records, and patients' response content were analyzed. Virtual scenarios were created using real-world clinical data, and a LLM was then consulted for such scenarios. Conclusions: Google BARD could accurately provide responses in accordance with the JCS 2022 Guideline in low-risk cases. Google Gemini has significantly improved its accuracy in intermediate- and high-risk cases., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)
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- 2024
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17. Correlation Between Dosimetric Parameters and Local Control in Definitive Radiotherapy for Head and Neck Cancers.
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Yamashita M, Ohira S, Tanabe H, Kokubo M, and Koizumi M
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- Humans, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted methods, Head and Neck Neoplasms radiotherapy, Radiotherapy, Conformal methods, Radiotherapy, Intensity-Modulated methods
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Background/aim: Radiotherapy (RT) outcomes are generally reported based on stage, patient background, and concomitant chemotherapy. This study aimed to investigate the effects of the prescribed dose to gross tumor volume (GTV) and the calculation algorithm on local control in definitive RT for head and neck (H&N) cancers using follow-up images after RT., Patients and Methods: This study included 154 patients with H&N cancers treated by Volumetric Modulated Arc Therapy at the Kobe City Medical Center General Hospital. Patients were classified into those receiving definitive RT (70 Gy of irradiation) and those not receiving it. Follow-up images were used to categorize the patients into the responders and non-responders groups. In the non-responders group, follow-up images were imported into the treatment planning system, and the contours of the residual or recurrent areas (local failure) were extracted and fused with computed tomography-simulated images for treatment planning. Dose evaluation parameters included maximum dose, dose administered to 1% of the volume, dose administered to 50% of the volume, dose administered to 99% of the volume (D
99% ), and minimum dose (Dmin ) administered to the GTV. The doses to the GTV were compared between responders and non-responders., Results: D99% exhibited significant differences between local failure and responders and between local failure and non-responders. Dmin showed significant differences between responders and non-responders and between responders and local failure., Conclusion: This study emphasizes the importance of verifying dose distribution in all slices of treatment planning, highlighting the need for precise assessment of the dose to the GTV in head and neck cancers., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2024
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18. Clinical outcomes of scalp or face angiosarcoma treatment with intensity-modulated radiotherapy: a multicenter study.
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Iwai T, Imagumbai T, Hiraoka S, Kishi T, Okabayashi S, Ashida R, Mitsuyoshi T, Matsuo Y, Ishigaki T, Mizowaki T, and Kokubo M
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- Humans, Scalp pathology, Retrospective Studies, Treatment Outcome, Radiotherapy Dosage, Hemangiosarcoma radiotherapy, Hemangiosarcoma pathology, Radiotherapy, Intensity-Modulated methods
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Combined modality therapy, including radiotherapy (RT), is a common treatment for scalp or face angiosarcoma. Although intensity-modulated radiotherapy (IMRT) can deliver homogeneous doses to the scalp or face, clinical data are limited. This multicenter study aimed to evaluate scalp or face angiosarcoma treated with definitive or post-operative IMRT. We retrospectively analyzed data from patients who received IMRT for scalp or face angiosarcoma at three institutions between January 2015 and March 2020. Local control (LC) rate, overall survival (OS), progression-free survival (PFS), recurrence patterns and toxicity were evaluated. Fifteen patients underwent IMRT during the study period. Definitive RT was performed on 10 patients and post-operative RT was performed on 5 patients. The 1-year LC rate was 85.7% (95% confidence interval [CI], 53.9-96.2%). The 1-year OS and PFS rates were 66.7% (95% CI, 37.5-84.6%) and 53.3% (95% CI, 26.3%-74.4%), respectively. Univariate analysis revealed that a clinical target volume over 500 cm3 was associated with poor LC. Distant metastasis was the most common recurrence pattern. All patients experienced Grade 2 or 3 radiation dermatitis, and five patients experienced grade ≥ 3 skin ulceration. One patient who underwent maintenance therapy with pazopanib developed Grade 5 skin ulceration. Fisher's exact test showed that post-operative RT was significantly associated with an increased risk of skin ulceration of grade ≥ 3. These results demonstrate that IMRT is a feasible and effective treatment for scalp or face angiosarcoma, although skin ulceration of grade ≥ 3 is a common adverse event in patients who receive post-operative RT., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)
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- 2024
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19. Transcriptome Discovery of Genes in the Three Phases of Autophagy That Are Upregulated During Atrial Fibrillation.
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Kamihara T, Hirashiki A, Kokubo M, and Shimizu A
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Background: Autophagy may contribute to the maintenance of atrial fibrillation (AF), but no previous study has concurrently surveyed all 3 phases of autophagy, namely autophagosome formation, lysosome formation, and autophagosome-lysosome fusion. Here we aimed to identify disorders involving various phases of autophagy during AF. Methods and Results: We used bioinformatic techniques to analyze publicly available DNA microarray datasets from the left atrium (LA) and right atrium (RA) of 7 patients with AF and 6 patients with normal sinus rhythm who underwent valvular surgeries. We compared gene expression levels in the LA (AF-LA) and RA of patients with AF with those in the LA and RA of patients with normal sinus rhythm. Several differentially expressed genes in the AF-LA sample were significantly associated with the Gene Ontogeny term 'Autophagy', indicating that the expression of autophagic genes was specifically altered in this dataset. In particular, the expression of genes known or suspected to be involved in autophagosome formation (autophagy related 5 [ ATG5 ], autophagy related 10 [ ATG10 ], autophagy related 12 [ ATG12 ], and light chain 3B [ LC3B ]), lysosome formation (lysosomal associated membrane protein 1 [ LAMP1 ] and lysosomal associated membrane protein 2 [ LAMP2 ]), and autophagosome-lysosome fusion (synaptosome associated protein 29 [ SNAP29 ], SNAP associated protein [ SNAPIN ], and syntaxin 17 [ STX17 ]) was significantly upregulated in the LA-AF dataset. Conclusions: Autophagy is activated excessively in, and may perpetuate, AF., Competing Interests: None of the authors has any competing interests regarding this study., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)
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- 2023
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20. Dynamic tumor-tracking stereotactic body radiotherapy with real-time monitoring of liver tumors using a gimbal-mounted linac: A multi-institutional phase II study.
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Iizuka Y, Hiraoka M, Kokubo M, Sakamoto T, Karasawa K, Murofushi K, Nakamura M, Matsuo Y, Morita S, Inokuchi H, and Mizowaki T
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Background and Purpose: This prospective multicenter phase II study aimed to evaluate the safety and efficacy of dynamic tumor tracking (DTT) stereotactic body radiotherapy (SBRT) with real-time monitoring of liver tumors using a gimbal-mounted system., Materials and Methods: Patients with < 4 primary or metastatic liver tumors with diameters ≤ 50 mm and expected to have a respiratory motion of ≥ 10 mm were eligible. The prescribed dose was 40 Gy in five fractions. The primary endpoint was local control (LC) at 2 years. The secondary endpoints were overall survival (OS), progression-free survival (PFS), treatment-related toxicity, and tracking accuracy., Results: Between September 2015 and March 2019, 48 patients (48 lesions) with a median age of 74 years were enrolled from four institutions. Of these, 39 were diagnosed with hepatocellular carcinoma and nine with metastatic liver cancer. The median tumor diameter was 17.5 mm. DTT-SBRT was successfully performed in all patients; the median treatment time was 28 min/fraction. The median follow-up period was 36.5 months. The 2-year LC, OS, and PFS rates were 98.0 %, 88.8 %, and 55.1 %, respectively. Disease progression was observed in 33 (68.8 %) patients. One patient (0.2 %) had local recurrence, 31 (64.6 %) developed new hepatic lesions outside the irradiation field, and nine (18.8 %) had distant metastases (including overlap). Grade 3 late adverse events were observed in seven patients (14.5 %). No grade 4 or 5 treatment-related toxicity was observed. The median tracking accuracy was 2.9 mm., Conclusion: Employing DTT-SBRT to treat liver tumors results in excellent LC with acceptable adverse-event incidence., Competing Interests: Masaki Kokubo is in a speaker’s bureau from AstraZeneca K.K.; Takashi Sakamoto is in a speaker’s bureau from SCETI.K.K.; Mitsuhiro Nakamura receives research funding from Varian Medical Systems, Inc. and a scholarship donation from Hitachi, Ltd.; Yukinori Matsuo receives research funding from Varian Medical Systems, Inc.; Takashi Mizowaki has received honoraria from Varian Medical Systems, Inc., Elekta K.K., Hitachi, Ltd., and Brainlab AG; played a consulting or advisory role for Varian Medical Systems, Inc. Hitachi, Ltd.; has research funding from Hitachi, Ltd. and educational projects from Varian Medical Systems and Brainlab AG. Other authors have no conflicts of interest to declare., (© 2023 The Author(s).)
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- 2023
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21. Multi-institutional phase II study of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for breast cancer in Japan: Kyoto Radiation Oncology Study Group (UPBEAT study).
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Mitsuyoshi T, Ono Y, Ashida R, Yamashita M, Tanabe H, Takebe S, Tokiwa M, Suzuki E, Imagumbai T, Yoshimura M, Yamauchi C, Mizowaki T, and Kokubo M
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- Female, Humans, Dose Fractionation, Radiation, Japan, Mastectomy, Segmental, Radiotherapy, Adjuvant adverse effects, Radiotherapy, Adjuvant methods, Breast Neoplasms radiotherapy, Breast Neoplasms surgery, Radiation Oncology
- Abstract
Purpose: The UK-FAST-Forward study showed that ultra-hypofractionated whole-breast irradiation (ultra-HF-WBI) involving five fractions of 26 Gy radiation over 1 week was not inferior to HF-WBI. However, it is not used in Japan due to safety concerns. In April 2022, we commenced a multi-institutional, single-arm, phase II trial. Our aim is to confirm the safety of ultra-HF-WBI after breast-conserving surgery (BCS) for breast cancer in Japanese women., Method: We plan to enroll 98 patients from 13 institutions. The primary endpoint is the proportion of late adverse events of grades ≥2 within 3 years., Discussion: We believe that this highly promising clinical study can positively impact the Japanese guidelines for breast cancer treatment. The results will help us decide whether or not ultra-HF-WBI can be used as a more convenient alternative to WBI., Registration Number and Date: This trial was registered in the UMIN Clinical Trials Registry (UMIN000047080) on March 4, 2022., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
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- 2023
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22. Radiotherapy for ductal carcinoma of the prostate: an analysis based on the Japanese radiation oncology study group survey.
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Kawamura H, Nakamura K, Yoshioka Y, Itasaka S, Tomita N, Onishi M, Iwata H, Aizawa T, Kikuchi K, Nagata K, Nakamura K, Nishioka K, Ishiyama H, Ueno S, Kokubo M, Yamazaki H, Watanabe K, Toyoda T, and Akimoto T
- Subjects
- Male, Humans, Prostate-Specific Antigen, Prostate pathology, Androgen Antagonists therapeutic use, East Asian People, Neoplasm Recurrence, Local drug therapy, Disease-Free Survival, Prostatic Neoplasms pathology, Radiation Oncology, Carcinoma, Ductal radiotherapy, Carcinoma, Ductal drug therapy
- Abstract
Background: The clinical characteristics of prostate ductal carcinoma is still unclear, and treatment strategy has not yet been established due to its rarity. Therefore, we conducted a multicenter survey of radiation therapy for prostate ductal carcinoma in Japan., Method: Data of patients with ductal carcinoma of the prostate treated with radiation therapy between 1996 and 2018 were extracted from the database of each facility., Results: Fifty-two treatment records of 41 patients were collected from nine institutions. The treatment purpose and situations were varied curative intent to palliation. Twenty-eight patients received curative treatments. The median follow-up period of these patients was 68 months. Androgen deprivation therapy was combined with radiation therapy in 26 cases (93%). X-ray and particle irradiation was used. Radiation dose range was 63-78 Gy; 5-year overall survival, progression-free survival and biochemical relapse-free survival were 87.0, 79.3 and 79.3%, respectively. One patient experienced Grade 3 radiation proctitis and one experienced Grade 3 radiation cystitis. There were no Grade 4 or worse adverse events., Conclusion: Most patient received similar treatment with adenocarcinoma of prostate, and the clinical results were compatible. For more reliable evidence, further studies are required., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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23. Septal E/e' Ratio Is Associated With Cerebral White Matter Hyperintensity Progression in Young-Old Hypertensive Patients.
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Nomoto K, Hirashiki A, Ogama N, Kamihara T, Kokubo M, Sugimoto T, Sakurai T, Shimizu A, Arai H, and Murohara T
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Background: The incidence of hypertension increases with age, as does that of brain abnormalities associated with cerebral pathologic and functional degeneration. Little is known about the relationship between hypertension-related cardiac changes and cerebral pathologic degeneration. We examined the relationship between left ventricular (LV) diastolic dysfunction and cerebral white matter hyperintensity (WMH) progression in young-old hypertensive patients. Methods and Results: This single-center prospective longitudinal observational study included 156 individuals aged 65-75 years with well-controlled hypertension, normal LV contraction, and no history of symptomatic heart failure. WMH was quantified on brain magnetic resonance imaging (MRI). The primary outcome was the rate of WMH volume progression between the baseline and follow-up MRI (∆WMH). Participants were classified into tertiles on the basis of ∆WMH (small, medium, and large ∆WMH). The mean (±SD) age at recruitment was 69.6±2.8 years, and the mean follow-up period was 4.6 years. The ratio of early diastolic mitral inflow velocity to early diastolic septal mitral annulus velocity (septal E/e') was significantly higher in the large ∆WMH group than in the small and medium ∆WMH groups. On multiple regression analysis, septal E/e' was significantly positively associated with square-root-transformed ∆WMH (β=0.457, P<0.001). Conclusions: Septal E/e' was significantly positively associated with the rate of progression of WMH volume, suggesting that LV diastolic dysfunction is associated with the progression of abnormal brain aging., Competing Interests: T.M. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)
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- 2023
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24. Long-term depression-inductive stimulation causes long-term potentiation in mouse Purkinje cells with a mutant thyroid hormone receptor.
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Ninomiya A, Amano I, Kokubo M, Takatsuru Y, Ishii S, Hirai H, Hosoi N, and Koibuchi N
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- Mice, Animals, Long-Term Potentiation physiology, Long-Term Synaptic Depression physiology, Calcium metabolism, Receptors, Thyroid Hormone metabolism, Depression, Synapses metabolism, Cerebellum physiology, Purkinje Cells metabolism, Congenital Hypothyroidism metabolism
- Abstract
Thyroid hormones (THs) regulate gene expression by binding to nuclear TH receptors (TRs) in the cell. THs are indispensable for brain development. However, we have little knowledge about how congenital hypothyroidism in neurons affects functions of the central nervous system in adulthood. Here, we report specific TH effects on functional development of the cerebellum by using transgenic mice overexpressing a dominant-negative TR (Mf-1) specifically in cerebellar Purkinje cells (PCs). Adult Mf-1 mice displayed impairments in motor coordination and motor learning. Surprisingly, long-term depression (LTD)-inductive stimulation caused long-term potentiation (LTP) at parallel fiber (PF)-PC synapses in adult Mf-1 mice, although there was no abnormality in morphology or basal properties of PF-PC synapses. The LTP phenotype was turned to LTD in Mf-1 mice when the inductive stimulation was applied in an extracellular high-Ca
2+ condition. Confocal calcium imaging revealed that dendritic Ca2+ elevation evoked by LTD-inductive stimulation is significantly reduced in Mf-1 PCs but not by PC depolarization only. Single PC messenger RNA quantitative analysis showed reduced expression of SERCA2 and IP3 receptor type 1 in Mf-1 PCs, which are essential for mGluR1-mediated internal calcium release from endoplasmic reticulum in cerebellar PCs. These abnormal changes were not observed in adult-onset PC-specific TH deficiency mice created by adeno-associated virus vectors. Thus, we propose the importance of TH action during neural development in establishing proper cerebellar function in adulthood, independent of its morphology. The present study gives insight into the cellular and molecular mechanisms underlying congenital hypothyroidism-induced dysfunctions of central nervous system and cerebellum.- Published
- 2022
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25. Life-Space Activities Are Associated with the Prognosis of Older Adults with Cardiovascular Disease.
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Hashimoto K, Hirashiki A, Oya K, Sugioka J, Tanioku S, Sato K, Ueda I, Itoh N, Kokubo M, Shimizu A, Kagaya H, and Kondo I
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Life-space activities are a measure of daily activity level. Here, we examined the association between life-space activities and prognosis in 129 cardiovascular diseases (CVD) patients 65 years of age or older (average age, 79.2 ± 7.6 years; mean left ventricular ejection fraction, 56.7 ± 13.2%) who had been admitted to our hospital for worsening CVD. Subjects were followed, and the primary endpoints were cardiovascular hospitalization and cardiovascular death. Receiver operating characteristic analysis produced a cutoff value for life-space assessment (LSA) score for increased risk of cardiovascular hospitalization for two years of 53.0 points (sensitivity, 55.9%; specificity, 82.1%). Kaplan−Meier analysis using this cutoff value revealed that the rates of cardiovascular hospitalization and cardiovascular death were significantly higher in subjects with an LSA score below the cutoff than in those with a score above the cutoff (both p < 0.001). Cox proportional analysis revealed that low LSA score was independently associated with cardiovascular hospitalization (HR, 2.540; 95% CI, 1.135−5.680; p = 0.023) and cardiovascular death (HR, 15.223; 95% CI, 1.689−137.180; p = 0.015), even after adjusting for age, sex, left ventricular ejection fraction, and log-transformed brain natriuretic peptide level. Thus, life-space activities are associated with prognosis in older adults with CVD.
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- 2022
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26. Perianal Bowen's disease treated with radiotherapy preserving anal function with a unique skin reaction considered as 'tumoritis'.
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Iwai T, Imagumbai T, Okabayashi S, Ashida R, Mitsuyoshi T, Tai Y, Matsumoto T, Yamashita D, Nagano T, and Kokubo M
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Bowen's disease (BD) is a form of intraepidermal squamous cell carcinoma (SCC), and it occasionally occurs on the perianal site. BD is often treated with surgical excision; however, sometimes surgical excision for perianal BD cannot preserve anal function. We report the case of a 72-year-old man presenting with perianal pain and BD. He was treated with Radiotherapy (RT) and preserved his normal anal sphincter function without any recurrence or late adverse event. Moreover, we observed the unique skin reaction called 'tumoritis', which is characterized by mucosal inflammation. Tumoritis indicates the true extent of the tumor and evaluating the tumor or lesion size based on the extent of tumoritis when performing RT is important., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
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- 2022
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27. Benefits of a Balance Exercise Assist Robot in the Cardiac Rehabilitation of Older Adults with Cardiovascular Disease: A Preliminary Study.
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Hashimoto K, Hirashiki A, Ozaki K, Kawamura K, Sugioka J, Tanioku S, Sato K, Ueda I, Itoh N, Nomoto K, Kokubo M, Shimizu A, and Kondo I
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We examined whether adding robot-supported balance exercises to cardiac rehabilitation improves the ability to balance in older adults with cardiovascular disease (CVD). We conducted a prospective study in 52 older adults who had been hospitalized for worsening CVD. Once weekly for four months, for a total of sixteen sessions as outpatients, the subjects used a Balance Exercise Assist Robot (BEAR) to perform balance exercises and an ergometer for aerobic exercises. Participants’ mean age was 76.9 ± 6.8 years (range, 65−95 years), and their mean brain natriuretic protein level was 164.0 ± 190.0 pg/mL. After the intervention, participants showed significant improvements in gait speed (before, 1.06 ± 0.33 m/s; after, 1.23 ± 0.30 m/s; p < 0.001), Short Physical Performance Battery score (before, 10.02 ± 2.25; after, 10.88 ± 1.79; p ˂ 0.001), timed up-and-go (before, 11.11 ± 5.07 s; after, 9.45 ± 3.45 s; p ˂ 0.001), and knee extension (before, 26.97 ± 11.78 kgf; after, 30.13 ± 13.04 kgf; p = 0.001). Cardiac rehabilitation including exercises using BEAR improved physical functioning and the ability to balance in older adults with CVD. Frail and prefrail patients improved, whereas robust ones did not change.
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- 2022
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28. Systematic Review of the Effectiveness of Community Intervention and Health Promotion Programs for the Prevention of Non-Communicable Diseases in Japan and Other East and Southeast Asian Countries.
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Hirashiki A, Shimizu A, Nomoto K, Kokubo M, Suzuki N, and Arai H
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Background: Non-communicable diseases (NCDs) are the leading cause of death worldwide. However, current evidence regarding the efficacy and cost-effectiveness of community intervention and health promotion programs for NCDs, specifically hypertension, obesity, diabetes, and dyslipidemia, in East and Southeast Asia has not yet been systematically reviewed. We systematically reviewed the literature from East and Southeast Asian countries to answer 2 clinical questions: (1) do health promotion programs for hypertension, obesity, diabetes, and dyslipidemia reduce cardiovascular events and mortality; and (2) are these programs cost-effective? Methods and Results: Electronic literature searches were performed across Medline, Cochrane Library, and Ichushi using key words and relevant subject headings related to randomized controlled trials, comparative studies, quasi-experimental studies, or propensity score matching that met eligibility criteria that were defined for each question. In all, 3,389 records were identified, of which 12 full-text articles were reviewed. Three papers were from Japan, 7 were from China/Hong Kong Special Administrative Region, and 2 were from South Korea. None were from Southeast Asia. Four papers examined the effect of community intervention or health promotion on the incidence of cardiovascular events or mortality. Eight studies examined the cost-effectiveness of interventions. Conclusions: The literature review revealed that community intervention and health promotion programs for the control of NCDs are a cost-effective means of reducing cardiovascular events and mortality in East Asian countries., Competing Interests: The Department of Geriatric Medicine, National Center for Geriatrics and Gerontology receives research promotion grants. The authors declare that they have no conflicts of interest., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)
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- 2022
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29. Development of AI-driven prediction models to realize real-time tumor tracking during radiotherapy.
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Zhou D, Nakamura M, Mukumoto N, Tanabe H, Iizuka Y, Yoshimura M, Kokubo M, Matsuo Y, and Mizowaki T
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- Computer Simulation, Computer Systems, Forecasting, Humans, Artificial Intelligence, Liver Neoplasms radiotherapy, Lung Neoplasms radiotherapy, Neural Networks, Computer, Pancreatic Neoplasms radiotherapy
- Abstract
Background: In infrared reflective (IR) marker-based hybrid real-time tumor tracking (RTTT), the internal target position is predicted with the positions of IR markers attached on the patient's body surface using a prediction model. In this work, we developed two artificial intelligence (AI)-driven prediction models to improve RTTT radiotherapy, namely, a convolutional neural network (CNN) and an adaptive neuro-fuzzy inference system (ANFIS) model. The models aim to improve the accuracy in predicting three-dimensional tumor motion., Methods: From patients whose respiration-induced motion of the tumor, indicated by the fiducial markers, exceeded 8 mm, 1079 logfiles of IR marker-based hybrid RTTT (IR Tracking) with the gimbal-head radiotherapy system were acquired and randomly divided into two datasets. All the included patients were breathing freely with more than four external IR markers. The historical dataset for the CNN model contained 1003 logfiles, while the remaining 76 logfiles complemented the evaluation dataset. The logfiles recorded the external IR marker positions at a frequency of 60 Hz and fiducial markers as surrogates for the detected target positions every 80-640 ms for 20-40 s. For each logfile in the evaluation dataset, the prediction models were trained based on the data in the first three quarters of the recording period. In the last quarter, the performance of the patient-specific prediction models was tested and evaluated. The overall performance of the AI-driven prediction models was ranked by the percentage of predicted target position within 2 mm of the detected target position. Moreover, the performance of the AI-driven models was compared to a regression prediction model currently implemented in gimbal-head radiotherapy systems., Results: The percentage of the predicted target position within 2 mm of the detected target position was 95.1%, 92.6% and 85.6% for the CNN, ANFIS, and regression model, respectively. In the evaluation dataset, the CNN, ANFIS, and regression model performed best in 43, 28 and 5 logfiles, respectively., Conclusions: The proposed AI-driven prediction models outperformed the regression prediction model, and the overall performance of the CNN model was slightly better than that of the ANFIS model on the evaluation dataset., (© 2022. The Author(s).)
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- 2022
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30. Composite Biomarkers for Assessing Frailty Status in Stable Older Adults With Cardiovascular Disease.
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Hirashiki A, Shimizu A, Suzuki N, Nomoto K, Kokubo M, Hashimoto K, Sato K, Kondo I, Murohara T, and Arai H
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Background: The relationship between frailty status and laboratory measurements in cardiovascular disease (CVD) remains unclear. We investigated which laboratory measurements indicated frailty in stable older CVD patients. Methods and Results: One-hundred thirty-eight stable older CVD patients were evaluated by laboratory measurements, with frailty assessed using the Kihon Checklist (KCL). Laboratory measurements were compared between frail and non-frail groups. Across the entire cohort, mean age was 81.7 years, mean left ventricular ejection fraction was 57.8%, and mean plasma B-type natriuretic peptide was 182 pg/mL. KCL scores were used to divide patients into non-frail (n=43; KCL <8) and frail (n=95; KCL ≥8) groups. Serum iron was significantly lower in the frail than non-frail group (mean [±SD] 61.2±30.3 vs. 89.5±26.1 μg/dL, respectively; P<0.001). Blood urea nitrogen (BUN; 27.3±16.5 vs. 19.7±8.2 mg/dL; P=0.013) and C-reactive protein (CRP; 1.05±1.99 vs. 0.15±0.21 mg/dL; P=0.004) were significantly higher in the frail than non-frail group. Multivariate analysis revealed that serum iron, CRP, and BUN were significant independent predictors of frailty (β=-0.069, 0.917, and 0.086, respectively). Conclusions: Frailty status was significantly associated with iron, CRP, and BUN in stable older CVD patients. Composite biomarkers (inflammation, iron deficiency, and renal perfusion) may be useful for assessing frailty in these patients., Competing Interests: T.M. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022, THE JAPANESE CIRCULATION SOCIETY.)
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- 2022
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31. The neurotoxic effect of lactational PFOS exposure on cerebellar functional development in male mice.
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Ninomiya A, Mshaty A, Haijima A, Yajima H, Kokubo M, Khairinisa MA, Ariyani W, Fujiwara Y, Ishii S, Hosoi N, Hirai H, Amano I, and Koibuchi N
- Subjects
- Animals, Anxiety, Behavior, Animal drug effects, Cerebellum growth & development, Cerebellum physiopathology, Female, Lactation, Male, Mice, Psychomotor Performance drug effects, Alkanesulfonic Acids toxicity, Cerebellum drug effects, Dietary Exposure, Fluorocarbons toxicity, Maternal Exposure, Neurotoxins toxicity
- Abstract
Recent studies showed a possible association between perfluorooctane sulfonate (PFOS) and developmental disabilities. We previously found the specific effects of PFOS exposure on learning and memory, however, its effect on the other developmental disabilities such as motor and social deficits remains unclear. We examined the effect of early lactational PFOS exposure on motor coordination, social activity, and anxiety in male mice. We orally administered a PFOS solution to dams from postnatal day 1-14. At 10 weeks old, we conducted a behavior test battery to evaluate motor performance, social activity, and anxiety, followed by electrophysiology and Western blot analysis. PFOS-exposed mice displayed impaired motor coordination. Whole-cell patch-clamp recordings from Purkinje cells revealed that the short-term and long-term plasticity at parallel fiber-Purkinje cell synapses are affected by PFOS exposure. Western blot analysis indicated that PFOS exposure increased syntaxin binding protein 1 (Munc18-1) and glutamate metabotropic receptor 1 (mGluR1) protein levels, which may be associated with the change in neurotransmitter release from parallel fibers and the level of long-term depression, respectively. The present study demonstrates that lactational PFOS exposure may have disrupted the pre- and postsynaptic plasticity at parallel fiber-Purkinje cell synapses, causing profound, long-lasting abnormal effects on the cerebellar function., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2022
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32. Exercise Capacity and Frailty Are Associated with Cerebral White Matter Hyperintensity in Older Adults with Cardiovascular Disease.
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Hirashiki A, Shimizu A, Suzuki N, Nomoto K, Kokubo M, Sugimoto T, Hashimoto K, Sato K, Sakurai T, Murohara T, Washimi Y, and Arai H
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- Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases diagnosis, Exercise Test, Female, Frailty diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Organ Size, White Matter diagnostic imaging, Cardiovascular Diseases complications, Cardiovascular Diseases physiopathology, Exercise Tolerance physiology, Frailty complications, Frailty physiopathology, White Matter pathology
- Abstract
Cerebral white matter hyperintensity (WMH) is highly prevalent among older adults. There is little information about the relationship among WMH extent, frailty status, and exercise capacity in older adults with cardiovascular disease (CVD). We assessed the association of WMH with frailty and exercise capacity in CVD patients.Seventy-eight stable older adults with CVD were evaluated for WMH, the Kihon Checklist (KCL), short physical performance battery score (SPPB), and cardiopulmonary exercise testing. WMH volume was quantified on brain magnetic resonance imaging. Patients were classified into 3 groups (using tertiles of 0.52% and 1.05%) according to WMH as a percentage of intracranial volume (ICV), and their KCL scores and exercise capacities were compared. The 3 WMH/ICV groups were mild (n = 26, 0.26% ± 0.14% of intracranial volume), moderate (n = 26, 0.70% ± 0.15%), and severe (n = 26, 1.75% ± 0.67%). Peak VO
2 was 15.2 ± 3.7 mL kg-1 minute-1 (mild group), 12.9 ± 3.5 mL kg-1 min-1 (moderate), and 11.4 ± 2.3 mL kg-1 minute-1 (severe) (mild versus moderate, P = 0.049; mild versus severe, P = 0.001). Multivariate regression analysis showed significant associations of severe WMH/ICV with peak VO2 and SPPB. Cerebral WMH was strongly negatively associated with SPPB and peak VO2 . WMH volume may be related to exercise capacity and frailty in stable older adult patients with CVD.- Published
- 2022
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33. Impact of pre-treatment C-reactive protein level and skeletal muscle mass on outcomes after stereotactic body radiotherapy for T1N0M0 non-small cell lung cancer: a supplementary analysis of the Japan Clinical Oncology Group study JCOG0403.
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Matsuo Y, Nagata Y, Wakabayashi M, Ishikura S, Onishi H, Kokubo M, Karasawa K, Shioyama Y, Onimaru R, and Hiraoka M
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- Aged, Aged, 80 and over, Biomarkers, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung surgery, Clinical Trials, Phase II as Topic statistics & numerical data, Combined Modality Therapy, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms blood, Lung Neoplasms pathology, Lung Neoplasms surgery, Male, Middle Aged, Multicenter Studies as Topic statistics & numerical data, Muscle, Skeletal diagnostic imaging, Organ Size, Pneumonectomy, Radiosurgery methods, Retrospective Studies, Sarcopenia diagnostic imaging, Sarcopenia etiology, Sarcopenia pathology, Survival Rate, Tomography, X-Ray Computed, Treatment Outcome, C-Reactive Protein analysis, Carcinoma, Non-Small-Cell Lung radiotherapy, Lung Neoplasms radiotherapy, Muscle, Skeletal pathology
- Abstract
This study aimed to evaluate the impact of pretreatment C-reactive protein (CRP) and skeletal muscle mass (SMM) on outcomes after stereotactic body radiotherapy (SBRT) for T1N0M0 non-small cell lung cancer (NSCLC) as a supplementary analysis of JCOG0403. Patients were divided into high and low CRP groups with a threshold value of 0.3 mg/dL. The paraspinous musculature area at the level of the 12th thoracic vertebra was measured on simulation computed tomography (CT). When the area was lower than the sex-specific median, the patient was classified into the low SMM group. Toxicities, overall survival (OS) and cumulative incidence of cause-specific death were compared between the groups. Sixty operable and 92 inoperable patients were included. In the operable cohort, OS significantly differed between the CRP groups (log-rank test p = 0.009; 58.8% and 83.6% at three years for high and low CRP, respectively). This difference in OS was mainly attributed to the difference in lung cancer deaths (Gray's test p = 0.070; 29.4% and 7.1% at three years, respectively). No impact of SMM on OS was observed. The incidence of Grade 3-4 toxicities tended to be higher in the low SMM group (16.7% vs 0%, Fisher's exact test p = 0.052). In the inoperable cohort, no significant impact on OS was observed for either CRP or SMM. The toxicity incidence was also not different between the CRP and SMM groups. The present study suggests that pretreatment CRP level may provide prognostic information in operable patients receiving SBRT for early-stage NSCLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)
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- 2021
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34. Bio-artificial pleura using autologous dermal fibroblast sheets to mitigate air leaks during thoracoscopic lung resection.
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Kanzaki M, Takagi R, Washio K, Kokubo M, Mitsuboshi S, Isaka T, and Yamato M
- Abstract
Lung air leaks (LALs) due to visceral pleura injury during surgery are a difficult-to-avoid complication in thoracic surgery (TS). Reliable LAL closure is an important patient management issue after TS. We demonstrated both safeties of transplantation of a cultured human autologous dermal fibroblast sheet (DFS) to LALs. From May 2016 to March 2018, five patients who underwent thoracoscopic lung resection met all the inclusion criteria. Skin biopsies were acquired from each patient to source autologous dermal cells for DFS fabrication. During the primary culture, fibroblasts migrated from the dermal tissue pieces and proliferated to form cell monolayers. These fibroblasts were subcultured to confluence. Transplantable DFSs were fabricated from these subcultured fibroblasts that were trypsinized and seeded onto temperature-responsive culture dishes. After 10 days of fabrication culture, intact patient-specific DFS were harvested. DFSs were analyzed for fibroblast cell content and tissue contaminants prior to application. For closing intraoperative LAL, mean number of transplanted autologous DFS per patient was 6 ± 2 sheets. Mean chest drainage duration was 5.0 ± 4.8 days. The two patients with major LAL had a drainage duration of more than 7 days. All patients currently have no LAL recurrence after discharge. DFSs effectively maintain LAL closure via remodeling of the deposited extracellular matrix. The use of autologous DFSs to permanently close air leaks using a patient-derived source is expected to reduce surgical complications during high-risk lung resections.
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- 2021
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35. Neurotoxic effects of lactational exposure to perfluorooctane sulfonate on learning and memory in adult male mouse.
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Mshaty A, Haijima A, Takatsuru Y, Ninomiya A, Yajima H, Kokubo M, Khairinisa MA, Miyazaki W, Amano I, and Koibuchi N
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- Animals, Female, Glutamic Acid metabolism, Hippocampus drug effects, Hippocampus metabolism, Humans, Lactation, Learning drug effects, Male, Memory drug effects, Mice, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects etiology, Prenatal Exposure Delayed Effects genetics, Prenatal Exposure Delayed Effects metabolism, gamma-Aminobutyric Acid metabolism, Alkanesulfonic Acids toxicity, Fluorocarbons toxicity, Maternal Exposure adverse effects, Neurotoxins toxicity, Prenatal Exposure Delayed Effects psychology
- Abstract
The present study aims to examine the effect of early lactational perfluorooctane sulfonate (PFOS) exposures on learning and memory in male mice and reveal the underlying mechanisms involved. PFOS solution was orally administered to dams from the postpartum days 1-14, so that pups would be exposed through breast milk. At 8-10 weeks of age, we performed object location test (OLT), object recognition test (ORT), and pairwise visual discrimination (VD) task. We also performed in vivo microdialysis, and mRNA and protein analysis of genes responsible for hippocampal development and function. In both OLT and ORT, the performance of mice in the PFOS-exposed group was significantly lower than those in the control group. In the VD task, the PFOS-exposed group learned significantly slower than the control group. Concentrations of glutamate and gamma-aminobutyric acid in the dorsal hippocampus were significantly higher in the PFOS-exposed group than in the control group. No notable differences were shown in our mRNA and protein studies. The present study showed that lactational PFOS exposure has a profound, long-lasting neurotoxic effect in the hippocampus and consequently leads to learning and memory deficits., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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36. Difficulty in distinguishing radiation-induced prostate sarcoma from radiation mucositis in a patient with persistent urinary retention and hematuria after prostate cancer radiotherapy.
- Author
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Hiraoka S, Imagumbai T, Kosaka Y, Ogura K, Hattori T, Ogata T, Yamashita D, Kawakita M, and Kokubo M
- Abstract
Urinary retention and hematuria owing to radiation-induced mucositis are occasional late adverse events in patients with prostate cancer. Moreover, radiation-induced secondary malignancies are late adverse events, although they are extremely rare. Herein, we describe a case of radiation-induced secondary malignancy of the prostate that was initially difficult to distinguish from radiation mucositis. A 74-year-old man with prostate cancer underwent brachytherapy and external beam radiotherapy 9 years ago. Twenty-eight months after irradiation, he presented with urinary retention and hematuria owing to radiation mucositis and underwent transurethral resection of the prostate. At 89 months after irradiation, the patient again showed urinary retention and hematuria. The cause of urinary retention and hematuria could not be identified on cystoscopy. Despite receiving medications, the patient's symptoms did not improve. Therefore, transurethral fulguration was performed, and prostate biopsy revealed spindle cell sarcoma. A diagnosis of radiation-induced undifferentiated pleomorphic/spindle cell sarcoma was made, and the patient underwent total cystectomy and construction of the ileal conduit. Two weeks after the surgery, computed tomography revealed peritoneal dissemination. The patient died 5 weeks after the surgery. The case findings indicate that clinicians should consider the possibility of radiation-induced secondary malignancy; moreover, thorough pathological examination of the prostate with CT and MRI is important to distinguish RISM from radiation mucositis even if no tumors are found on cystoscopy., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Japan Society of Clinical Oncology 2020.)
- Published
- 2020
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37. Peak Work Rate during Exercise Could Detect Frailty Status in Elderly Patients with Stable Heart Failure.
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Kawashima K, Hirashiki A, Nomoto K, Kokubo M, Shimizu A, Sakurai T, Kondo I, Washimi Y, Arai H, Toba K, and Murohara T
- Subjects
- Aged, Aged, 80 and over, Blood Pressure physiology, Checklist, Exercise Test, Female, Frailty complications, Heart Failure complications, Humans, Male, Oxygen Consumption physiology, Predictive Value of Tests, Exercise physiology, Exercise Tolerance physiology, Frailty diagnosis, Frailty physiopathology, Heart Failure physiopathology
- Abstract
The Kihon Checklist (KCL) is a reliable tool for determining frailty status in the elderly. However, there is no information in the literature about the relationship between frailty status and exercise capacity. Here, we examined the associations between cardiopulmonary exercise testing parameters and frailty status in elderly patients with stable heart failure (HF).Ninety-two elderly patients with stable HF were evaluated using cardiopulmonary exercise testing and the KCL. A KCL score of 0-3 was classified as robust, 4-7 as pre-frail, and ≥ 8 as frail.Mean age, peak VO
2 , and KCL score were 81.7 years, 13.2 mL/kg/minute, and 10.7, respectively. KCL score was significantly correlated with peak VO2 (r = -0.527, P < 0.001) and peak work rate (r = -0.632, P < 0.001). In patients with frailty (n = 63), the peak work rate (WR) was significantly lower than it was in patients without frailty (n = 29; 39.9 versus 69.5 W, respectively; P < 0.001). Multivariate analysis revealed that peak WR and peak systolic blood pressure were significant, independent predictors of frailty (β = -0.108 and -0.045, respectively). In a diagnostic performance plot analysis, a cutoff value for peak WR of 51.9 W was the best predictor of frailty.Frailty status was significantly associated with peak WR and peak systolic blood pressure in elderly patients with stable HF. Therefore, cardiopulmonary exercise testing may be useful for assessing frailty status in this patient population.- Published
- 2019
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38. Association of Glucose Fluctuations with Sarcopenia in Older Adults with Type 2 Diabetes Mellitus.
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Ogama N, Sakurai T, Kawashima S, Tanikawa T, Tokuda H, Satake S, Miura H, Shimizu A, Kokubo M, Niida S, Toba K, Umegaki H, and Kuzuya M
- Abstract
Type 2 diabetes mellitus accelerates loss of muscle mass and strength. Patients with Alzheimer's disease (AD) also show these conditions, even in the early stages of AD. The mechanism linking glucose management with these muscle changes has not been elucidated but has implications for clarifying these associations and developing preventive strategies to maintain functional capacity. This study included 69 type 2 diabetes patients with a diagnosis of cognitive impairment ( n = 32) and patients with normal cognition ( n = 37). We investigated the prevalence of sarcopenia in diabetes patients with and without cognitive impairment and examined the association of glucose alterations with sarcopenia. Daily glucose levels were evaluated using self-monitoring of blood glucose, and we focused on the effects of glucose fluctuations, postprandial hyperglycemia, and the frequency of hypoglycemia on sarcopenia. Diabetes patients with cognitive impairment displayed a high prevalence of sarcopenia, and glucose fluctuations were independently associated with sarcopenia, even after adjusting for glycated hemoglobin A1c (HbA1c) levels and associated factors. In particular, glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed. Our observation suggests the importance of glucose management by considering glucose fluctuations to prevent the development of disability.
- Published
- 2019
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39. Label-free classification of neurons and glia in neural stem cell cultures using a hyperspectral imaging microscopy combined with machine learning.
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Ogi H, Moriwaki S, Kokubo M, Hikida Y, and Itoh K
- Subjects
- Algorithms, Humans, Image Processing, Computer-Assisted, Neuroglia cytology, Spectrum Analysis, Raman, Machine Learning, Neural Stem Cells cytology
- Abstract
Due to a growing demand for a viable label-free observation method in the biomedical field, many techniques, such as quantitative phase imaging and Raman spectroscopy, have been studied, and a complementary approach, hyperspectral imaging, has also been introduced. We developed a high-speed hyperspectral imaging microscopy imaging method with commercially available apparatus, employing a liquid crystal tunable bandpass filter combined with a pixel-wise machine learning classification. Next, we evaluated the feasibility of the application of this method for stem cell research utilizing neural stem cells. Employing this microscopy method, with a 562 × 562 μm
2 field of view, 2048 × 2048 pixel resolution images containing 63 wavelength pixel-wise spectra could be obtained in 30 seconds. The neural stem cells were differentiated into neurons and astroglia (glia), and a four-class cell classification evaluation (including neuronal cell body, glial cell body, process and extracellular region) was conducted under co-cultured conditions. As a result, an average of 88% of the objects of interest were correctly classified, with an average precision of 94%, and more than 99% of the extracellular pixels were correctly segregated. These results indicated that the proposed hyperspectral imaging microscopy is feasible as a label-free observation method for stem cell research.- Published
- 2019
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40. Final report of survival and late toxicities in the Phase I study of stereotactic body radiation therapy for peripheral T2N0M0 non-small cell lung cancer (JCOG0702).
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Onimaru R, Onishi H, Ogawa G, Hiraoka M, Ishikura S, Karasawa K, Matsuo Y, Kokubo M, Shioyama Y, Matsushita H, Ito Y, and Shirato H
- Subjects
- Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung complications, Carcinoma, Non-Small-Cell Lung mortality, Female, Humans, Lung Neoplasms complications, Lung Neoplasms mortality, Male, Survival Analysis, Carcinoma, Non-Small-Cell Lung radiotherapy, Lung Neoplasms radiotherapy, Radiosurgery methods
- Abstract
Purpose: A dose escalation study to determine the recommended dose with stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinomas (JCOG0702) was conducted. The purpose of this paper is to report the survival and the late toxicities of JCOG0702., Materials and Methods: The continual reassessment method was used to determine the dose level that patients should be assigned to and to estimate the maximum tolerated dose. The starting dose was 40 Gy in four fractions at D95 of PTV., Results: Twenty-eight patients were enrolled. Ten patients were treated with 40 Gy at D95 of PTV, four patients with 45 Gy, eight patients with 50 Gy, one patient with 55 Gy and five patients with 60 Gy. Ten patients were alive at the last follow-up. Overall survival (OS) for all patients was 67.9% (95% CI 47.3-81.8%) at 3 years and 40.8% (95% CI 22.4-58.5%) at 5 years. No Grade 3 or higher toxicity was observed after 181 days from the beginning of the SBRT. Compared to the toxicities up to 180 days, chest wall related toxicities were more frequent after 181 days., Conclusions: The 5-year OS of 40.8% indicates the possibility that SBRT for peripheral T2N0M0 non-small cell lung cancer is superior to conventional radiotherapy. The effect of the SBRT dose escalation on OS is unclear and further studies are warranted.
- Published
- 2018
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41. New Method of Flush Saphenofemoral Ligation that is Expected to Inhibit Varicose Vein Recurrence in the Groin: Flush Ligation Using the Avulsion Technique Method.
- Author
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Kokubo M, Nozaka T, and Takahashi Y
- Abstract
Recently, with the spread of laser ablation therapy, it has been called into question whether flush ligation of the great saphenous vein (GSV) reduces varicose vein recurrence after surgery. Because we thought such recurrence was caused by a narrow branch resection area, we developed a new method of flush ligation (the avulsion technique method)., Materials and Methods: A total of 214 limbs in 180 patients whose GSV had become varicose were studied. In our procedure, we dissect the GSV, lift its proximal stump, and expose the tributaries. We pull out the distal side of the tributaries without ligature as far as possible. We evaluate the area of subcutaneous ecchymosis within a 15-cm radius of the inguinal incision visually on the third post-operative day., Results: We were able to pull out over 10 cm per branch by this method. The area of subcutaneous ecchymosis was mostly less than 10%. No hematoma or pain was observed after the operation., Conclusion: This method was safe, with subcutaneous ecchymosis occurring only rarely. We expect this method to reduce saphenofemoral junction recurrence after the operation. (This is a translation of Jpn J Phlebol 2017; 28: 11-16.).
- Published
- 2018
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42. Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus.
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Ogama N, Sakurai T, Kawashima S, Tanikawa T, Tokuda H, Satake S, Miura H, Shimizu A, Kokubo M, Niida S, Toba K, Umegaki H, and Kuzuya M
- Abstract
Type 2 diabetes mellitus is associated with neurodegeneration and cerebrovascular disease. However, the precise mechanism underlying the effects of glucose management on brain abnormalities is not fully understood. The differential impacts of glucose alteration on brain changes in patients with and without cognitive impairment are also unclear. This cross-sectional study included 57 older type 2 diabetes patients with a diagnosis of Alzheimer's disease (AD) or normal cognition (NC). We examined the effects of hypoglycemia, postprandial hyperglycemia and glucose fluctuations on regional white matter hyperintensity (WMH) and brain atrophy among these patients. In a multiple regression analysis, postprandial hyperglycemia was independently associated with frontal WMH in the AD patients. In addition, postprandial hyperglycemia was significantly associated with brain atrophy, regardless of the presence of cognitive decline. Altogether, our findings indicate that postprandial hyperglycemia is associated with WMH in AD patients but not NC patients, which suggests that AD patients are more susceptible to postprandial hyperglycemia associated with WMH.
- Published
- 2018
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43. Early-life stress induces motor coordination dysfunction in adult mice.
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Kokubo M, Toya S, Amano I, and Takatsuru Y
- Subjects
- Aging, Animals, Male, Maternal Deprivation, Mice, Mice, Inbred C57BL, Microdialysis, Receptors, AMPA genetics, Receptors, AMPA metabolism, Psychomotor Performance, Stress, Psychological physiopathology
- Abstract
Although child abuse has become a serious social problem in most countries, the neural mechanisms by which it induces adulthood mental disorders is not yet fully understood. Mice exposed to early-life stresses, such as maternal deprivation (MD) during lactation, are a good model for studying the effects of neglect of humans in early life. Early-life stress induces structural/functional changes of neurons in the hippocampus, prefrontal cortex, and amygdala, and causes mental disorders in adulthood. In this study, we found motor coordination dysfunction in male MD mice. We also found that the expression levels of the aminomethylphosphonic acid receptor subunits GluA1 and GluA3 were high in the cerebellum of male MD mice. The basal activity of the cerebellum detected by field-potential analysis was higher in male MD mice than in male control mice. Caloric stimulation increased the activity of the cerebellum of control mice, but it did not significantly increase the activity of the cerebellum in male MD mice. We concluded that early-life stress induced a functional change in the cerebellum of MD mice and that this change induced motor coordination dysfunctions.
- Published
- 2018
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44. In Utero and Postnatal Propylthiouracil-Induced Mild Hypothyroidism Impairs Maternal Behavior in Mice.
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Khairinisa MA, Takatsuru Y, Amano I, Kokubo M, Haijima A, Miyazaki W, and Koibuchi N
- Abstract
Thyroid hormones (THs) play crucial roles in general and brain development. Even if the hypothyroidism is mild, it may alter brain function, resulting in irreversible behavioral alterations. Although various behavioral analyses have been conducted, the effects of propylthiouracil (PTU) treatment during in utero and postnatal periods on maternal behavior have not yet been studied. The present study examined in mice whether THs insufficiency during development induce behavioral changes. Pregnant C57BL/6j mice were divided into three groups, and each group was administered different dosages of PTU (0, 5, or 50 ppm) in drinking water during in utero and postnatal periods (from gestational day 14 to postnatal day 21). First, locomotor activity and cognitive function were assessed in the offspring at 10 weeks. Next, female offspring were mated with normal mice and they and their offspring were used to assess several aspects of maternal behavior (identifying first pup, returning all pups to nest, time spent nursing, and licking pups). As expected, locomotor and cognitive functions in these mice were disrupted in a PTU dose-dependent manner. On postpartum day 2, dams who had been exposed 50 ppm PTU during in utero and postnatal periods displayed a significantly longer time identifying the first pup and returning all three pups back to the nest, less time nursing, and decreased licking behavior. The decrease in maternal behavior was significantly correlated with a decrease in cognition. These results indicate that insufficiency of THs during in utero and postnatal periods impairs maternal behavior, which may be partly induced by impaired cognitive function.
- Published
- 2018
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45. Effects of Mild Perinatal Hypothyroidism on Cognitive Function of Adult Male Offspring.
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Amano I, Takatsuru Y, Khairinisa MA, Kokubo M, Haijima A, and Koibuchi N
- Subjects
- Animals, Animals, Newborn, Disease Models, Animal, Hippocampus metabolism, Hypothyroidism chemically induced, Hypothyroidism metabolism, Male, Mice, Propylthiouracil, Rats, Synapses metabolism, Cognition physiology, Hypothyroidism psychology
- Abstract
Mild perinatal hypothyroidism may result from inadequate iodine intake, insufficient treatment of congenital hypothyroidism, or exposure to endocrine-disrupting chemicals. Because thyroid hormones are critical for brain development, severe hypothyroidism that is untreated in infancy causes irreversible cretinism. Milder hypothyroidism may also affect cognitive development; however, the effects of mild and/or moderate hypothyroidism on brain development are not fully understood. In this study, we examined the behavior of adult male mice rendered mildly hypothyroid during the perinatal period using low-dose propylthiouracil (PTU). PTU was administered through drinking water (5 or 50 ppm) from gestational day 14 to postnatal day 21. Cognitive performance, studied by an object in-location test (OLT), was impaired in PTU-treated mice at postnatal week 8. These results suggest that, although the hypothyroidism was mild, it partially impaired cognitive function. We next measured the concentration of neurotransmitters (glutamate, γ-aminobutyric acid, and glycine) in the hippocampus using in vivo microdialysis during OLT. The concentrations of neurotransmitters, particularly glutamate and glycine, decreased in PTU-treated mice. The expression levels of N-methyl-d-aspartate receptor subunits, which are profound regulators of glutamate neurotransmission and memory function, also were decreased in PTU-treated mice. These data indicate that mild perinatal hypothyroidism causes cognitive disorders in adult offspring. Such disorders may be partially induced secondary to decreased concentrations of neurotransmitters and receptor expression.
- Published
- 2018
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46. Melanoma antigen family A4 protein produced by transgenic silkworms induces antitumor immune responses.
- Author
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Motokawa Y, Kokubo M, Kuwabara N, Tatematsu KI, Sezutsu H, Takahashi H, Sakakura K, Chikamatsu K, and Takeda S
- Abstract
Recent clinical trials with the aim of developing tumor antigen (TA)-specific cancer vaccines against a number of malignancies have focused on the identification of TAs presented by tumor cells and recognized by T cells. In the present study, the TA melanoma antigen family A4 (MAGE-A4) protein was produced using a transgenic (TG) silkworm system. Using in vitro stimulation, it was subsequently determined whether MAGE-A4 protein induced MAGE-A4-specific T cells from peripheral blood mononuclear cells of healthy donors. TG silkworm lines expressing a MAGE-A4 gene under an upstream activating sequence (UAS) were mated with those expressing a yeast transcription activator protein (GAL4) at the middle silk glands (MSGs) and embryos that harbored both the GAL4 and UAS constructs were selected. Recombinant MAGE-A4 protein was extracted from the MSGs of TG silkworms and evaluated using SDS-PAGE and western blot analysis. It was observed that MAGE-A4 produced by the TG silkworm system successfully induced MAGE-A4-specific CD4
+ T cell responses. Furthermore, MAGE-A4-specific CD4+ T cells recognized antigen-presenting cells when pulsed with a MAGE-A4+ tumor cell lysate. The present data suggests that recombinant tumor antigen production using the TG silkworm system may be a novel tool in the preparation of cancer vaccines.- Published
- 2018
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47. Case Series of 23 Patients Who Developed Fatal Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer.
- Author
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Onishi H, Marino K, Yamashita H, Terahara A, Onimaru R, Kokubo M, Shioyama Y, Kozuka T, Matsuo Y, Aruga T, and Hiraoka M
- Subjects
- Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Lung pathology, Lung radiation effects, Lung Neoplasms complications, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Radiation Pneumonitis diagnosis, Radiation Pneumonitis etiology, Radiation Pneumonitis mortality, Risk Factors, Lung Neoplasms radiotherapy, Radiation Pneumonitis physiopathology, Radiosurgery adverse effects
- Abstract
The purpose of this study was to examine the characteristics and treatment plans of patients who experienced fatal radiation pneumonitis after stereotactic body radiation therapy for primary or oligometastatic lung cancer. Records of 1789 patients treated with stereotactic body radiation therapy for primary or oligometastatic lung cancer were retrospectively reviewed to identify those who developed fatal radiation pneumonitis. Twenty-three (1.3%; 18 men and 5 women) patients developed fatal radiation pneumonitis after stereotactic body radiation therapy for lung cancer; their median age was 74 years. The mean Krebs von den Lungen-6 level and percent vital capacity were 1320 U/mL and 82%, respectively. Prestereotactic body radiation therapy computed tomography revealed pulmonary interstitial change in 14 (73.7%) of 19 patients in whom computed tomography data could be reviewed. Seven (30.4%) of 23 patients had regularly used steroids. The median time duration between stereotactic body radiation therapy commencement and pneumonia symptom appearance was 75 (range: 14-204) days. Median survival time following pneumonia symptom appearance was 53 (range: 4-802) days. The 6- and 12-month overall survival rates were 34.8% and 13.0%, respectively. The 6-month overall survival rates in patients with and without heart disease were 50.0%, 16.7%, and 46.7% for heart disease existence, respectively. There were 4 patients in whom fatal radiation pneumonitis occurred within 2 months after stereotactic body radiation therapy and who died within 1 month. Three of them had no pulmonary interstitial change before stereotactic body radiation therapy, but had heart disease. In summary, the survival time in this case series was generally short but varied widely. More than half of the patients had pulmonary interstitial change before stereotactic body radiation therapy, although immediately progressive fatal radiation pneumonitis was also observed in patients without pulmonary interstitial change. True risk factors for fatal radiation pneumonitis should be examined in a prospective study with a larger cohort.
- Published
- 2018
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48. Salvage Pulmonary Operations Following Stereotactic Body Radiotherapy for Small Primary and Metastatic Lung Tumors: Evaluation of the Operative Procedures.
- Author
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Hamakawa H, Takahashi Y, Sakanoue I, Saito T, Date N, Tomii K, Katakami N, Imagunbai T, and Kokubo M
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Length of Stay, Male, Middle Aged, Radiosurgery methods, Ribs radiation effects, Time Factors, Lung Neoplasms radiotherapy, Lung Neoplasms surgery, Salvage Therapy adverse effects
- Abstract
Stereotactic body radiotherapy is an alternative treatment option for small-sized, primary lung cancers and pulmonary metastatic diseases. In the case of local relapse after stereotactic body radiotherapy, salvage pulmonary resection is considered cautiously. However, no study has described the difficulty of the salvage operations. This study aimed to assess the difficulty associated with salvage operative procedures. Eight patients who developed local relapse after stereotactic body radiotherapy and had undergone salvage pulmonary operations were enrolled in this study (stereotactic body radiotherapy group). Additionally, 439 patients who underwent video-assisted thoracoscopic lobectomy without previous stereotactic body radiotherapy were enrolled as the standard operative control group (non-stereotactic body radiotherapy group). In the stereotactic body radiotherapy group, 1 of the 8 patients had undergone lobectomy with composite resection of the third and fourth ribs. Of the 8 patients, 6 had undergone video-assisted thoracoscopic lobectomy and 1 had been inoperable because of rapid tumor progression. The operation time and the incision length of the utility port were apt to be longer in the stereotactic body radiotherapy group than in the non-stereotactic body radiotherapy group. On the contrary, the duration of drain placement and the length of hospital stay after the operation were not different. Thus, the salvage pulmonary operations were performed in the usual video-assisted thoracoscopic lobectomy approach, but slightly complicated than the standard video-assisted thoracoscopic lobectomy. Although to decide the indication of salvage operation might be difficult, it could be a feasible treatment option in local relapse after stereotactic body radiotherapy.
- Published
- 2018
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49. Bio-artificial pleura using an autologous dermal fibroblast sheet.
- Author
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Kanzaki M, Takagi R, Washio K, Kokubo M, and Yamato M
- Abstract
Air leaks (ALs) are observed after pulmonary resections, and without proper treatment, can produce severe complications. AL prevention is a critical objective for managing patients after pulmonary resection. This study applied autologous dermal fibroblast sheets (DFS) to close ALs. For sealing ALs in a 44-year-old male human patient with multiple bullae, a 5 × 15-mm section of skin was surgically excised. From this skin specimen, primary dermal fibroblasts were isolated and cultured for 4 weeks to produce DFSs that were harvested after a 10-day culture. ALs were completely sealed using surgical placement of these autologous DFSs. DFS were found to be a durable long-term AL sealant, exhibiting requisite flexibility, elasticity, durability, biocompatibility, and usability, resulting reliable AL closure. DFS should prove to be an extremely useful tissue-engineered pleura substitute., Competing Interests: Dr. Masayuki Yamato has equity financial interest in CellSeed, Tokyo, Japan, a publicly traded Japanese biotechnology company exclusively developing cell sheet technology for regenerative medicine purposes. All the other authors declare that they have no competing financial interests.
- Published
- 2017
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50. Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients.
- Author
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Fujimoto D, Uehara K, Sato Y, Sakanoue I, Ito M, Teraoka S, Nagata K, Nakagawa A, Kosaka Y, Otsuka K, Imai Y, Hamakawa H, Takahashi Y, Kokubo M, and Tomii K
- Subjects
- Aged, B7-H1 Antigen metabolism, Biomarkers, Tumor, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Chemoradiotherapy, Female, Gene Expression, Humans, Kaplan-Meier Estimate, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lymphocyte Count, Male, Middle Aged, Neoplasm Staging, Prognosis, Treatment Outcome, B7-H1 Antigen genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Lung Neoplasms genetics, Lung Neoplasms mortality
- Abstract
Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.
- Published
- 2017
- Full Text
- View/download PDF
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