Publications by authors named "Satoshi Fujii"

410 Publications

Endoscopic resection combined with the Cryoballoon focal ablation system in the porcine normal esophagus: a preclinical study.

BMC Gastroenterol 2021 May 22;21(1):234. Epub 2021 May 22.

Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, 277-8577, Japan.

Background: The Cryoballoon focal ablation system (CbFAS) for dysplastic Barrett's esophagus is simple, time-saving and has high therapeutic efficacy. This study aimed to evaluate the technical feasibility and tissue damage with combination therapy of endoscopic resection (ER) and CbFAS in porcine models.

Methods: Three pigs (A, B, and C) were included, and all ER procedures were performed by endoscopic mucosal resection using the Cap method (EMR). Combination therapy for each pig was performed as follows: (a) CbFAS was performed for a post-EMR mucosal defect for Pig A; (b) CbFAS for post-EMR scar for Pig B, and (c) EMR for post-CbFAS scar for Pig C. All pigs were euthanized at 32 days after the initial procedure, and the tissue damage was evaluated.

Results: All endoscopic procedures were followed as scheduled. None of the subjects experienced anorexia, rapid weight loss, bleeding, and perforation during the observation period. They were euthanized at 32 days after the initial endoscopic procedure. On histological assessment, there was little difference between the tissue that was treated with CbFAS alone and that treated with CbFAS in combination with ER.

Conclusion: Combination therapy with ER and CbFAS can be technically feasible, and its outcome was not significantly different from CbFAS alone in terms of tissue damage.
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http://dx.doi.org/10.1186/s12876-021-01819-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141162PMC
May 2021

Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer.

Gastric Cancer 2021 Jul 16;24(4):780-789. Epub 2021 May 16.

Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan.

Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.
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http://dx.doi.org/10.1007/s10120-021-01196-3DOI Listing
July 2021

Dataset for the reporting of carcinoma of the esophagus in resection specimens: recommendations from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 May 13;114:54-65. Epub 2021 May 13.

Department of Pathology, Radboud University Medical Centre, Nijmegen, 6500, the Netherlands. Electronic address:

Background And Objectives: A standardized data set for esophageal carcinoma pathology reporting was developed based on the approach of the International Collaboration on Cancer Reporting (ICCR) for the purpose of improving cancer patient outcomes and international benchmarking in cancer management.

Materials And Methods: The ICCR convened a multidisciplinary international expert panel to identify the best evidence-based clinical and pathological parameters for inclusion in the data set for esophageal carcinoma. The data set incorporated the current edition of the World Health Organization Classification of Tumours of the Digestive System, and Tumour-Node-Metastasis staging systems.

Results: The scope of the data set encompassed resection specimens of the esophagus and esophagogastric junction with tumor epicenter ≤20 mm into the proximal stomach. Core reporting elements included information on neoadjuvant therapy, operative procedure used, tumor focality, tumor site, tumor dimensions, distance of tumor to resection margins, histological tumor type, presence and type of dysplasia, tumor grade, extent of invasion in the esophagus, lymphovascular invasion, response to neoadjuvant therapy, status of resection margin, ancillary studies, lymph node status, distant metastases, and pathological staging. Additional non-core elements considered useful to report included clinical information, specimen dimensions, macroscopic appearance of tumor, and coexistent pathology.

Conclusions: This is the first international peer-reviewed structured reporting data set for surgically resected specimens of the esophagus. The ICCR carcinoma of the esophagus data set is recommended for routine use globally and is a valuable tool to support standardized reporting, to benefit patient care by providing diagnostic and prognostic best-practice parameters.
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http://dx.doi.org/10.1016/j.humpath.2021.05.003DOI Listing
May 2021

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Cancer Med 2021 Jun 15;10(12):3848-3861. Epub 2021 May 15.

Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe, Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.
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http://dx.doi.org/10.1002/cam4.3927DOI Listing
June 2021

Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 μg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.

J Fungi (Basel) 2021 Apr 16;7(4). Epub 2021 Apr 16.

Department of Infection Control and Prevention, Hyogo College of Medicine, Hyogo 663-8501, Japan.

This systematic review and meta-analysis examined the optimal trough concentration of voriconazole for adult patients with invasive fungal infections. We used stepwise cutoffs of 0.5-2.0 μg/mL for efficacy and 3.0-6.0 μg/mL for safety. Studies were included if they reported the rates of all-cause mortality and/or treatment success, hepatotoxicity, and nephrotoxicity according to the trough concentration. Twenty-five studies involving 2554 patients were included. The probability of mortality was significantly decreased using a cutoff of ≥1.0 μg/mL (odds ratio (OR) = 0.34, 95% confidence interval (CI) = 0.15-0.80). Cutoffs of 0.5 (OR = 3.48, 95% CI = 1.45-8.34) and 1.0 μg/mL (OR = 3.35, 95% CI = 1.52-7.38) also increased the treatment success rate. Concerning safety, significantly higher risks of hepatotoxicity and neurotoxicity were demonstrated at higher concentrations for all cutoffs, and the highest ORs were recorded at 4.0 μg/mL (OR = 7.39, 95% CI = 3.81-14.36; OR = 5.76, 95% CI 3.14-10.57, respectively). Although further high-quality trials are needed, our findings suggest that the proper trough concentration for increasing clinical success while minimizing toxicity is 1.0-4.0 μg/mL for adult patients receiving voriconazole therapy.
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http://dx.doi.org/10.3390/jof7040306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072959PMC
April 2021

Correction: Lättman, K., et al. Perceived Accessibility, Satisfaction with Daily Travel, and Life Satisfaction among the Elderly. 2019, , 4498.

Int J Environ Res Public Health 2021 Apr 12;18(8). Epub 2021 Apr 12.

Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8540, Japan.

There were errors in the original article [...].
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http://dx.doi.org/10.3390/ijerph18084047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069020PMC
April 2021

Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients.

J Infect Chemother 2021 Jul 17;27(7):1051-1057. Epub 2021 Apr 17.

Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

Introduction: The antiviral drug favipiravir has been shown to have in vitro antiviral activity against severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2). In this study, we investigated the clinical benefits and initiation of favipiravir treatment in patients with non-severe coronavirus-disease-2019 (COVID-19).

Methods: This study was a single-center retrospective cohort study. Receiver operating characteristic curves were drawn to calculate the area under the curve, and the optimal cut-off values for the time to initiate favipiravir treatment were calculated to predict defervescence within seven days. Univariate and multivariate Cox regression analyses were performed to identify potential influencing factors of defervescence. This was defined as a body temperature of less than 37 °C for at least 2 days.

Results: Data from 41 patients were used for the efficacy assessment. The days from the onset of fever to defervescence showed a positive correlation with the duration from the onset of fever to initiation of favipiravir treatment (r = 0.548, P < 0.001). The optimal cut-off value was the administration of favipiravir on day 4. Patients were assigned to two groups based on the optimal cut-off value from onset to initiation of favipiravir treatment: early treatment group (within 4-days) and late treatment group (more than 4-days). In the multivariate analysis, when adjusted for age, sex, and days from onset to initiation of favipiravir treatment, the significant factors were male sex and days of initiation of the favipiravir treatment.

Conclusions: We recommend that if favipiravir is to be used for treatment, it should be initiated as early as possible.
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http://dx.doi.org/10.1016/j.jiac.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052467PMC
July 2021

Pathogenic variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis.

Ann Rheum Dis 2021 Mar 31. Epub 2021 Mar 31.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objectives: To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 ().

Methods: Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1-78.0)). Sanger sequencing of was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively.

Results: was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR.

Conclusions: Genetic screening for pathogenic variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in in the female patient is the first to be reported.
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http://dx.doi.org/10.1136/annrheumdis-2021-220089DOI Listing
March 2021

Analytical evaluation of serum non-transferrin-bound iron and its relationships with oxidative stress and cardiac load in the general population.

Medicine (Baltimore) 2021 Feb;100(7):e24722

Department of Cardiology, Nagoya City University Graduate School of Medical Sciences.

Abstract: Excessive iron accumulation provokes toxic effects, especially in the cardiovascular system. Under iron overload, labile free non-transferrin-bound iron (NTBI) can induce cardiovascular damage with increased oxidative stress. However, the significance of NTBI in individuals without iron overload and overt cardiovascular disease has not been investigated. We aimed to examine the distribution of serum NTBI and its relationship with oxidative stress and cardiac load under physiological conditions in the general population.We enrolled individuals undergoing an annual health check-up and measured serum NTBI and derivatives of reactive oxygen metabolites (d-ROM), an oxidative stress marker. In addition, we evaluated serum levels of B-type natriuretic peptide (BNP) to examine cardiac load. We excluded patients with anemia, renal dysfunction, cancer, active inflammatory disease, or a history of cardiovascular disease.A total of 1244 individuals (57.8 ± 11.8 years) were enrolled, all of whom had detectable serum NTBI. d-ROM and BNP showed significant trends across NTBI quartiles. Multivariable regression analysis revealed that serum iron and low-density lipoprotein cholesterol were positively associated with NTBI but that age, d-ROM, and BNP showed an inverse association with this measure. In logistic regression analysis, NTBI was independently associated with a combination of higher levels of both d-ROM and BNP than the upper quartiles after adjustment for possible confounding factors.Serum NTBI concentration is detectable in the general population and shows significant inverse associations with oxidative stress and cardiac load. These findings indicate that serum NTBI in physiological conditions does not necessarily reflect increased oxidative stress, in contrast to the implications of higher levels in states of iron overload or pathological conditions.
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http://dx.doi.org/10.1097/MD.0000000000024722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899901PMC
February 2021

The optimal trough-guided monitoring of vancomycin in children: Systematic review and meta-analyses.

J Infect Chemother 2021 May 6;27(5):781-785. Epub 2021 Feb 6.

Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.

We carried out a systematic review and meta-analysis exploring the relationship between vancomycin (VCM) trough concentrations and its effectiveness and nephrotoxicity in pediatric patients. We conducted our analysis using MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials as electronic databases (June 29, 2019). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 16 studies that were eligible for the meta-analysis. A total of 351 and 3,266 patients were included in the analysis for effectiveness and nephrotoxicity, respectively. Pediatric MRSA infection patients with VCM trough concentrations ≥ 10 μg/mL had significantly lower treatment failure rates (OR 0.54, 95% CI 0.30-0.96). The incidence of nephrotoxicity was significantly higher in trough concentrations ≥ 15 μg/mL than when they were < 15 μg/mL (OR 3.02, 95% CI 2.08-4.38). We identified the optimal VCM trough concentrations associated with effectiveness and nephrotoxicity in pediatric patients with MRSA infection. Further prospective studies are needed to find optimal dosing and monitoring strategy on VCM in pediatric population.
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http://dx.doi.org/10.1016/j.jiac.2021.01.015DOI Listing
May 2021

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer.

ESMO Open 2020 30;5(1):e000624. Epub 2020 Sep 30.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Background: While the BRAF V600E mutation occurs in 5%-15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.

Trial Design: The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m and subsequently 250 mg/m, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.

Trial Registration Numbers: UMIN000031857 and 000031860.
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http://dx.doi.org/10.1136/esmoopen-2019-000624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046405PMC
September 2020

The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.

BMC Infect Dis 2021 Feb 6;21(1):153. Epub 2021 Feb 6.

Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.

Background: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety.

Methods: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47-0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15-20 μg/mL (OR 2.39, 95% CI 1.78-3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18-0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13-3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28-1.01); however, it was not significant in the analysis of mortality.

Conclusions: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.
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http://dx.doi.org/10.1186/s12879-021-05858-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866743PMC
February 2021

Optimal trough concentration of teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus infection: A systematic review and meta-analysis.

J Clin Pharm Ther 2021 Jun 6;46(3):622-632. Epub 2021 Feb 6.

Department of Infection Control and Prevention, Hyogo College of Medicine, Nishinomiya, Japan.

What Is Known And Objective: It has been recommended that the trough concentration (C ) of teicoplanin should be maintained at ≥20 μg/ml for difficult-to-treat complicated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Conversely, C of teicoplanin of at least 10 μg/ml is required for non-complicated MRSA infections. Considering the low incidence of nephrotoxicity for teicoplanin, C  = 15-30 μg/ml has been suggested for most MRSA infections. Thus, we assessed the clinical efficacy and adverse effects of teicoplanin at this target C .

Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials and Ichushi-Web) to identify eligible studies. Studies were included if they provided the incidence of treatment success, mortality in patients with MRSA infection, and/or hepatotoxicity and nephrotoxicity according to the C range.

Results And Discussion: Four trials assessing clinical success (n = 299) and three studies assessing adverse effects (n = 546) were included. C  = 15-30 μg/ml significantly increased the probability of treatment success compared with C  < 15 μg/ml (odds ratio [OR] = 2.68, 95% confidence interval [CI] = 1.14-6.32, p = 0.02). The all-cause mortality rate did not differ between the groups (OR = 0.46, 95% CI = 0.13-1.61, p = 0.22). C  = 15-30 μg/ml did not increase the risks of nephrotoxicity (OR = 0.91, 95% CI = 0.49-1.69, p = 0.76) or hepatotoxicity (OR = 0.67, 95% CI = 0.18-2.44, p = 0.54).

What Is New And Conclusion: Teicoplanin therapy using a C target of 15-30 μg/ml is likely to be associated with better clinical responses than C  < 15 μg/ml without increasing the risk of adverse effects.
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http://dx.doi.org/10.1111/jcpt.13366DOI Listing
June 2021

[Efficacy and Safety of Linaclotide in Elderly Patients].

Yakugaku Zasshi 2021 ;141(2):255-262

Department of Pharmacy, Sapporo Medical University Hospital.

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.
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http://dx.doi.org/10.1248/yakushi.20-00176DOI Listing
May 2021

Efficient Lipid Bilayer Formation by Dipping Lipid-Loaded Microperforated Sheet in Aqueous Solution.

Micromachines (Basel) 2021 Jan 5;12(1). Epub 2021 Jan 5.

Artificial Cell Membrane Systems Group, Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.

This paper describes a method for a bilayer lipid membrane (BLM) formation using a perforated sheet along with an open chamber. Microscopic observation of the formed membrane showed a typical droplet interface bilayer. We proved that the formed membrane was a BLM based on electrical measurements of the membrane protein α-hemolysin, which produces nanopores in BLMs. Unlike the conventional approach for BLM formation based on the droplet contact method, this method provides aqueous surfaces with no organic solvent coating layer. Hence, this method is suitable for producing BLMs that facilitate the direct addition of chemicals into the aqueous phase.
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http://dx.doi.org/10.3390/mi12010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824848PMC
January 2021

Prognostic impact of the tumor immune microenvironment in pulmonary pleomorphic carcinoma.

Lung Cancer 2021 03 8;153:56-65. Epub 2021 Jan 8.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address:

Introduction: Pulmonary pleomorphic carcinoma (PC) is a rare non-small cell lung carcinoma (NSCLC) and is characterized by sarcomatoid and NSCLC components. This study aimed to characterize the association between immune microenvironmental factors and clinicopathological characteristics of PC.

Methods: Eighty consecutive PC patients who had undergone complete surgical resection were enrolled. We calculated the immunohistochemical staining scores for E-cadherin, vimentin, programmed death ligand 1 (PD-L1), and carbonic anhydrase IX in cancer cells and counted the numbers of CD204-positive tumor-associated macrophages (TAMs) and Foxp3-, CD8-, and CD20-positive tumor-infiltrating lymphocytes (TILs). We also examined the association between these scores and the prognostic outcomes.

Results: The staining score for PD-L1 in cancer cells and the number of CD204-positive TAMs in the sarcomatoid component were significantly higher than those in the NSCLC component; E-cadherin score in the sarcomatoid component was significantly lower. Patients with high PD-L1 expression in the NSCLC component had significantly longer overall survival (OS) and recurrence-free survival (RFS) than those with low PD-L1 expression in the NSCLC component (OS: p = 0.001, RFS: p = 0.038). Multivariate analysis revealed that high PD-L1 expression in the NSCLC component was an independent favorable prognostic factor for OS (p = 0.018), whereas high PD-L1 expression in the sarcomatoid component was not. The number of CD8-positive TILs was significantly higher in the high PD-L1 expression group than in the low expression group (NSCLC components: p < 0.001).

Conclusion: High PD-L1 expression in the NSCLC component may be associated with a favorable prognostic value in pulmonary PC.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.007DOI Listing
March 2021

Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma.

Lung Cancer 2021 03 24;153:1-10. Epub 2020 Dec 24.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address:

Aim: Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) harbor a fibrous tumor microenvironment that promotes cancer progression in lung adenocarcinoma. In this study, we investigated whether tumor-promoting PDPN CAFs contribute to the immunosuppressive microenvironment in lung squamous cell carcinoma (SqCC). M&M: The gene expression profiles of immunosuppressive cytokines were compared using The Cancer Genome Atlas (TCGA) microarray lung SqCC data (n = 484) between a PDPN-high group and a PDPN-low group. Further, using patient-derived CAFs from surgically resected lung SqCC, the PDPN fraction was sorted and gene and protein expressions were analyzed. Finally, immunohistochemical staining was conducted on 131 surgically resected lung SqCC; CD8 and FOXP3 tumor infiltrating lymphocytes (TILs), and CD204 tumor-associated macrophages (TAMs) were evaluated in cases with PDPN and PDPN CAFs.

Results: Analysis of TCGA database revealed that the PDPN-high group exhibited significantly higher expression of interleukin (IL)-1A, IL-1B, IL-6, IL-10, monocyte chemoattractant protein-1 (CCL2), colony stimulating factor 1 (CSF1), fibroblast growth factor 2 (FGF2), galectin 1 (LGALS1), platelet derived growth factor subunit A (PDGFA), PDGFB, and transforming growth factor-β1 (TGFB1) than those in the PDPN-low group. Among them, it was found that TGFB1 expression was higher in patient-derived PDPN CAFs. Immunohistochemical analyses revealed that more CD204 TAMs infiltrated the tumor tissues in cases with PDPN CAFs than in cases with PDPN CAFs (P <  0.03), while CD8 and FOXP3 TILs did not. Furthermore, in the same tumor, CD204 TAMs infiltrated more in PDPN CAF-rich areas (P =  0.005).

Conclusion: PDPN CAFs showed higher expression of TGFB1 and were associated with CD204 TAM infiltration in stage-I lung SqCC, suggesting that PDPN CAFs were associated with the immunosuppressive tumor microenvironment.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.020DOI Listing
March 2021

Nuclear grade and comedo necrosis of ductal carcinoma in situ as histopathological eligible criteria for the Japan Clinical Oncology Group 1505 trial: an interobserver agreement study.

Jpn J Clin Oncol 2021 Mar;51(3):434-443

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.

Objective: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists.

Methods: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics.

Results: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753).

Conclusion: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.
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http://dx.doi.org/10.1093/jjco/hyaa235DOI Listing
March 2021

Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2020 Nov 13. Epub 2020 Nov 13.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address:

Background: The prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear.

Patients And Methods: This study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing.

Results: Between 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036).

Conclusion: HER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.
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http://dx.doi.org/10.1016/j.clcc.2020.11.002DOI Listing
November 2020

Optimal trough concentration of voriconazole with therapeutic drug monitoring in children: A systematic review and meta-analysis.

J Infect Chemother 2021 Feb 26;27(2):151-160. Epub 2020 Dec 26.

Department of Infection Control and Prevention, Hyogo College of Medicine, Nishinomiya, Japan.

Objectives: This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs).

Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0-2.0 mg/L for efficacy and 3.0-6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events.

Results: Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20-5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36-51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e), no correlation was demonstrated for neurotoxicity (y = 0.3913e).

Conclusion: Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0-3.0 mg/L.
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http://dx.doi.org/10.1016/j.jiac.2020.11.014DOI Listing
February 2021

A Lipid-Bilayer-On-A-Cup Device for Pumpless Sample Exchange.

Micromachines (Basel) 2020 Dec 18;11(12). Epub 2020 Dec 18.

Artificial Cell Membrane Systems Group, Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.

Lipid-bilayer devices have been studied for on-site sensors in the fields of diagnosis, food and environmental monitoring, and safety/security inspection. In this paper, we propose a lipid-bilayer-on-a-cup device for serial sample measurements using a pumpless solution exchange procedure. The device consists of a millimeter-scale cylindrical cup with vertical slits which is designed to steadily hold an aqueous solution and exchange the sample by simply fusing and splitting the solution with an external solution. The slit design was experimentally determined by the capabilities of both the retention and exchange of the solution. Using the optimized slit, a planar lipid bilayer was reconstituted with a nanopore protein at a microaperture allocated to the bottom of the cup, and the device was connected to a portable amplifier. The solution exchangeability was demonstrated by observing the dilution process of a blocker molecule of the nanopore dissolved in the cup. The pumpless solution exchange by the proposed cup-like device presents potential as a lipid-bilayer system for portable sensing applications.
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http://dx.doi.org/10.3390/mi11121123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767076PMC
December 2020

Real-Time Facile Detection of the WO Catalyst Oxidation State under Microwaves Using a Resonance Frequency.

ACS Omega 2020 Dec 1;5(49):31957-31962. Epub 2020 Dec 1.

School of Materials and Chemical Technology, Tokyo Institute of Technology, E4-3, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8552, Japan.

Microwaves (MWs) are often used to enhance various heterogeneous catalytic reactions. Here, we demonstrate real-time monitoring of a catalyst's oxidation state in a microwave catalytic reaction using a resonance frequency. The changes in the catalyst's oxidation state during the reaction induced changes in the resonance frequency in the cavity resonator. The resonance frequency was not affected by 2-propanol adsorption, while the frequency decreased with the reduction of WO → WO. That is, the redox state of the WO catalyst could be detected using the resonance frequency. The oxidation state of the WO catalyst was then directly observed by the resonance frequency during the dehydration reaction of 2-propanol by microwaves as a model reaction. Resonance frequency monitoring revealed that the enhanced dehydration of 2-propanol by microwaves was attributable to the reduction of the WO catalyst. Moreover, the temporal changes in the oxidation state of the WO catalyst detected by the resonance frequency coincided with that observed by Raman spectroscopy. Therefore, real-time resonance frequency monitoring allowed facile detection of the bulk catalyst oxidation state under microwaves without using any spectroscopic apparatus.
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http://dx.doi.org/10.1021/acsomega.0c04862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745404PMC
December 2020

Case Reports: Transformation of End-Stage Neuroendocrine Tumors With Uncontrollable Liver Metastasis Into a Novel or Additional Functional Phenotype.

Front Oncol 2020 25;10:555963. Epub 2020 Sep 25.

Department of Oncology, Yokohama City University Hospital, Yokohama, Japan.

Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events. A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration. The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.
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http://dx.doi.org/10.3389/fonc.2020.555963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544986PMC
September 2020

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity.

J Infect Chemother 2021 Feb 17;27(2):256-261. Epub 2020 Oct 17.

Department of Infection Prevention and Control, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. Electronic address:

Introduction: Antimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity.

Methods: We conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin.

Results: No randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12-0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01-0.21).

Conclusions: Although further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.
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http://dx.doi.org/10.1016/j.jiac.2020.09.033DOI Listing
February 2021

FMS-like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer.

Cancer Sci 2021 Jan 20;112(1):314-322. Epub 2020 Nov 20.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

FMS-like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co-altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co-alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non-FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.
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http://dx.doi.org/10.1111/cas.14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780005PMC
January 2021

Impact of DNA integrity on the success rate of tissue-based next-generation sequencing: Lessons from nationwide cancer genome screening project SCRUM-Japan GI-SCREEN.

Pathol Int 2020 Dec 8;70(12):932-942. Epub 2020 Oct 8.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

In the nationwide cancer genome screening project SCRUM-Japan GI-SCREEN, 2590 archival formalin-fixed paraffin-embedded (FFPE) tumor tissues from 19 institutions were analyzed with two tissue-based next-generation sequencing (NGS) panels at the Clinical Laboratory Improvement Amendments (CLIA)-certified College of American Pathologists (CAP)-accredited central laboratory. The Oncomine Cancer Research Panel (OCP; 143 genes) succeeded in producing validated results for only 68.3% of the samples (%OCP-success). CE-IVD (25 genes) succeeded in 45.9% of the OCP-failed samples, leading to an overall NGS success (%combined-success) rate as high as 82.9%. Among 2573 samples, the DNA-integrity (ΔC )-high (ΔC  < 4.4, n = 1253) samples showed significantly higher %OCP- and %combined-success rates (90.2% and 97.4%, respectively) than the DNA-integrity-intermediate (4.4 < ΔC  < 6.3, n = 911; 68.9% and 88.7%) and DNA-integrity-low ones (ΔC  > 6.3 or polymerase chain reaction-failed, n = 409; 5.6% and 24.7%). Other factors associated with NGS success included the FFPE-sample storage period (<4 years), the specimen type (surgical) and the primary tumor site (colorectal). Multivariable analysis revealed DNA integrity as the factor with the strongest independent association with NGS success, although it was suggested that other institution-specific factors contribute to the discordance of inter-institutional NGS success rates. Our results emphasize the importance of DNA quality in FFPE samples for NGS tests and the impact of DNA integrity on quality monitoring of pathology specimens for achieving successful NGS.
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http://dx.doi.org/10.1111/pin.13029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820973PMC
December 2020

Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.

Sci Rep 2020 09 23;10(1):15530. Epub 2020 Sep 23.

Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified HSD17B4 methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only HSD17B4 methylation was significantly different. The HSD17B4 methylation was at the transcriptional start site of its major variant, and was associated with its silencing. HSD17B4 was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and HSD17B4 methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy, HSD17B4 methylation was the most reliable marker to monitor response to the therapy. These results showed that HSD17B4 methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.
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http://dx.doi.org/10.1038/s41598-020-72661-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511952PMC
September 2020

CERS6 required for cell migration and metastasis in lung cancer.

J Cell Mol Med 2020 10 9;24(20):11949-11959. Epub 2020 Sep 9.

Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.
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http://dx.doi.org/10.1111/jcmm.15817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579715PMC
October 2020

Relationship of pulmonary function with myocardial microdamage and oxidative stress in the Japanese population without a history of cardiopulmonary disease.

Medicine (Baltimore) 2020 Aug;99(35):e21945

Department of Cardiology, Nagoya City University Graduate School of Medical Sciences.

An association between pulmonary and cardiovascular impairment has been reported, but studies are lacking that focus on individuals without advanced impairment in the pulmonary or cardiovascular system. We aimed to investigate the relationship between myocardial microdamage and reduced pulmonary function in the Japanese population without a history of cardiopulmonary disease and to assess whether oxidative stress links the 2 features.We enrolled patients undergoing an annual health check-up and measured serum high-sensitivity cardiac troponin I (hs-cTnI) and derivatives of reactive oxygen metabolites (d-ROM) to evaluate myocardial microdamage and oxidative stress. To assess pulmonary function, we calculated forced vital capacity as a percentage of predicted value, forced expiratory volume in 1 second as a percentage of predicted value, and the ratio of forced expiratory volume in 1 second to forced vital capacity. Possible associations between each parameter of pulmonary function, hs-cTnI, and d-ROM were cross-sectionally investigated.The study included 1265 participants (57 ± 12 years). In multivariate regression analysis, the forced vital capacity as a percentage of predicted value was inversely associated with hs-cTnI levels after adjustment for possible confounders. In another multivariate model, all indices of pulmonary function were inversely correlated with d-ROM levels. We observed similar relationships in a multivariate regression model that included hs-cTnI and d-ROM simultaneously as independent variables. Levels of d-ROM and hs-cTnI also were significantly associated.These results highlight an inverse association of pulmonary function with hs-cTnI and d-ROM in the Japanese population without a history of cardiopulmonary disease. The findings suggest that in individuals without obvious cardiovascular and pulmonary diseases, reduced pulmonary function could reflect myocardial microdamage, at least in part through increased oxidative stress.
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http://dx.doi.org/10.1097/MD.0000000000021945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458258PMC
August 2020

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis.

J Infect Chemother 2021 Jan 20;27(1):26-31. Epub 2020 Aug 20.

Department of Infection Control and Prevention, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. Electronic address:

Introduction: Arbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis.

Methods: A literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web.

Results: Nine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15-16 μg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30-1.24). A trough arbekacin concentration of <2 μg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15-0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39-0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16-1.75).

Conclusions: Once-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 μg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15-16 μg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.
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http://dx.doi.org/10.1016/j.jiac.2020.08.002DOI Listing
January 2021