Publications by authors named "Satoshi Yasuda"

732 Publications

Intra-individual Comparisons of the Ultrasound-Guided Attenuation Parameter and the Magnetic Resonance Imaging-Based Proton Density Fat Fraction Using Bias and Precision Statistics.

Ultrasound Med Biol 2022 May 22. Epub 2022 May 22.

Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.

Ultrasound-based techniques using the attenuation coefficient, including the ultrasound-guided attenuation parameter (UGAP), have been developed for the quantification of hepatic steatosis. The magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) is considered to be more accurate than liver biopsy for liver fat quantification. The aim of this study was to perform intra-individual comparisons of UGAP and MRI-PDFF for determining hepatic steatosis grade. The study enrolled 309 patients who underwent UGAP and MRI-PDFF measurements. Bland-Altman analysis was conducted after transforming MRI-PDFF values to a normal distribution and converted to a common set of units using linear regression analysis for differing scales. The expected limits of agreement (LOA) was defined as the square root of the sum of the squares of UGAP and MRI-PDFF precision. A Bland-Altman plot revealed that the bias and upper and lower LOAs (ULOA and LLOA) were -0.0047, 0.1160 and -0.1255, respectively. The percentage difference indicated that the mean, ULOA and LLOA were -1.1434%, 18.1723% and -20.4590%, respectively. The calculated expected LOA was 18.5449%, and 283 of 309 patients (91.6%) had a percentage difference within 18.5449%. Bland-Altman analysis revealed that UGAP and MRI-PDFF were interchangeable within a clinically acceptable range.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2022.03.019DOI Listing
May 2022

Impact of statins in patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

J Cardiol 2022 May 21. Epub 2022 May 21.

Department of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.

Background: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood.

Methods: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors.

Results: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98).

Conclusion: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients.
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http://dx.doi.org/10.1016/j.jjcc.2022.03.009DOI Listing
May 2022

The prognosis of elderly patients with hepatocellular carcinoma: A multi-center 19-year experience in Japan.

Cancer Med 2022 May 24. Epub 2022 May 24.

Department of Nursing, Gifu Kyoritsu University, Japan.

Aims: This retrospective study compared the survival between elderly and non-elderly patients.

Methods: A total of 5545 treatment-naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively.

Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non-elderly patients, the median albumin-bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non-elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non-elderly patients did (p = 0.017). Non-liver-related death in elderly patients significantly differed among periods (p = 0.023), while liver-related death did not (p = 0.050). Liver- and non-liver-related death in non-elderly patients significantly differed among periods (p < 0.001, p = 0.005).

Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient.
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http://dx.doi.org/10.1002/cam4.4850DOI Listing
May 2022

C-reactive protein to albumin ratio predicts survival in patients with unresectable hepatocellular carcinoma treated with lenvatinib.

Sci Rep 2022 May 19;12(1):8421. Epub 2022 May 19.

Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2-22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495-2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.
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http://dx.doi.org/10.1038/s41598-022-12058-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120140PMC
May 2022

Misunderstanding of hepatitis C virus (HCV) infection status by non-specialized medical doctors in patients who achieved sustained virologic response to anti-HCV therapy.

J Infect Chemother 2022 May 6. Epub 2022 May 6.

Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.

Introduction: With the increase in the number of patients with sustained virologic response (SVR) in whom hepatitis C virus (HCV) was eradicated by the anti-HCV therapy, there are now many individuals in whom serum HCV RNA is absent despite positive serum HCV antibodies. However, in general clinical practice, HCV infection remains usually screened by measurement of serum HCV antibodies and patients with SVR can be misunderstood regarding HCV infection status.

Methods: In the multicenter study, we conducted interviews with administered questionnaires to SVR individuals who had regular hospital visits after SVR. The prevalence of experiencing an incorrect diagnosis of HCV infection after SVR was assessed. Individuals who experienced this misunderstanding were further asked where they experienced it and how it made them feel.

Results: In a survey of 2,246 SVR individuals, 197 individuals (8.8%) were misunderstood as having persistent HCV infection by medical doctors due to positive HCV antibody, despite the absence of HCV viremia. These misunderstandings occurred most prevalently at a private clinic (55.3%). More than half (53.3%) of these individuals felt anxious about their HCV infection with becoming unsure about their HCV eradication status.

Conclusions: Misunderstanding HCV status is commonly occurred in SVR individuals. Specialists in hepatology and infectious diseases should broadly emphasize the fact that most patients with HCV antibodies are now HCV-free because of the use of anti-HCV therapy.
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http://dx.doi.org/10.1016/j.jiac.2022.04.024DOI Listing
May 2022

Liver Stiffness Measurements by 2D Shear-Wave Elastography: Effect of Steatosis on Fibrosis Evaluation.

AJR Am J Roentgenol 2022 May 4. Epub 2022 May 4.

Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.

Please see the Editorial Comment by Maxime Ronot discussing this article. Hepatic steatosis has been shown to not effect liver stiffness measurements (LSM) by MR elastography (MRE). However, the effect of steatosis on LSM by 2D shear-wave elastography (SWE) remains controversial. To evaluate the effect of hepatic steatosis on the diagnostic performance of LSM from 2D SWE (hereafter, LSM2D-SWE) for evaluation of liver fibrosis, using LSM from MRE (hereafter, LSMMRE) as the reference standard. This retrospective study included 888 patients (442 women, 446 men; median age, 67 years) with chronic liver disease who underwent LSM by both 2D SWE and MRE within a 3-month window. Steatosis was also assessed on the ultrasound examinations by ultrasound-guided attenuation parameter (UGAP) and on the MRI examinations by MRI-based proton-density fat fraction (MRI-PDFF). Fibrosis stages and steatosis grades were classified using previously established thresholds. The effect of steatosis on LSM2D-SWE was evaluated using Kruskal-Wallis tests with post hoc tests and ROC analysis. LSM2D-SWE was significantly higher in patients with severe steatosis than no steatosis by MRI-PDFF among patients with F0 fibrosis [5.5 (interquartile range [IQR], 4.7-6.0) vs 4.7 (IQR, 4.2-5.5), p=.009)] and F1 fibrosis [6.3 (IQR, 6.0-7.2) vs 5.9 (IQR, 5.0-6.6), p=.009]. LSM2D-SWE was significantly higher in patients with severe steatosis than no steatosis by UGAP among patients with F1 fibrosis [6.6 (IQR, 5.9-7.3) vs 5.9 (IQR, 5.1-6.5), p=.008)]. Otherwise, LSM2D-SWE did not vary significantly across steatosis grades at a given fibrosis stage (all p>.05). Sensitivity and specificity for ≥F1 fibrosis were 63.8% and 91.5% in patients without, versus 60.4% and 80.9% in patients with, severe steatosis by MRI-PDFF, and were 62.4% and 91.5% in patients without, versus 72.1% and 78.3% in patients with, severe steatosis by UGAP. Severe hepatic steatosis may result in overestimation of LSM2D-SWE in patients with no or mild steatosis, thus reducing specificity for liver fibrosis detection. UGAP performed at the time of 2D SWE may help identify patients in whom LSM2D-SWE should be assessed with caution. In patients with no or mild steatosis by 2D SWE and severe steatosis by UGAP, MRE may help provide a more reliable measure of liver fibrosis.
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http://dx.doi.org/10.2214/AJR.22.27656DOI Listing
May 2022

Crizotinib for ROS1-rearranged lung cancer and pulmonary tumor thrombotic microangiopathy under venoarterial extracorporeal membrane oxygenation.

Pulm Circ 2022 Jan 21;12(1):e12047. Epub 2022 Feb 21.

Department of Cardiovascular Medicine National Cerebral and Cardiovascular Center Suita Japan.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive subtype of pulmonary hypertension (PH) associated with impaired right ventricular adaptation and very poor prognosis in cancer, and its rapid progression makes antemortem diagnosis and treatment extremely difficult. We describe the case of a 35-year-old woman who developed severe PH with subsequent circulatory collapse. The patient was clinically diagnosed with PTTM induced by lung adenocarcinoma harboring the c-ros oncogene 1 (ROS1) rearrangement within 1-2 weeks, while hemodynamics were stabilized by rescue venoarterial extracorporeal membrane oxygenation support. Crizotinib, an oral tyrosine kinase inhibitor targeting anaplastic lymphoma kinase, MET, and ROS1 kinase domains dramatically resolved PH, resulting in more than 3 years of survival. Targeted gene-tailored therapy with mechanical support can improve survival in PTTM.
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http://dx.doi.org/10.1002/pul2.12047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052980PMC
January 2022

Update on the roles of imaging in the management of chronic thromboembolic pulmonary hypertension.

J Cardiol 2022 Apr 27. Epub 2022 Apr 27.

Department of Diagnostic Radiology, Tohoku University Hospital, Sendai, Miyagi, Japan.

Chronic thromboembolic pulmonary hypertension (CTEPH), classified as group 4 pulmonary hypertension (PH), is caused by stenosis and obstruction of the pulmonary arteries by organized thrombi that are incompletely resolved after acute pulmonary embolism. The prognosis of patients with CTEPH is poor if untreated; however, in expert centers with multidisciplinary teams, a treatment strategy for CTEPH has been established, dramatically improving its prognosis. CTEPH is currently not a fatal disease and is the only curable form of PH. Despite these advances and the establishment of treatment approaches, early diagnosis is still challenging, especially for non-experts, for several reasons. One of the reasons for this is insufficient knowledge of the various diagnostic imaging modalities, which are essential in the clinical practice of CTEPH. Imaging modalities should detect the following pathological findings: lung perfusion defects, thromboembolic lesions in pulmonary arteries, and right ventricular remodeling and dysfunction. Perfusion lung scintigraphy and catheter angiography have long been considered gold standards for the detection of perfusion defects and assessment of vascular lesions, respectively. However, advances in imaging technology of computed tomography and magnetic resonance imaging have enabled the non-invasive detection of these abnormal findings in a single examination. Cardiac magnetic resonance (CMR) is the gold standard for evaluating the morphology and function of the right heart; however, state-of-the-art techniques in CMR allow the assessment of cardiac tissue characterization and hemodynamics in the pulmonary arteries. Comprehensive knowledge of the role of imaging in CTEPH enables appropriate use of imaging modalities and accurate image interpretation, resulting in early diagnosis, determination of treatment strategies, and appropriate evaluation of treatment efficacy. This review summarizes the current roles of imaging in the clinical practice for CTEPH, demonstrating the characteristic findings observed in each modality.
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http://dx.doi.org/10.1016/j.jjcc.2022.03.001DOI Listing
April 2022

Renin-angiotensin system blocker and the COVID-19 aggravation in patients with hypertension, diabetes, renal failure, Cerebro-cardiovascular disease, or pulmonary disease: Report by the COVID-19 Registry Japan.

J Cardiol 2022 Apr 8. Epub 2022 Apr 8.

Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: The role of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in the pandemic context of coronavirus disease 2019 (COVID-19) continues to be debated. Patients with hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or chronic obstructive pulmonary disease (COPD), who often use ACEi/ARB, may be at risk of severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population.

Methods: This study is an observational study of patients with a positive severe acute respiratory syndrome coronavirus 2 test and inpatient treatment at a healthcare facility, using the registry information of COVIREGI-JP. Our primary outcomes were in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and intensive care unit admission. Out of the 6055 patients, 1921 patients with preexisting hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or COPD were enrolled.

Results: Factors associated with an increased risk of the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes mellitus. No correlations were observed with ACEi/ARB, cerebro-cardiovascular diseases, or hypertension. Associated factors in male patients were aging, renal impairment, hypertension, and diabetes. In female patients, factors associated with an increased risk were aging, ACEi/ARB, renal impairment, and diabetes, whereas hypertension was associated with a lower risk of the primary outcomes.

Conclusions: Independent factors for the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes, but not ACEi/ARB. Based on this registry data analysis, more detailed data collection and analysis is needed with the cooperation of multiple healthcare facilities.
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http://dx.doi.org/10.1016/j.jjcc.2022.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989871PMC
April 2022

Treatment strategies and in-hospital mortality in patients with type A acute aortic dissection and coronary artery involvement.

J Thorac Cardiovasc Surg 2022 Mar 29. Epub 2022 Mar 29.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Objective: Type A acute aortic dissection (AAD), especially that with coronary artery involvement and malperfusion, is a life-threatening disease. In the present study we aimed to investigate the association of surgical treatment and percutaneous coronary intervention (PCI) with in-hospital mortality in patients with type A AAD and coronary artery involvement.

Methods: This retrospective multicenter registry in Japan included 225 patients with type A AAD and coronary artery involvement. Treatment strategies including surgical treatment and/or PCI were left to treating physicians. The primary end point was in-hospital death.

Results: Of 225 patients, dissection extended into the right and left coronary arteries and both in 115 (51.1%), 105 (46.7%), and 5 (2.2%), respectively. Overall, 94 (41.8%) patients died during the hospitalization. Coronary angiography was performed in 53 (23.6%) patients, among whom 39 (73.6%) underwent PCI. Surgical repair was performed in 188 (83.6%) patients. In patients who received neither procedure, 33 of 35 (94.3%) died during the hospitalization. PCI was performed as a bridge to surgical repair in 37 of 39 (94.9%) patients, and in-hospital mortality of patients who underwent PCI and surgical procedures was 24.3%. Multivariable analysis identified PCI and surgical procedures as factors associated with lower in-hospital mortality rates.

Conclusions: Coronary artery involvement in type A AAD was associated with high in-hospital mortality of more than 40% in the current era. An early reperfusion strategy with PCI as a bridge to surgical repair might improve clinical outcomes in this fatal condition.
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http://dx.doi.org/10.1016/j.jtcvs.2022.03.016DOI Listing
March 2022

Optical coherence tomography in coronary atherosclerosis assessment and intervention.

Nat Rev Cardiol 2022 Apr 21. Epub 2022 Apr 21.

Centro Cardiologico Monzino, IRCCS, Milan, Italy.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.
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http://dx.doi.org/10.1038/s41569-022-00687-9DOI Listing
April 2022

Correlation Between Genetic Abnormalities in Induced Pluripotent Stem Cell-Derivatives and Abnormal Tissue Formation in Tumorigenicity Tests.

Stem Cells Transl Med 2022 Apr 21. Epub 2022 Apr 21.

R&D Center for Cell Therapy, Foundation for Biomedical Research and Innovation, Kobe, Japan.

Cell therapy using induced pluripotent stem cell (iPSC) derivatives may result in abnormal tissue generation because the cells undergo numerous cycles of mitosis before clinical application, potentially increasing the accumulation of genetic abnormalities. Therefore, genetic tests may predict abnormal tissue formation after transplantation. Here, we administered iPSC derivatives with or without single-nucleotide variants (SNVs) and deletions in cancer-related genes with various genomic copy number variant (CNV) profiles into immunodeficient mice and examined the relationships between mutations and abnormal tissue formation after transplantation. No positive correlations were found between the presence of SNVs/deletions and the formation of abnormal tissues; the overall predictivity was 29%. However, a copy number higher than 3 was correlated, with an overall predictivity of 86%. Furthermore, we found CNV hotspots at 14q32.33 and 17q12 loci. Thus, CNV analysis may predict abnormal tissue formation after transplantation of iPSC derivatives and reduce the number of tumorigenicity tests.
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http://dx.doi.org/10.1093/stcltm/szac014DOI Listing
April 2022

Safety and efficacy of atezolizumab plus bevacizumab in elderly patients with hepatocellular carcinoma: A multicenter analysis.

Cancer Med 2022 Apr 19. Epub 2022 Apr 19.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.

Aim: The safety and efficacy of atezolizumab plus bevacizumab (Atez/Bev) in elderly patients with unresectable hepatocellular carcinoma (HCC) have not been sufficiently investigated.

Methods: A total of 317 patients with HCC treated with Atez/Bev were studied. We compared the survival and frequency of adverse events in elderly versus non-elderly patients with HCC who were treated with Atez/Bev using an analysis of inverse probability weighting (IPW).

Results: Univariate analysis adjusted with IPW showed that being elderly is not associated with worse overall or progression-free survival (hazard ratio [HR], 1.239; 95% confidence interval [CI], 0.640-2.399; p = 0.526 and HR, 1.256; 95% CI, 0.871-1.811; p = 0.223, respectively). Regarding treatment-related adverse events, any grade of fatigue, proteinuria, decreased appetite, hypertension, and liver injury occurred in ≥10% of patients. There were no significant differences in treatment-related adverse events between the elderly and non-elderly groups. In a subgroup analysis of elderly patients aged 75-79, 80-84, or ≥ 85 years, there were no significant differences in cumulative overall or progression-free survival among these age groups (p = 0.960 and 0.566, respectively). In addition, there were no significant differences in treatment-related adverse events among these three age groups, except for proteinuria of any grade. In a subgroup analysis of patients treated with Atez/Bev as first-line systemic therapy, there were no significant differences in cumulative overall or progression-free survival between the elderly and non-elderly groups (p = 0.728 and 0.805, respectively).

Conclusions: Atez/Bev can be used efficaciously and safely in spite of age in patients with unresectable HCC.
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http://dx.doi.org/10.1002/cam4.4763DOI Listing
April 2022

Prognostic impact of a history of cancer and atrial fibrillation in antithrombotic therapy for chronic heart failure.

ESC Heart Fail 2022 Apr 17. Epub 2022 Apr 17.

Department of Cardiovascular Medicine, Tohoku University Hospital, Seiryo-machi 1-1-1, Aobaku, Sendai, Miyagi, 9810933, Japan.

Aims: This study aimed to examine the prognostic significance of a history of cancer and atrial fibrillation (AF) in antithrombotic therapy for patients with chronic heart failure (CHF).

Methods And Results: We enrolled consecutive 4876 CHF patients (69 ± 12 years; women, 31.9%) in our multicentre, hospital-based cohort study, the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2), with a median follow-up of 8.7 years. Among them, 14% and 41% had a history of cancer and AF, respectively. AF patients with a history of cancer were older, more frequently men. History of cancer was not statistically associated with higher rate of composite of stroke, systemic thrombosis, and major bleeding defined by International Society on Thrombosis and Haemostasis [Fine-Gray sub-distribution hazard ratio (sHR) accounting for the competing risk of all-cause death, 0.91; 95% confidence interval (CI), 0.56-1.48; P = 0.715]. The patients with history of cancer and AF had a heightened risk for the composite of stroke, systemic thrombosis, and major bleeding (sHR, 1.64; 95% CI, 1.04-2.60; P = 0.033), especially in those aged >75 years (sHR, 2.14; 95% CI, 1.01-4.53; P = 0.046) and those with ischaemic heart disease (IHD; 2.48; 1.30-4.72; P = 0.006). Furthermore, 36% of AF patients with a history of cancer did not receive anticoagulant therapy.

Conclusions: The CHF patients with history of cancer and AF had higher risk for stroke, systemic thrombosis, and major bleeding, especially in the elderly and those with IHD, but considerable number of the patients did not receive anticoagulant therapy, indicating the need for better optimal anticoagulation strategy.
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http://dx.doi.org/10.1002/ehf2.13941DOI Listing
April 2022

Mac-2-binding protein glycan isomer predicts all malignancies after sustained virological response in chronic hepatitis C.

Hepatol Commun 2022 Mar 28. Epub 2022 Mar 28.

Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.

Despite reports of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection after achieving sustained virological response (SVR), only few studies have demonstrated the incidence of other (non-HCC) malignancies. This study aimed to clarify the incidence, survival probability, and factors associated with malignancy, especially non-HCC malignancies, in patients with chronic HCV infection after achieving SVR. In this retrospective study, records of 3580 patients with chronic HCV infection who achieved SVR following direct-acting antiviral (DAA) treatment were analyzed. The cumulative post-SVR incidence of non-HCC malignancies was 0.9%, 3.1%, and 6.8% at 1, 3, and 5 years, respectively. The survival probability for patients with non-HCC malignancies was 99.1%, 78.8%, and 60.2% at 1, 3, and 5 years, respectively, and the rate was significantly lower than that for patients with HCC. The Cox proportional hazards regression model identified Mac-2-binding protein glycan isomer (M2BPGi) cutoff index (COI) ≥ 1.90 at baseline and ≥ 1.50 at 12 weeks following DAA treatment as significant and independent factors associated with the post-SVR incidence of non-HCC malignancies. Furthermore, patients with either M2BPGi COI ≥ 1.90 at baseline or M2BPGi COI ≥ 1.50 at SVR12 had a significantly higher risk of post-SVR incidence of non-HCC malignancies than of HCC. Conclusion: M2BPGi measurements at baseline and SVR12 may help predict the post-SVR incidence of non-HCC malignancies in patients with chronic HCV infection who achieved SVR following DAA treatment. Early identification of these patients is critical to prolong patient survival.
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http://dx.doi.org/10.1002/hep4.1941DOI Listing
March 2022

Usefulness of Right Ventricular Free Wall Strain Obtained with Two-Dimensional Speckle-Tracking Echocardiography in Patients with Repaired Tetralogy of Fallot and Pulmonary Regurgitation.

Tohoku J Exp Med 2022 May 24;257(1):7-15. Epub 2022 Mar 24.

Biomedical Imaging Laboratory, Tohoku University Graduate School of Medicine.

Right ventricular (RV) dysfunction caused by chronic pulmonary regurgitation (PR) is a major determinant of clinical outcome in adults with repaired tetralogy of Fallot (rTOF). However, the accurate assessment of RV function by conventional echocardiography remains challenging. This study tested the feasibility and usefulness of RV free-wall (RVFW) strain obtained by two-dimensional (2D) speckle-tracking echocardiography (STE) in evaluation of RV function in adults with rTOF by comparing cardiac magnetic resonance (CMR) imaging. We enrolled 22 consecutive patients (male/female, 8/14; mean age, 25.0 years) with rTOF who underwent transthoracic echocardiography at Tohoku University Hospital from July 2016 to June 2019. We measured RVFW strain by STE and compared them with 22 hemodynamically normal subjects (NOR) (male/female, 9/13; mean age, 32.0 years). The correlation between RV strain and CMR-derived RV ejection fraction (RVEF) or PR fraction (PRF) were also evaluated. All rTOF patients had more than moderate PR but were near asymptomatic. RVFW longitudinal strain (RVFW-LS) was significantly decreased in the rTOF group compared with that in the NOR group (-19.6 vs. -24.7, P < 0.01). In the rTOF group, RVFW-LS correlated with PRF (r = 0.44, P < 0.05), whereas RVFW circumferential strain at the mid-ventricular level correlated with RVEF (r = 0.57, P < 0.01). Intra-observer variability of RVFW strain was acceptable. These results indicate that RV systolic function and PR severity in rTOF could be assessed by RVFW strain measured by 2D STE. This method is feasible and can be used as a complement to CMR imaging.
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http://dx.doi.org/10.1620/tjem.2022.J011DOI Listing
May 2022

Clinically Relevant Late-Onset Biliary Complications After Pancreatoduodenectomy.

World J Surg 2022 Jun 19;46(6):1465-1473. Epub 2022 Mar 19.

Department of Surgery, Nara Medical University, 840 Shijo cho, Kashihara, Nara, 634 8522, Japan.

Background: Late-onset biliary complications (LBC) after pancreatoduodenectomy (PD) can be serious. This study aimed to clarify the frequency and risk factors of severe LBC after PD.

Methods: We defined LBC as biliary complications occurring 3 months after PD and severe LBC as cases that required intensive care. A total of 318 patients who underwent PD between 2010 and 2018 with at least 1 year of postoperative follow-up were evaluated.

Results: Hospitalization for severe LBC was required in 59 patients (19%), of whom 20 had liver abscesses (6.3%); 18, acute cholangitis (5.7%); 12, biliary stones (3.8%); and 21, biliary strictures (6.6%). Interventional radiological or endoscopic treatment was required in 32 patients (10%), of whom 9 had a benign primary disease with biliary stones and/or strictures. Thirteen of the remaining 23 patients with a malignant primary disease had liver abscesses and cholangitis. Significant independent risk factors for severe LBC in patients with malignant primary disease were recurrence around the hepaticojejunostomy (odds ratio 6.5, P = 0.013) and chemotherapy (odds ratio 13.5, P < 0.001).

Conclusions: Severe LBC after PD may occur regardless of whether the primary disease is benign or malignant. The course of severe LBC differs according to the primary disease, and therefore, appropriate follow-up and optimal treatment should be recommended according to the condition of the patient and the disease state.
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http://dx.doi.org/10.1007/s00268-022-06511-2DOI Listing
June 2022

Impact of laparoscopic liver resection on liver regeneration.

Surg Endosc 2022 Mar 11. Epub 2022 Mar 11.

Department of Surgery, Nara Medical University, 840 Shijo, Kashihara, Nara, 634-8522, Japan.

Background: Liver regeneration after liver resection plays an important role in preventing posthepatectomy liver failure. In this study, we aimed to evaluate and compare the impact of laparoscopic liver resection (LLR) and open liver resection (OLR) on liver regeneration.

Methods: Patients who underwent curative anatomical liver resection for hepatocellular carcinoma, cholangiocellular carcinoma, and colorectal liver metastases at our institution between January 2010 and December 2018 were included in this study. The patients were divided into the OLR and LLR groups. Preoperative liver volume (PLV), future remnant liver volume, resected liver volume (RLV), liver volume at 1 month after the surgery, and liver volume at 6 months after the surgery were calculated. The liver regeneration rate was defined as the increase in the rate of RLV, and the liver recovery rate was defined as the rate of return to the PLV.

Results: The study included 72 patients. Among them, 43 were included in the OLR group and 29 were included in the LLR group. No differences were observed in the baseline characteristics and surgical procedures between the two groups. Moreover, no significant difference was observed in the liver regeneration rate at 1 month after the surgery (OLR vs. LLR: 68.9% vs. 69.0%, p = 0.875) and at 6 months after the surgery (91.8% vs. 93.2%, p = 0.995). Furthermore, the liver recovery rates were not significantly different between the two groups at 1 month after the surgery (90.3% vs. 90.6%, p = 0.893) and at 6 months after the surgery (96.9% vs. 98.8%, p = 0.986).

Conclusion: Liver regeneration after liver resection is not affected by the type of surgical procedure and both laparoscopic and open procedures yield similar regeneration and recovery rates.
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http://dx.doi.org/10.1007/s00464-022-09155-4DOI Listing
March 2022

Associations among cardiovascular and cerebrovascular diseases: Analysis of the nationwide claims-based JROAD-DPC dataset.

PLoS One 2022 11;17(3):e0264390. Epub 2022 Mar 11.

President, Kumamoto University, Kumamoto, Japan.

Cardiovascular and cerebrovascular diseases are frequently interconnected due to underlying pathology involving atherosclerosis and thromboembolism. The aim of this study was to investigate the impact of clinical interactions among cardiovascular and cerebrovascular diseases on patient outcomes using a large-scale nationwide claims-based dataset. Cardiovascular diseases were defined as myocardial infarction, heart failure, atrial fibrillation, and aortic dissection. Cerebrovascular diseases were defined as cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage. This retrospective study included 2,736,986 inpatient records (1,800,255 patients) at 911 hospitals from 2015 to 2016 from Japanese registry of all cardiac and vascular disease-diagnostic procedure combination dataset. Interactions among comorbidities and complications, rehospitalization, and clinical outcomes including in-hospital mortality were investigated. Among hospitalization records that involved cardiovascular disease, 5.9% (32,686 records) had cerebrovascular disease as a comorbidity and 2.1% (11,362 records) included an incident cerebrovascular complication after hospitalization. Cerebrovascular disease as a comorbidity or complication was associated with higher in-hospital mortality than no cerebrovascular disease (adjusted odds ratio (OR) [95% confidence interval]: 1.10 [1.06-1.14], 2.02 [1.91-2.13], respectively). Among 367,904 hospitalization records that involved cerebrovascular disease, 17.7% (63,647 records) had cardiovascular disease listed as comorbidity and 3.3% (11,834 records) as a complication. Only cardiovascular disease as a complication was associated with higher in-hospital mortality (adjusted OR [95% confidence interval]: 1.29 [1.22-1.37]). In addition, in-hospital mortality during rehospitalization due to the other disease was significantly higher than mortality during the hospitalization due to the first disease. In conclusion, substantial associations were observed between cardiovascular and cerebrovascular disease in a large-scale nationwide claims-based dataset; these associations had a significant impact on clinical outcomes. More intensive prevention and management of cardiovascular and cerebrovascular disease might be crucial.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264390PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916648PMC
April 2022

The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial.

BMC Med 2022 02 25;20(1):69. Epub 2022 Feb 25.

Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan.

Background: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy.

Methods: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events.

Results: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group.

Conclusions: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function.

Trial Registration: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.
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http://dx.doi.org/10.1186/s12916-022-02268-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876785PMC
February 2022

Adherence to regular surveillance visits for hepatocellular carcinoma in patients with chronic hepatitis C virus infection who achieved sustained virologic response.

Eur J Gastroenterol Hepatol 2022 Jun 14;34(6):693-697. Epub 2022 Feb 14.

Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.

Objective: Patients with chronic hepatitis C virus (HCV) infection who achieve sustained virologic response (SVR) to anti-HCV therapy, that is the eradication of HCV, are recommended to continue regular hospital visits for the surveillance of hepatocellular carcinoma (HCC) that can develop after SVR. However, it is unclear how well patients with SVR adhere to post-SVR follow-up over the long term. We investigated this adherence and the factors associated with it.

Methods: Medical record data on regular hospital visits were reviewed in 1329 patients with no history of HCC who achieved SVR by anti-HCV therapy. At the time of SVR confirmation, all patients were advised to continue regular visits, and the risk of post-SVR HCC was explained. The adherence rate of post-SVR follow-up and associated factors were analyzed.

Results: Adherence rates decreased continuously over time, as follows: 76.6% at 5 years, 62.4% at 10 years, 48.8% at 15 years, and 35.3% at 20 years after SVR. Adherence rates did not differ based on the degree of baseline liver fibrosis and were significantly lower in patients who achieved SVR by interferon (IFN)-free therapy and those with HCV genotype 2b.

Conclusion: Adherence to post-SVR follow-up decreased over the long term, and rates differed by patient background. Adherence was especially poor in patients who achieved SVR by IFN-free therapy, and therefore, strategies are necessary to encourage these patients to maintain their regular schedule of hospital visits.
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http://dx.doi.org/10.1097/MEG.0000000000002358DOI Listing
June 2022

Neutrophil-lymphocyte ratio predicts early outcomes in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab: a multicenter analysis.

Eur J Gastroenterol Hepatol 2022 Jun 14;34(6):698-706. Epub 2022 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo.

Objective: To investigate whether neutrophil-to-lymphocyte ratio (NLR) can predict outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev).

Methods: A total of 249 patients with unresectable HCC treated with Atez/Bev were included. We analyzed survival and discontinuation of this therapy in this cohort.

Results: Cumulative overall survival at 2, 4, 6, and 8 months was 97.6%, 94.9%, 88.9%, and 82.8%, respectively. Cumulative overall survival differed significantly between patients with low (<3.0) versus high (≥3.0) NLR (P = 0.001). Conversely, cumulative progression-free survival did not differ between patients with low versus high NLR. The distribution of response was 1.5% for complete response, 17.1% for partial response, 60.5% for stable disease, and 21.0% for progressive disease. Responses were not different between patients with low and high NLR. Regarding adverse events, immune-related liver injury of any grade and grade of at least 3, decreased appetite of any grade, grade of at least 3 proteinuria, and other adverse events of any grade differed significantly between patients with low and high NLR. There were 56, 18, and 2 patients who discontinued Atez/Bev therapy due to progression of disease, adverse event, and other reasons, respectively. The cumulative discontinuation rate for Atez/Bev therapy due to adverse events differed significantly between patients with low versus high NLR (P = 0.022). Cox proportional hazards modeling analysis with inverse probability weighting showed that NLR of at least 3.0 was significantly associated with overall survival (hazard ratio, 3.369; 95% confidence interval, 1.024-11.080).

Conclusions: NLR can predict outcomes in patients with unresectable HCC treated with Atez/Bev.
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http://dx.doi.org/10.1097/MEG.0000000000002356DOI Listing
June 2022

The association between time to extracorporeal cardiopulmonary resuscitation and outcome in patients with out-of-hospital cardiac arrest.

Eur Heart J Acute Cardiovasc Care 2022 Feb 10. Epub 2022 Feb 10.

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

Aims: Extracorporeal cardiopulmonary resuscitation (ECPR) is considered for potentially reversible out-of-hospital cardiac arrest (OHCA). However, the association between time to ECPR and outcome has not been well established.

Methods And Results: Between June 2014 and December 2017, we enrolled 34 754 OHCA patients in a multicentre, prospective fashion [Japanese Association for Acute Medicine (JAAM)-OHCA registry]. After the application of exclusion criteria, 695 OHCA patients who underwent ECPR for cardiac causes were eligible for this study. We investigated the association between the call-to-ECPR interval and favourable neurological outcome (cerebral performance category 1 or 2) at 30 days. Seventy-seven patients (11%) had a favourable neurological outcome at 30 days. The call-to-ECPR intervals in these patients were significantly shorter than in those with an unfavourable neurological outcome [49 (41-58) vs. 58 (48-68) min, respectively, P < 0.001]. A longer call-to-ECPR interval was associated with a smaller proportion of patients undergoing percutaneous coronary intervention (PCI) (P = 0.034) or target temperature management (TTM) (P < 0.001). Stepwise multivariable logistic regression analysis revealed that the call-to-ECPR interval was an independent predictor of favourable neurological outcome [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.94-0.99, P = 0.001], as were age, male gender, initial shockable rhythm, transient return of spontaneous circulation in the prehospital setting, arterial pH at hospital arrival, PCI (OR 2.30, 95% CI 1.14-4.66, P = 0.019), and TTM (OR 2.28, 95% CI 1.13-4.62, P = 0.019).

Conclusion: A shorter call-to-ECPR interval and implementation of PCI and TTM predicted a favourable neurological outcome at 30 days in OHCA patients who underwent ECPR for cardiac causes.
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http://dx.doi.org/10.1093/ehjacc/zuac010DOI Listing
February 2022

Integrative analysis identifies activated anti-tumor immune microenvironment in lung metastasis of pancreatic cancer.

Int J Clin Oncol 2022 May 10;27(5):948-957. Epub 2022 Feb 10.

Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Background: Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup.

Methods: We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features.

Results: We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites.

Conclusion: We identified that lung metastasis revealed an immunologically "hot" tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup.
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http://dx.doi.org/10.1007/s10147-022-02131-xDOI Listing
May 2022

Identification of the suitable candidates for EOB-MRI with the high risk of the presence of non-hypervascular hypointense nodules in patients with HCV infection.

Eur Radiol 2022 Feb 10. Epub 2022 Feb 10.

Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.

Objectives: Non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of progressing to hepatocellular carcinoma (HCC). The presence of NHHNs is a strong risk factor for HCC development in patients with chronic hepatitis C virus (HCV) infection after the achievement of sustained virologic response (SVR). However, it is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection. We therefore explored serum markers that potentially indicate the presence of NHHNs.

Methods: Three serum markers, alpha-fetoprotein (AFP), FIB-4 index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi), were measured in 481 patients with HCV infection and no history of HCC who underwent EOB-MRI. The associations between these serum marker levels and the presence of NHHNs were investigated.

Results: All three markers were associated with the presence of NHHNs. M2BPGi predicted the presence of NHHNs more accurately than AFP and FBB-4 index; M2BPGi had the highest area under the receiver operating characteristic curve. Multivariate analysis identified male gender and high M2BPGi as factors associated with the presence of NHHNs. When patients were stratified by the degree of liver fibrosis, M2BPGi increased with the progression of fibrosis. In addition, NHHNs were more prevalently detected in patients with higher M2BPGi (COI > 3.46) in patients with similar fibrosis degree.

Conclusions: M2BPGi is a serum marker that potentially identifies HCV patients with high risk of the presence of NHHNs, for whom EOB-MRI should be considered.

Key Points: • Non-hypervascular hypointense nodule on EOB-DTPA-enhanced MRI is pre-HCC nodule with high likelihood of progressing to HCC, which is a strong predictor for HCC that develops after the eradication of HCV in patients with HCV infection. • It is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection due to limited access, limited availability of MRI equipment, and high costs. • Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi) levels effectively indicate the presence of NHHNs and can be used to identify patients with high risk of their presence, for whom EOB-DTPA-enhanced MRI should be considered.
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http://dx.doi.org/10.1007/s00330-022-08570-4DOI Listing
February 2022

The Prognostic Significance of the Geriatric Nutritional Risk Index in Colorectal Cancer Patients.

Nutr Cancer 2022 Feb 7:1-8. Epub 2022 Feb 7.

Department of Surgery, Nara Prefectural Seiwa Medical Center, Ikoma, Nara, Japan.

This study retrospectively investigated the prognostic impact of the geriatric nutritional risk index (GNRI) in colorectal cancer (CRC). This study reviewed the medical records of 329 CRC patients who underwent curative surgery. The GNRI was calculated from the serum albumin level and the body weight. The cutoff value for the GNRI was set at 98. One hundred ninety (57.8%) patients had a GNRI of ≥98, and 139 (42.9%) had a GNRI of <98. The patients with a lower GNRI had a significantly lower overall survival (OS) rate than those with a higher GNRI ( 0.001). The multivariate analysis demonstrated that the GNRI was an independent predictor of the OS ( 0.042). Non-cancer death was more frequent in the patients with a lower GNRI than in those with a higher GNRI ( 0.003). The mean age was significantly higher in the patients with a lower GNRI ( < 0.001). The GNRI was significantly associated with tumor location ( 0.048), tumor depth ( 0.001) and carcinoembryonic antigen (CEA) level ( 0.032). The GNRI is a simple and useful prognostic factor in CRC. The present study suggests that a low GNRI be associated with a higher risk of non-cancer death.
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http://dx.doi.org/10.1080/01635581.2022.2036768DOI Listing
February 2022

Controlling the Rigidity of Kinesin-Propelled Microtubules in an Gliding Assay Using the Deep-Sea Osmolyte Trimethylamine -Oxide.

ACS Omega 2022 Feb 24;7(4):3796-3803. Epub 2022 Jan 24.

Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.

The biomolecular motor protein kinesin and its associated filamentous protein microtubule have been finding important nanotechnological applications in the recent years. Rigidity of the microtubules, which are propelled by kinesin motors in an gliding assay, is an important metric that determines the success of utilization of microtubules and kinesins in various applications, such as transportation, sensing, sorting, molecular robotics, etc. Therefore, regulating the rigidity of kinesin-propelled microtubules has been critical. In this work, we report a simple strategy to regulate the rigidity of kinesin-propelled microtubules in an gliding assay. We demonstrate that rigidity of the microtubules, propelled by kinesins in an gliding assay, can be modulated simply by using the natural osmolyte trimethylamine -oxide (TMAO). By varying the concentration of TMAO in the gliding assay, the rigidity of microtubules can be modulated over a wide range. Based on this strategy, we are able to reduce the persistence length of microtubules, a measure of microtubule rigidity, ∼8 fold by using TMAO at the concentration of 1.5 M. Furthermore, we found that the decreased rigidity of the kinesin-propelled microtubules can be restored upon elimination of TMAO from the gliding assay. Alteration in the rigidity of microtubules is accounted for by the non-uniformity of the force applied by kinesins along the microtubules in the presence of TMAO. This work offers a facile strategy to reversibly regulate the rigidity of kinesin-propelled microtubules , which would widen the applications of the biomolecular motor kinesin and its associated protein microtubule in various fields.
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http://dx.doi.org/10.1021/acsomega.1c06699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811939PMC
February 2022

Development of an Outward Proton Pumping Rhodopsin with a New Record in Thermostability by Means of Amino Acid Mutations.

J Phys Chem B 2022 02 28;126(5):1004-1015. Epub 2022 Jan 28.

Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.

We have developed a methodology for identifying further thermostabilizing mutations for an intrinsically thermostable membrane protein. The methodology comprises the following steps: (1) identifying thermostabilizing single mutations (TSSMs) for residues in the transmembrane region using our physics-based method; (2) identifying TSSMs for residues in the extracellular and intracellular regions, which are in aqueous environment, using an empirical force field FoldX; and (3) combining the TSSMs identified in steps (1) and (2) to construct multiple mutations. The methodology is illustrated for thermophilic rhodopsin whose apparent midpoint temperature of thermal denaturation is ∼91.8 °C. The TSSMs previously identified in step (1) were F90K, F90R, and Y91I with Δ ∼5.6, ∼5.5, and ∼2.9 °C, respectively, and those in step (2) were V79K, T114D, A115P, and A116E with Δ ∼2.7, ∼4.2, ∼2.6, and ∼2.3 °C, respectively (Δ denotes the increase in ). In this study, we construct triple and quadruple mutants, F90K+Y91I+T114D and F90K+Y91I+V79K+T114D. The values of Δ for these multiple mutants are ∼11.4 and ∼13.5 °C, respectively. of the quadruple mutant (∼105.3 °C) establishes a new record in a class of outward proton pumping rhodopsins. It is higher than of rhodopsin (∼100.8 °C) that was the most thermostable in the class before this study.
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http://dx.doi.org/10.1021/acs.jpcb.1c08684DOI Listing
February 2022
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