Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. METHODS: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity. RESULTS: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis. CONCLUSIONS: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma.

DOI： 10.1007/s10388-021-00905-2

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Choking can lead to mortality and residual impairments. This study aimed to determine the factors associated with choking among acute hospital patients and examine error-producing conditions to suggest choking-prevention policies. Among 36,364 cases reported by hospital staff at an acute university hospital from 2012 to 2018 were examined using a retrospective study, 35,440 were analysis as the number of cases analysed for the study. We used descriptive statistics to present patient characteristics and conducted univariable and multivariable logistic regression analyses to identify factors associated with choking. Additionally, we conducted content analysis (root cause analysis) to examine error-producing conditions and prevention policies. Sixty-eight cases were related to choking injuries; of these, 43 patients (63.2%) were male, and 38 (55.9%) were aged 65 years and older. Choking cases had a high percent of adverse outcomes involving residual impairment or death (n = 23, 33.8%). Mental illness (adjusted odds ratio [95% confidence interval]: 3.14 [1.39-7.08]), and hospitalisation in the general wards (adjusted odds ratio [95% confidence interval]: 3.13 [1.70-5.76]) were associated with an increased probability of choking. Error production was caused by food (n = 25, 36.8%) and medical devices or supplies (n = 13, 19.1%). Almost all contributory factors were associated with inadequate checking (n = 66, 97.1%) and misperception of risk (n = 65, 95.6%). Choking poses a highly significant burden on patients, and hospital administrators should minimise the risk of choking to prevent related injuries. Hospital administrators should provide training and education to their staff and develop adequate protocols and procedures to prevent choking.

DOI： 10.1371/journal.pone.0267430

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/23311908.2021.1968991

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BACKGROUND: The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. METHODS: We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. RESULTS: Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48-1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81-2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02-1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09-1.35]; p < 0.01). Additionally, HAQ-DI scores ≤ 0.5 were associated with anxiety symptoms (OR [95% CI] 3.51 [1.85-6.64]; p < 0.01) and depression symptoms (OR [95% CI] 2.65 [1.56-4.50]; p < 0.01). Patients using steroids were more likely to have depression than those not using steroids (OR [95% CI] 1.66 [1.03-2.67]; p = 0.04). CONCLUSIONS: No association was found between RA disease activity and anxiety and depression symptoms in the multivariable logistic regression analysis. Patients with high PtGA scores or HAQ-DI scores ≤ 0.5 were more likely to experience anxiety and depression symptoms, irrespective of disease activity remission status. Rather than focusing solely on controlling disease activity, treatment should focus on improving or preserving physical function and the patient's overall sense of well-being.

DOI： 10.1186/s42358-021-00223-2

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OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by localized and generalized bone loss. The risk of fractures is doubled in patients with RA. Denosumab, an anti-RANKL monoclonal antibody, is used for those with osteoporosis at high risk fracture and it has inhibitory effect of progressive bone erosion in patients with RA. While the increase in bone mineral density by denosumab has been reported in patients with RA, preventive effect of fracture by denosumab remains unknown. This study aimed to evaluate the efficacy of denosumab in treating clinical fracture risk in patients with RA. METHODS: Patients with RA who received denosumab treatment between 2013 and 2019 were retrospectively evaluated using the ANSWER (Kansai Consortium for the Well-Being of Rheumatic Disease Patients) cohort data. Fracture rates were evaluated between 0 and 6 months (reference period) versus > 6 months (post-reference period) of denosumab use. RESULTS: A total of 873 patients with RA received denosumab, and their characteristics were as follows: 88% females, mean age 68 years, and average disease duration 14.5 years. The hazard rates of all clinical fractures were 0.69 (per 100 person-years) in the reference period and 0.35 in the post-reference period, indicating a 49.2% decrease (p = 0.03). CONCLUSIONS: Denosumab suppresses the risk of clinical fractures in patients with RA.

DOI： 10.1093/mr/roab043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

<sec><title>Objectives</title> It is important to clarify the relationship between irreversible organ damage and the quality of life (QOL) by considering the unique factors of patients with systemic lupus erythematosus (SLE). We aimed to clarify their correlation using SLE-specific QOL assessment tools. We also aimed to identify which type of organ damage is adversely correlated with the QOL.

</sec><sec><title>Methods</title> We conducted a questionnaire-based survey of outpatients with SLE at Kyoto University Hospital and evaluated irreversible organ damage using the SLICC/ACR damage index (SDI). LupusPRO and the SLE symptom checklist (SSC) were employed as SLE-specific QOL tools, and the SF-36v2 was used as a conventional QOL tool. Multiple linear regression analyses were performed to examine the correlations between the total SDI score and each QOL score, and between each SDI item/system score and each QOL score.

</sec><sec><title>Results</title> We analyzed the data of 265 patients. The total SDI score was significantly correlated with physical (PCS) and role/social component summary (RCS) of the SF-36v2, health-related QOL (HRQOL) of LupusPRO, and SSC ( p &lt; 0.001). Among the SDI items, atrophy/weakness and osteoporosis with fracture/vertebral collapse were negatively correlated with PCS (β = −0.40, p &lt; 0.001/β = −0.28, p &lt; 0.001), RCS (β = −0.30, p &lt; 0.001/β = −0.35, p &lt; 0.001), and HRQOL (β = −0.34, p &lt; 0.001/β = −0.31, p &lt; 0.001), respectively. Among the SDI systems, musculoskeletal damage had higher negative correlations with PCS (β = −0.51, p &lt; 0.001), RCS (β = −0.29, p &lt; 0.001), and HRQOL (β = −0.40, p &lt; 0.001).

</sec><sec><title>Conclusion</title> We demonstrated the QOL of patients with SLE is negatively correlated with irreversible organ damage. We also revealed musculoskeletal damage is adversely correlated with the health-related QOL, especially the physical and role/social QOL.

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DOI： 10.1177/09612033211025614

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia caused by mutated HPGD or SLCO2A1. Plasma prostaglandin (PG)E2 levels are increased in these patients. However, other eicosanoids have not been quantitated. We aimed to quantitate plasma eicosanoid levels in four patients carrying SLCO2A1 mutations by high-performance liquid chromatography-tandem mass spectrometry. PGE2 level was elevated in all patients; PGD2 and 11β-PGF2 α levels were also increased in some patients, whereas eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were decreased in all patients. Our data indicate a dysfunctional eicosanoid homeostasis and varied levels of PG in patients with a complete form of PDP carrying SLCO2A1 mutations. PGE2 levels seem to mostly affect the symptoms, with other eicosanoids possibly having a minor effect.

DOI： 10.1111/1346-8138.16012

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Publishing type：Research paper (scientific journal)   Publisher：BMJ  

<sec><title>Introduction</title>Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD.

</sec><sec><title>Methods and analysis</title>This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted.

</sec><sec><title>Ethics and dissemination</title>The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process.

</sec><sec><title>Trial registration number</title>jRCT2041200008, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04413344">NCT04413344</ext-link>.

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DOI： 10.1136/bmjopen-2021-051343

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT.

DOI： 10.1002/cam4.3920

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

<sec><title>Background</title>Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting.

</sec><sec><title>Materials and Methods</title>This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed.

</sec><sec><title>Results</title>Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count &amp;gt;820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (&amp;gt;4.3) or the lymphocyte-to-monocyte ratio (&amp;gt;2.2) at 2 weeks following treatment initiation.

</sec><sec><title>Conclusions</title>The absolute lymphocyte count &amp;gt;820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

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DOI： 10.3389/fonc.2021.618570

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Purpose</title>
To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients.


</sec><sec>
<title>Methods</title>
Patients in group A (aged &lt; 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline <italic>BRCA</italic> mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged &lt; 65 years with HRD score &lt; 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety.


</sec><sec>
<title>Results</title>
The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%–81%) and 45% (27%–65%) in groups A1 and A2, respectively, and 19% (8%–35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively.


</sec><sec>
<title>Conclusions</title>
In patients aged &lt; 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of &gt; 60% and &gt; 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. <italic>Trial registration</italic>:The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.umin.ac.jp/ctr/index-j.htm">http://www.umin.ac.jp/ctr/index-j.htm</ext-link>) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.


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DOI： 10.1007/s10549-021-06184-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/rli.0000000000000766

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

<italic>Uterine sensitization–associated gene-1</italic>(<italic>USAG-1</italic>) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through<italic>USAG-1</italic>knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that<italic>USAG-1</italic>controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

DOI： 10.1126/sciadv.abf1798

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an adverse event induced by antiresorptive agents (ARAs). The purpose of this study was to evaluate variables, mainly surgery and hyperbaric oxygen (HBO) therapy, associated with treatment outcomes in patients with a diagnosis of ARONJ at a single center. We enrolled consecutive patients who presented to our hospital for the management of stage 2 or 3 ARONJ between January 2003 and December 2019. The relationship between potentially predictive factors and outcome variables was examined using statistical analyses, along with a subgroup analysis based on disease stage. Of 252 patients included in this study, 206 had stage 2 ARONJ and 46 had stage 3 ARONJ. There were 119 patients with osteoporosis and 133 with malignant disease. In total, 139 patients were healed, and the healing rate of patients with stage 3 ARONJ was lower than that of patients with stage 2 ARONJ. With regard to the combination of surgery and HBO therapy, most patients underwent HBO before and after surgery. In the univariable analysis, surgery showed a therapeutic effect in both stage 2 and 3 ARONJ, whereas HBO showed a therapeutic effect in stage 2 ARONJ. In the multivariable analysis for stage 2 ARONJ, extensive surgery showed a stronger association with healing than conservative surgery, whereas ≥46 sessions of HBO therapy was less associated with healing than was non-HBO therapy. Our findings suggest that extensive surgery is highly effective against ARONJ regardless of disease stage if there is a sequestrum separation and systemic tolerance, whereas HBO therapy before and after surgical approach can be effective. Further studies are needed to identify treatment strategies for patients with treatment-refractory ARONJ who may be forced to undergo long-term HBO therapy with the expectation of sequestrum separation.

DOI： 10.1371/journal.pone.0244859

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OBJECTIVES: Drug-resistant overactive bladder (OAB) represents an unmet medical need in that treatment options are limited. We developed a treatment model based on cognitive behavioral therapy and evaluated its feasibility and acceptability for drug-resistant OAB in women. METHODS: This was an open-label, single-arm, multicenter pilot study. We defined drug-resistant OAB as OAB with moderate to severe symptoms despite pharmacotherapy for more than 12 weeks. A face-to-face intervention was prescribed as six sessions (30 minutes each) over 6 to 12 weeks according to a treatment manual. The effects were assessed by self-reported questionnaires and frequency voiding charts (FVC) at baseline, during intervention, immediately after intervention, and at follow-up. RESULTS: Ten patients participated in this study. Median age was 72 years, median OAB Symptom Score was nine points, and median duration of prior treatment for OAB was 5.5 years at baseline. Two participants dropped out of the study. Among the remaining patients, the scores of the OAB Questionnaire subscales improved (effect size: 0.75-1.73), and the mean urinary frequency in the FVC also improved from baseline (9.0 times, SD: 2.1) to follow-up (6.2 times, SD: 1.2). All participants were satisfied with the intervention. There were no adverse events during this study. CONCLUSIONS: The new treatment based on cognitive behavioral therapy was well tolerated and feasible in women with drug-resistant OAB. Further randomized research is needed to rigorously evaluate the efficacy of the treatment.

DOI： 10.1111/luts.12333

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.rmed.2020.106279

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ivyspring International Publisher  

Background: Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. Methods: We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. Results: In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. Conclusions: The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.

DOI： 10.7150/jca.53242

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.nut.2020.110871

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND/PURPOSE: The aim in the present study was to elucidate the diagnostic ability of presepsin for postoperative infectious complications following major hepato-biliary-pancreatic (HBP) surgery. METHODS: Between 2017 and 2019, 50 patients with major hepatectomy and 55 patients with pancreatoduodenectomy were enrolled. Presepsin, the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and procalcitonin (PCT) were prospectively measured for the first 2 weeks after surgery. The diagnostic abilities of these biomarkers were compared multidirectionally. RESULTS: All biomarkers returned to normal ranges within 2 weeks after surgery. However, presepsin, unlike the other biomarkers, showed less nonspecific elevation in response to the invasiveness of the surgical procedure immediately after surgery. Receiver operating characteristic curve analysis revealed that presepsin (area under the curve (AUC), 0.959) had a greater ability to discriminate bacterial infection than PCT (AUC, 0.723), CRP (AUC, 0.800), and the NLR (AUC, 0.804). A very high sensitivity of 93.3% and a specificity of 89.2% were achieved at the cutoff value of 620 pg/mL. Multivariable analysis revealed that presepsin on day 3 (P = .013) independently predicted bacterial infection after HBP surgery. CONCLUSIONS: Presepsin may have a better predictive ability than existing biomarkers for infection following major HBP surgery, which may help us achieve faster and more accurate detection of bacterial infections.

DOI： 10.1002/jhbp.802

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

BACKGROUND: Several studies reported favorable outcomes of small-for-size (SFS) grafts with graft-to-recipient weight ratio (GRWR) <0.8% in living-donor liver transplantation (LDLT). However, their indications should be carefully determined because they must have been indicated for lower-risk cases over larger grafts with 0.8%≤ GRWR. Furthermore, evidence for minimum requirements of GRWR remains inconclusive. We investigated the safety of SFS grafts against larger grafts by adjusting for confounding risk factors, and minimum requirement of graft volume in adult LDLT. METHODS: We enrolled 417 cases of primary adult-to-adult LDLT in our center between 2006 and 2019. The outcomes of small grafts (0.6%≤ GRWR <0.8%, n =113) and large grafts (0.8%≤ GRWR, n =289) were mainly compared using a multivariate analysis and Kaplan-Meier estimates. RESULTS: The multivariate analysis showed that small grafts were not a significant risk factor for overall graft survival (GS). In the Kaplan-Meier analysis, small grafts did not significantly affect overall GS regardless of lobe selection (vs large grafts). However, GRWR <0.6% was associated with poor overall GS. Although there were no significant differences between the two groups, unadjusted Kaplan-Meier curves of small grafts were inferior to those of large grafts in sub-cohorts with ABO incompatibility, and donor age ≥50 years. CONCLUSIONS: Similar outcomes were observed for small and large graft use regardless of lobe selection. 0.6% in GRWR was reasonable as the minimum requirement of graft volume in LDLT. However, small grafts should be indicated carefully for high-risk cases.

DOI： 10.1097/tp.0000000000003472

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Medical Association (AMA)  

DOI： 10.1001/jamanetworkopen.2020.13952

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

BACKGROUND: Overactive bladder (OAB) symptoms affect daily life by decreasing health-related quality of life (HRQol). However, there remain no very effective treatment for OAB. Pharmacotherapy is one of the best treatments, but it is not always efficient and may incur adverse events. Although behavioral therapy is another effective treatment, there are very few structured treatment manuals on how to prescribe behavioral therapy to treat OAB for whom. Cognitive behavioral therapy (CBT) is a psychotherapy consisting of structured sessions to solve problems with the collaborative empiricism between therapists and patients. OAB symptoms are supposed to worsen with cognitive distortion, and CBT is expected to be effective in treating OAB by modifying such cognitive processes. In this trial, we will evaluate the efficacy of CBT for OAB. METHODS: A randomized, controlled, open-label, multicenter parallel-group superiority trial will be conducted. Participants with moderate to severe OAB symptoms with or without pharmacotherapy will be recruited and will be randomly allocated 1:1 to two different groups by minimization (age, baseline OAB severity, treatment status, types of intervention, and treating institutions). The intervention group will be prescribed an individual CBT program covering six techniques in 4 sessions (30 min each), with or without pharmacotherapy. The primary outcome is the change scores in an OAB-questionnaire (OAB-q) from baseline to the end of the trial (week 13). Secondary outcomes will include other patient reported outcome measures and the frequency volume chart. All analyses will be conducted on an intention-to-treat principle. DISCUSSION: This trial will determine the efficacy of CBT to treat OAB using a rigorous methodology. The effectiveness of CBT with a structured manual may not only lead to a new treatment option for patients suffering from OAB symptoms, but may also reduce the social burden by OAB. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, CTR-UMIN000038513 . Registered on November 7, 2019.

DOI： 10.1186/s12894-020-00697-0

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Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.

DOI： 10.1002/lt.25814

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Clinical Oncology (ASCO)  

e15046

Background: Advances in immuno-oncology (IO), i.e., programmed cell-death protein 1 (PD-1) inhibitors, are revolutionizing cancer treatment by offering hope for a cure. However, the benefit of IO agents in metastatic breast cancer (MBC) remains limited. For immunotherapy to be successful, it is essential to understand the tumor immune contexture. Systemic immune alterations, such as the signature of peripheral blood mononuclear cells (PBMC) and cytokine expression, are one of the hallmarks of successful immunotherapy in MBC. The abscopal effect induced by radiation therapy (RT) is known to be a modulator of systemic immune alterations, and the abscopal effect is considered as a systemic anti-tumor immune response. In this study, we integrated time series multi-omics data in order to identify alteration of the immune signatures after RT combined with nivolumab, a PD-1 inhibitor, using a longitudinal liquid biopsy with artificial intelligence. Methods: This study was conducted as translational research, part of the KBCRN-B-002 trial, which is a multicenter phase Ib/II study evaluating the safety and efficacy of nivolumab in combination with RT in patients with HER2-negative MBC (UMIN: UMIN000026046). Twenty-nine patients were included in the translational analysis set. The multi-omics data included data from RNAseq, mass cytometry (CyTOF) and multiple cytokines, using PBMC, serum and plasma. We collected time series data, which covered the baseline, two weeks after starting therapy, four weeks after starting therapy and the timing of progressive disease. For integrated analysis of the multi-omics data, a machine-learning method was developed. Results: Our integrated analysis (involving a longitudinal liquid biopsy and machine-learning method) identified an apparent cluster of responder groups and alteration of the systemic immune signatures. Single-cell analysis using CyTOF results including the signature of the immune cell composition, effector immune cells and immune suppressor cells. Conclusions: Our method clustered responders well and identified candidates of the systemic immune signatures for actionable hallmarks of RT combined with IO agent by a longitudinal liquid biopsy. Clinical trial information: NCT03430479 .

DOI： 10.1200/jco.2020.38.15_suppl.e15046

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PURPOSE: Venous pain induced by peripheral intravenous infusion of gemcitabine has remained an unresolved issue in clinical practice. This study aimed to identify differences between gemcitabine formulations as well as risk factors associated with gemcitabine-induced venous pain in patients with cancer. METHODS: We retrospectively analyzed data from consecutive patients with cancer who had received chemotherapy including a lyophilized or liquid formulation of gemcitabine diluted with 5% glucose solution via a peripheral vein. The study was conducted at Ehime University Hospital using electronic medical records dated between January 2015 and July 2017. The primary end point was the prevalence of venous pain at the administration site during gemcitabine infusion, classified as injection site reaction of grade ≥2 according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate logistic regression analysis with generalized estimating equations for longitudinal data was used to identify risk factors for venous pain during all courses of gemcitabine treatment. FINDINGS: A total of 1150 treatment courses in 141 Japanese patients were evaluated in this study. Venous pain occurred in 115 courses (10.0%) and in 49 patients (34.8%). The multivariate logistic regression analysis with generalized estimating equations revealed that a dose increase of gemcitabine and use of the liquid formulation of gemcitabine were significantly associated with an increased risk for venous pain (dose increase, adjusted odds ratio [OR] = 1.25; 95% CI, 1.11-1.40 [P < 0.001]; and liquid formulation, adjusted OR = 12.43, 95% CI, 5.61-27.51 [P < 0.001]), whereas age, course number of gemcitabine, and use of the soft-back product of 5% glucose solution were significantly associated with a reduced risk for venous pain (age, adjusted OR = 0.75; 95% CI, 0.57-0.98 [P = 0.037]; course number, adjusted OR = 0.96; 95% CI, 0.92-0.99 [P = 0.023]; and soft back, adjusted OR = 0.39; 95% CI, 0.21-0.74 [P = 0.004]). IMPLICATIONS: The use of the liquid formulation of gemcitabine was associated with a significant increase in the frequency of gemcitabine-induced venous pain despite dilution with 5% glucose solution compared to that with the lyophilized formulation. The lyophilized formulation of gemcitabine should hence be used in peripheral intravenous infusion for the treatment of patients with cancer.

DOI： 10.1016/j.clinthera.2020.02.010

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We evaluated the hypothesis that grafts from donors with high muscle mass and quality may have a better outcome after living-donor-liver-transplantation (LDLT) than those from usual donors. A total of 376 primary adult-to-adult LDLT cases were enrolled in this study. Donor skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) were used as markers of muscle mass and quality. In male donor cases (n = 198), those with higher SMI and lower IMAC than age-adjusted values were defined as the "high muscularity donors" (n = 38) and the others were defined as the "control" (n = 160). The high muscularity donor showed better 1-year (97% vs 82%, P = .020) and overall graft survival rate (88% vs 67%, P = .024) than the control group after LDLT. Contrastingly, the influence of the muscularity was not observed in female donor cases. Multivariable analysis including donor age confirmed that a high muscularity donor was an independent protective factor for overall graft survival after LDLT (hazard ratio, 0.337; 95% CI: 0.101-0.838; P = .017). Our study first confirmed that high muscle mass and quality of a male donor is a protective factor of allograft loss after LDLT, independently from donor age.

DOI： 10.1111/ajt.15884

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/art.41105

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/art.41105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objective</title>
We aimed to clarify the clinical significance of serum levels of MMPs in interstitial lung disease (ILD) complicated with PM/DM (PM/DM-ILD).


</sec>
<sec>
<title>Methods</title>
We retrospectively analysed serum levels of seven subsets of MMPs in 52 PM/DM-ILD patients diagnosed at Kyoto University Hospital or Tenri Hospital from January 2005 to December 2014. The patients were sub-grouped based on the presence of anti-amimoacyl-tRNA synthetase antibody (anti-ARS antibody), anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody) or lack of the antibodies (ARS-ILD, MDA5-ILD and other-ILD groups, respectively) and independently analysed. Eighteen PM/DM patients without ILD and 55 healthy control were also analysed. Associations between serum levels of MMPs and clinical findings including mortality were analysed.


</sec>
<sec>
<title>Results</title>
Among the MMPs analysed, MMP-7 serum levels in the ARS-ILD group were significantly higher compared with those in any of the other groups of PM/DM patients or in healthy controls. On the other hand, in the MDA5-ILD group, serum MMP-7 levels &gt;5.08 ng/ml were associated with worse overall survival both in univariate (P = 0.017; odds ratio 18.0; 95% CI 1.69, 192.00) and multivariate (P = 0.027; odds ratio 14.60; 95% CI 1.11, 192.00) analyses. Immunohistochemical analysis suggested that MMP-7 was expressed in type II alveolar epithelial cells adjacent to the fibrotic lesions.


</sec>
<sec>
<title>Conclusion</title>
Serum MMP-7 levels were higher in anti-ARS antibody-positive PM/DM-ILD patients, while higher serum MMP-7 levels among anti-MDA5 antibody-positive PM/DM-ILD patients were associated with a worse prognosis. Fibrotic processes may be associated with the elevation of serum MMP-7 levels.


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DOI： 10.1093/rheumatology/kez065

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DOI： 10.1186/s13063-019-3570-6

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While the prevalence of supernumerary teeth (ST) is high in permanent dentition, the etiology of ST in humans remains unclear. However, multiple murine models of ST have elaborated on dated mechanisms traditionally ascribed to ST etiology: one involves the rescue of rudimental teeth, and the second considers the contribution of odontogenic epithelial stem cells. It remains unclear whether these mechanisms of ST formation in mice are applicable to humans. The third dentition is usually regressed apoptotic—that is, the teeth do not completely form in humans. Recently, it was suggested that ST result from the rescue of regression of the third dentition in humans. The present investigation evaluates the proportion of collected general ST cases that evinced a third dentition based on the clinical definition of ST derived from the third dentition. We also investigated the contribution of SOX2-positive odontogenic epithelial stem cells to ST formation in humans. We collected 215 general ST cases from 15,008 patients. We confirmed that the general characteristics of the collected ST cases were similar to the results from previous reports. Of the 215 cases, we narrowed our analysis to the 78 patients who had received a computed tomography scan. The frequency of ST considered to have been derived from the third dentition was 26 out of 78 cases. Evidence of a third dentition was especially apparent in the premolar region, was more common in men, and was more likely among patients with ≥3 ST. SOX2-positive odontogenic epithelial stem cells within the surrounding epithelial cells of developing ST were observed in non–third dentition cases and not in third dentition cases. In conclusion, the third dentition is the main cause of ST in humans. The odontogenic epithelial stem cells may contribute to ST formation in cases not caused by a third dentition.

DOI： 10.1177/0022034519858282

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients. Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses. Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia. Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.

DOI： 10.1080/14397595.2018.1510565

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BACKGROUND: There has been growth in the treatment options for castration-sensitive metastatic prostate cancer (mPCa), but without clear guidance for risk stratification. OBJECTIVE: To identify clinical parameters associated with overall survival (OS) and establish a prognostic model for use with treatment-naïve castration-sensitive mPCa. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 304 patients treated at Kyoto University Hospital was performed. A prognostic model was created using clinical parameters associated with OS. The model was externally validated in an independent cohort of 520 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable analysis was performed to identify the clinical parameters associated with OS. Risk scores were calculated using Cox proportional hazards analysis for each combination of risk factors, and patients were grouped into categories based on those scores. RESULTS AND LIMITATIONS: Over 80% of the cohort had a Gleason sum score ≥8. The median OS was 53mo among patients with CHAARTED high-volume PCa (n=172) and 131mo among those with low-volume PCa (n=100). Independent factors associated with OS were extent of disease score ≥2 or the presence of liver metastasis; lactate dehydrogenase >250U/L; and a primary Gleason score of 5. The median OS for the high-, intermediate-, and low-risk groups according to the new model were 28mo, 59mo, and not reached, respectively; the corresponding values in the validation cohort were 41mo, 63mo, and not reached. Harrell's C-index was 0.649. CONCLUSIONS: Our simple and reproducible prognostic model for treatment-naïve castration-sensitive mPCa could aid in risk stratification and treatment selection. PATIENT SUMMARY: We identified clinical parameters associated with prognosis in castration-sensitive metastatic prostate cancer and established a reproducible prognostic model that could be used to guide treatment decisions.

DOI： 10.1016/j.euo.2018.10.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12282-018-0920-2

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Other Link： http://link.springer.com/article/10.1007/s12282-018-0920-2/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/03009742.2018.1477989

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The interpretation of bacterial cholangitis after liver transplantation (LT) remains vague, because the presence of bacteria in bile, namely bacteriobilia, does not necessarily indicate an active infection. We investigated the association between post-LT bacterial cholangitis and a variety of short- and long-term outcomes. Two-hundred-seventy-four primary adult-to-adult living donor LT recipients from 2008 to 2016 were divided into three groups according the presence or absence of bacteriobilia and clinical symptoms: (1) no bacteriobilia (N group), (2) asymptomatic bacteriobilia (B group), and (3) cholangitis (C group). The number of patients was by group: N, 161; B, 64; and C, 49. Donor age ≥ 45 years (p = 0.012), choledochojejunostomy (p < 0.001), and post-LT portal hypertension (p = 0.023) were independent risk factors for developing cholangitis. Survival analysis revealed that the C group had significantly worse short- and long-term graft survival. The C group was associated with an increased incidence of early graft loss (EGL) (p < 0.001). While the frequency of readmission for recurrent cholangitis was significantly higher in both the B and C groups (p < 0.001), late graft loss (LGL) due to chronic cholangitis was only commonly observed in the C group (p = 0.002). Post-LT cholangitis could result in not only EGL but also chronic cholangitis and associated LGL.

DOI： 10.1007/s10096-018-3333-4

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Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) ≥ 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima-media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub-classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 ≤ BMI < 25 kg/m2 and VFA ≥ 100 cm2) had the highest IMT (mean IMT, 0.93 ± 0.29 mm; maximum IMT, 1.44 ± 0.71 mm) and PS (1.43 ± 0.61), compared to all other BMI and VFA subgroups. RA patients have increased visceral adiposity, which is associated with a high prevalence of atherosclerotic of plaques. Non-obese RA patients who have visceral adiposity have a specifically higher risk for atherosclerosis.

DOI： 10.1007/s00296-018-4095-0

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BACKGROUND: Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be considered. This study aimed to determine the factors associated with BFR achievement in clinical practice. METHODS: Patients with RA were enrolled from a Japanese multicenter observational registry. Patients with RA who achieved clinical remission (Disease Activity Score 28-C-reactive protein < 2.3) at the time of bDMARD discontinuation were included. Serial disease activities and treatment changes were followed up. BFR was considered to have failed if the disease activity exceeded the remission cutoff value or if bDMARDs were restarted. RESULTS: Overall, 181 RA patients were included. BFR was maintained in 21.5% of patients at 1 year after bDMARD discontinuation. BFR was more successfully achieved after discontinuation of anti-tumor necrosis factor (TNF) monoclonal antibodies (TNFi(mAb)) (infliximab, adalimumab, and golimumab), followed by CTLA4-Ig (abatacept), soluble TNF receptor or Fab fragments against TNF fused with polyethylene glycol (etanercept and certolizumab), and anti-interleukin-6 receptor Ab (tocilizumab). After multivariate analysis, sustained remission (> 6 months), Boolean remission, no glucocorticoid use at the time of bDMARD discontinuation, and use of TNFi(mAb) or CTLA4-Ig remained as independent factors associated with BFR. CONCLUSIONS: BFR can be achieved in some patients with RA after bDMARD discontinuation in clinical practice. Use of TNFi(mAb) or CTLA4-Ig, sustained remission, Boolean remission, and no glucocorticoid use at the time of bDMARD discontinuation are advantageous for achieving BFR.

DOI： 10.1186/s13075-018-1673-1

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PURPOSE: Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy. METHODS: This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors. FINDINGS: A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non-RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18-0.99]; P = 0.048). IMPLICATIONS: The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy.

DOI： 10.1016/j.clinthera.2018.05.011

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Objectives/Hypothesis: Endoscopic laryngopharyngeal surgery (ELPS), a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, has been attracting attention as a new therapeutic modality for superficial laryngopharyngeal cancers. Although this technique is less invasive than traditional open procedures, some complications including postoperative bleeding, subcutaneous emphysema, or aspiration pneumonia can occur after treatment. The purpose of this study was to investigate the complications associated with ELPS to better understand the indications for this procedure. Study Design: Retrospective medical chart review. Methods: One hundred five patients with 159 laryngeal or pharyngeal lesions were treated with ELPS between August 2009 and September 2015 at Kyoto University Hospital. In total, 147 resections were performed, and complications after the resections were reviewed. Results: Of the 147 resections, postoperative bleeding, subcutaneous emphysema, and aspiration pneumonia were observed in 10, 17, and 10 cases, respectively. All cases with postoperative bleeding and aspiration pneumonia occurred in patients over 65 years of age. A history of taking anticoagulation/platelet medications, and macroscopic 0–IIa lesions were shown to correlate with postoperative bleeding after ELPS. Resection of lesions in the pyriform sinus was found to be associated with subcutaneous emphysema. Conclusions: All complications after ELPS were safely managed. A history of taking anticoagulation/platelet medications and macroscopic 0–IIa lesions were identified as risk factors for postoperative bleeding, whereas resection of pyriform sinus lesions was found to be a risk factor for subcutaneous emphysema. These risk factors should be carefully considered when treating pharyngeal and laryngeal lesions by ELPS. Level of Evidence: 4. Laryngoscope, 128:1546–1550, 2018.

DOI： 10.1002/lary.26953

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Churchill Livingstone  

Purpose: The aim of this study was to examine and compare morphological and functional outcomes after either isolated mandibular setback or bimaxillary surgery in males and females. Materials and methods: A retrospective study was done on 52 patients, in whom surgical correction for mandibular prognathism was performed either by isolated mandibular setback (30 cases) or by bimaxillary surgery (22 cases). Morphological changes were studied using cephalograms and functional changes studied using impulse oscillometry (IOS) taken before surgery (T0), 3 months (T1) and 1 year after surgery (T2). Also 3% oxygen desaturation index (ODI) was measured at T0 and T2. Result: Posterior airway space decreased significantly in both groups and both sexes but more so in males after mandibular setback surgery and in females after bimaxillary surgery. Changes in supine R20 (central airway resistance at 20 Hz) and supine R5 (total airway resistance at 5 Hz) in IOS statistically significantly increased in the period T0–T1 in males compared with females after mandibular setback surgery (p &lt
0.05). Conclusion: Gender dimorphism is present according to morphological and functional outcomes, with males at a higher risk for obstructive sleep apnea (OSA) after mandibular setback surgery and females after bimaxillary surgery
however, compensatory changes act as a barrier against this.

DOI： 10.1016/j.jcms.2018.04.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Churchill Livingstone  

Introduction Adjuvant bisphosphonates lead to better prognosis in postmenopausal breast cancer. However, the association between clinical outcomes and immune modulation by them is still unclear. Methods In this prospective, open-label phase II study, postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer received neoadjuvant letrozole (LET) for one month, followed by treatment with a single dose of zoledronic acid. The patients underwent an additional 5 months of treatment with LET prior to surgery. The primary endpoint was the tumor objective response rate (ORR) determined by diameter via MRI. The association between the ORR and γδT cell frequencies was assessed as a secondary endpoint. Results Out of sixty patients, 55 patients were evaluable for response by MRI. The ORR for LET with zoledronic acid was 38.2% (21/55), which was comparable to that of historical controls (45%). A decrease in the frequency of the Vδ2 T cell subset was observed throughout treatment, and Vδ2 T cells were activated for 6 months. In planned subgroup analyses, patients with low frequencies of Vδ2 T cells prior to zoledronic acid infusion experienced a favorable tumor response compared to those with high frequencies (59.3% [16/27] vs 17.9% [5/28], p =.002). There were no serious adverse events with this treatment regimen. Conclusion These results showed that neoadjuvant LET with zoledronic acid could not achieve overall effect for local tumor response. However, patients with a low frequency of γδ T cells would benefit from the treatment including zoledronic acid. (UMIN 000008701).

DOI： 10.1016/j.breast.2017.12.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

Background Portal hypertension (PHT) is defined as a portal venous pressure gradient (PVPG) exceeding 5 mm Hg, which results in severe clinical manifestations. However, the validity of intraoperative PVPG monitoring and the association between PHT and bacterial translocation after liver transplantation remain unclear. Methods In this retrospective study, 223 patients who underwent primary adult-to-adult living donor liver transplantation from 2008 to 2015 were divided into 2 groups based on the PVPG at the end of the operation: high PVPG (&gt
5 mm Hg, n = 69) and low PVPG (≤5 mm Hg, n = 154). The clinical factors were compared between the groups, and the association between a high PVPG and posttransplant bacteremia/bacterial infections was investigated. Results The high PVPG group had a significantly higher incidence of bacteremia (46% vs 24%, P &lt
0.001), higher 90-day mortality rate (20% vs 7%, P = 0.002), and poorer 1-year survival (71% vs 86%, P = 0.006). The high PVPG group had a particularly higher incidence of bacteremia caused by "gut bacteria" including Enterobacteriaceae, Bacteroides spp., and Enterococcus spp. (29% vs 12%, P = 0.003). Multivariate analysis showed that a PVPG greater than 5 mm Hg (odds ratio, 2.55
95% confidence interval, 1.18-5.55
P = 0.017) was an independent predictor of bacteremia due to gut bacteria. Conclusions Monitoring of the PVPG is clinically meaningful for predicting patients' prognosis. In particular, a high PVPG with a threshold of 5 mm Hg at the end of adult-to-adult living donor liver transplantation may increase gut-related bacteremia through the mechanism of bacterial translocation, resulting in early mortality.

DOI： 10.1097/TP.0000000000002047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Background: Recently, numerous pharmaceutical sponsors have expressed a great deal of interest in the development of biosimilars, which requires clinical trials to demonstrate that the pharmacokinetic (PK) and clinical efficacy are equivalent. Pharmacodynamics (PD) may be used in evaluating efficacy if there are relevant PD markers available. However, in their absence, it is necessary to design the associated clinical trials to include efficacy measures as the primary endpoint.
Methods: In this study, we propose a novel adaptive seamless PK and efficacy design with an efficient framework to remedy the risk of misspecification of efficacy parameters and to discontinue the trial evaluating the efficacy for futility based on the PK evaluation. Here, we consider the clinical development of biosimilars including their evaluation in patients rather than healthy volunteers under a situation where both PK and efficacy parameters are required to demonstrate equivalence. The original idea of the proposed method was to organize a clinical trial that includes the statistical analysis of PK as an interim analysis, with sample size recalculation of the efficacy data.
Results: Our simulation study indicated that the proposed design would allow trials to be more efficient than with the classical design.
Conclusions: This proposal provides appealing advantages, such as a shorter time period, additional cost savings, and a smaller number of patients required.

DOI： 10.1177/2168479017706526

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Background. In rectal cancer, anastomotic leakage was reported to have a negative impact on both short and long-term outcomes. However, there is limited data on the impact of anastomotic leakage on oncologic outcomes in patients with colon cancer. We aimed to evaluate the impact of anastomotic leakage on disease recurrence and long-term survival after curative resection of colon cancer.
Methods. This multicenter; retrospective cohort study of 4, 919 consecutive patients utilized data from the Japanese Society for Cancer of the Colon and Rectum. Multivariable Cox regression analysis was used to adjust for confounding
Results. The incidence of anastomotic leakage was 2.5 % and 30-day mortality was 0.21 %. The 5-year overall survival rate was 80.8% in the anastomotic leakage group, compared with 90.3% in the no leak group (P =.001). In the multivariable analysis, anastomotic leakage was significantly associated with reduced overall survival rate (hazard ratio = 1.84; 95 % confidence interval, 1.06-2.96). Overall disease recurrence rate was 14.1 %: 21.2 % in the anastomotic leakage group and 13.9% in the no leak group. There was a significant association between anastomotic leakage and local recurrence (hazard ratio = 4.63; 95% confidence interval, 1.60-10.6). In contrast, anastomotic leakage was not significantly associated with total distant recurrence. However, anastomotic leakage did show a tendency toward increasing peritoneal recurrence, although it did not reach statistical significance (hazard ratio = 2.59; 95 % confidence interval, 0.79-6.29).
Conclusion. In our study population, anastomotic leakage was associated with reduced overall survival and with increased rate of local recurrence after curative resection for colon cancer.

DOI： 10.1016/j.surg.2017.03.005

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DOI： 10.1007/s12032-017-0996-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Yale Journal of Biology and Medicine Inc.  

Background: Pneumonia is a major complication of influenza that contributes to mortality. Clinical characteristics and factors of influenza virus contributing to the severity and mortality of pneumonia have not been fully elucidated. Objective: The objective was to clarify clinical characteristics and factors contributing to the severity and mortality of influenza-associated pneumonia (flu-p†). Methods: We retrospectively analyzed patients with flu-p. Results: From December 1999 to March 2016, 210 patients with a median age of 69 (range, 17 to 92) years with flu-p based on positive rapid antigen tests, increased antibody titers of paired sera, or positive results of reverse transcription polymerase chain reaction were admitted to our institution. A multivariate analysis found that advanced age (≥ 65 years), pneumonia subtypes (unclassified), diabetes mellitus, and acute kidney injury complicated with flu-p were independent factors associated with disease severity, whereas pneumonia subtypes (mixed viral and bacterial pneumonia and unclassified), healthcare-associated pneumonia, acute kidney injury complicated with flu-p, and severity on admission (severe) were independent factors associated with non-survival. Conclusion: The clinical characteristics of flu-p are varied, and the contribution of several factors to the severity and mortality of flu-p suggest their importance in either preventing flu-p or managing flu-p after it develops.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Adaptive designs in oncology clinical trials with interim analyses for population selection could be used in the development of targeted therapies if a predefined biomarker hypothesis exists. In this article, we consider an interim analysis using overall survival (OS), progression-free survival (PFS), and both OS and PFS, to determine whether the whole population or only the biomarker-positive population should continue into the subsequent stage of the trial, whereas the final decision is made based on OS data only. In order to increase the probability of selecting the most appropriate population at the interim analysis, we propose an interim decision-making strategy in adaptive designs with correlated endpoints considering the post-progression survival (PPS) magnitudes. In our approach, the interim decision is made on the basis of predictive power by incorporating information on OS as well as PFS to supplement the incomplete OS data. Simulation studies assuming a targeted therapy demonstrated that our interim decision-making procedure performs well in terms of selecting the proper population, especially under a scenario in which PPS affects the correlation between OS and PFS.

DOI： 10.1080/10543406.2016.1148714

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INTRODUCTION: Impaired coordination between breathing and swallowing (breathing-swallowing discoordination) may be a significant risk factor for the exacerbation of chronic obstructive pulmonary disease (COPD). We examined breathing-swallowing discoordination in patients with COPD using a non-invasive and quantitative technique and determined its association with COPD exacerbation. METHODS: We recruited 65 stable outpatients with COPD who were enrolled in our prospective observational cohort study and did not manifest an apparent swallowing disorder. COPD exacerbation was monitored for 1 year before and 1 year after recruitment. Swallowing during inspiration (the I-SW pattern) and swallowing immediately followed by inspiration (the SW-I pattern) were identified. RESULTS: The mean frequency of the I-SW and/or SW-I patterns (I-SW/SW-I rate) was 21.5%±25.5%. During the 2-year observation period, 48 exacerbation incidents (25 patients) were identified. The I-SW/SW-I rate was significantly associated with the frequency of exacerbation. During the year following recruitment, patients with a higher I-SW/SW-I frequency using thicker test foods exhibited a significantly higher probability of future exacerbations (p=0.002, log-rank test). CONCLUSIONS: Breathing-swallowing discoordination is strongly associated with frequent exacerbations of COPD. Strategies that identify and improve breathing-swallowing coordination may be a new therapeutic treatment for patients with COPD.

DOI： 10.1136/bmjresp-2017-000202

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本嚥下医学会  

われわれは、嚥下障害患者において嚥下しやすい食品と嚥下が難しい食品があるのは、病態に応じて嚥下動態が変化し、それぞれ適応となる食品が異なるためと考えている。物性が異なる検査食で嚥下造影検査を施行し、嚥下反射の時相について検討を行った。ゼリーやペーストと比較して液体造影剤では喉頭挙上遅延時間(以下、LEDT)が延長していた。舌骨の急速挙上時から、安静位に戻るまでの時間(以下、PRD)はゼリー、ペースト、液体造影剤の間で相違がみられた。誤嚥、喉頭侵入がある群のLEDT延長例では、液体造影剤で喉頭侵入および喉頭挙上期型誤嚥がみられた。また、誤嚥、喉頭侵入がある群のPRDはゼリーよりペースト、液体造影剤が有意に延長していた。以上の結果から、ゼリーとペーストは喉頭挙上期型誤嚥に有効な形態であり、それぞれ適応が異なることが示唆された。また、嚥下障害患者の各々の病態によって、食品別の嚥下反射の時相に相違があることが明らかとなった。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J05944&link_issn=&doc_id=20160916080008&doc_link_id=%2Feg1engei%2F2016%2F000502%2F001%2F0206-0213%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Feg1engei%2F2016%2F000502%2F001%2F0206-0213%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

The aim of this study was to investigate the effect of the timing of valve surgery on the clinical outcomes of patients with active infective endocarditis (IE) accompanied by cerebral complications.
We retrospectively analysed a cohort of 568 patients, comprising 118 with non-haemorrhagic cerebral infarction (CI), 54 with intracranial haemorrhage (ICH) and 396 without cerebral events (C; control), who underwent surgery for left-sided active IE in 15 Japanese institutes from 2000 to 2011. The mean age was 58.4 +/- 16.9 years in the CI group; 54.5 +/- 17.4 years in the ICH group and 56.9 +/- 16.0 years in the C group. Clinical outcomes were analysed according to the timing of surgery after the diagnosis of CI or ICH was made.
In the CI group, there were 9 (7.6%) hospital deaths, 13 (11%) new cerebral events and 1 (0.8%) redo valve surgery. In the ICH group, there were 3 (5.6%) hospital deaths, 8 (14.8%) new cerebral events and 2 (3.7%) redo valve surgeries. In the C group, there were 36 (9.1%) hospital deaths, 23 (5.8%) new cerebral events and 9 (2.3%) redo valve surgeries. Risk factors for hospital death were prosthetic valve endocarditis (P = 0.045), high C-reactive protein (CRP; P &lt; 0.001) and the elderly (P &lt; 0.001) in the CI group. Delayed surgery (2 weeks after CI) seemed result in a higher incidence of hospital death in the CI group. Patients who had surgery between 15 and 28 days or after 29 days from the onset of CI had higher incidences of hospital death [odds ratio 5.90 (P = 0.107) and 4.92 (P = 0.137), respectively] compared with those who had surgery within 7 days. In the ICH group, risk factors for hospital death were high CRP (P = 0.002) and elderly (P &lt; 0.001). Contrary to CI patients, patients who had surgery between 8 and 21 days or after 22 days after the onset of ICH had lower incidences of hospital death [odds ratio 0.79 (P = 0.843) and 0.12 (P = 0.200), respectively] compared with those who had surgery within 7 days.
Although statistically insignificant, early surgery in active IE patients with CI is safe, but very early surgery (within 7 days) should be avoided in patients with ICH.

DOI： 10.1093/ejcts/ezw035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background: Several diagnostic criteria have been proposed to differentiate allergic bronchopulmonary mycosis (ABPM) from asthma, but there have been no studies to establish diagnostic criteria to classify ABPM differently from other eosinophilic lung diseases. Methods: We retrospectively investigated both patients with ABPM (n=42) diagnosed by clinical (Rosenberg–Patterson criteria modified to apply to fungi other than Aspergillus spp., with consideration of computed tomography and bronchoscopy findings) or pathological criteria and those with other eosinophilic lung diseases (n=118) to establish elaborate diagnostic criteria for ABPM. Results: Etiologies of ABPM included fungi other than Aspergillus spp. or unidentified pathogens in 16 patients. Fourteen patients (33.3%) did not have asthma. When the diagnostic cutoff line was set to satisfy six or more primary plus secondary modified Rosenberg–Patterson criteria, ABPM could be diagnosed with good sensitivity, specificity, and positive/negative predictive values (97.6%, 98.3%, 95.3%, and 99.1%, respectively). When the diagnostic criteria were combined with pathological criteria, the values further improved to 100%, 98.3%, 95.5%, and 100%, respectively. Conclusions: Our results suggest that these novel criteria offer good sensitivity, specificity, and positive/negative predictive values for the diagnosis and classification of ABPM.

DOI： 10.1016/j.resinv.2016.01.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.55.5227

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective The long-term clinical course and prognosis of patients with chronic eosinophilic pneumonia (CEP) including factors predictive of the relapse of CEP have not been fully investigated. The aim of the present study was to investigate these issues.
Methods We retrospectively investigated the rate of relapse and prognosis in 73 patients diagnosed as having CEP.
Results Systemic corticosteroid therapy was administered at a prednisolone dose of 29.4 +/- 7.6 mg/day. During a median follow-up period of 1,939 days, 27 patients suffered from relapse of CEP. Two patients developed steroid-induced diabetes mellitus, and 1 patient developed pulmonary nontuberculous mycobacteriosis. Five patients died; however, none died of CEP. A history of smoking was the only independent negative risk factor for relapse of CEP [hazard ratio, 0.37 (0.14-0.98)].
Conclusion Patients with CEP frequently relapse. During the follow-up, metabolic and infectious complications under prolonged corticosteroid therapy are problematic. A history of smoking was a negative factor for predicting the risk of CEP relapse.

DOI： 10.2169/internalmedicine.55.6765

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