Publications by authors named "Hiroki Yamaguchi"

202 Publications

A novel nairovirus associated with acute febrile illness in Hokkaido, Japan.

Nat Commun 2021 Sep 20;12(1):5539. Epub 2021 Sep 20.

International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, 001-0020, Sapporo, Japan.

The increasing burden of tick-borne orthonairovirus infections, such as Crimean-Congo hemorrhagic fever, is becoming a global concern for public health. In the present study, we identify a novel orthonairovirus, designated Yezo virus (YEZV), from two patients showing acute febrile illness with thrombocytopenia and leukopenia after tick bite in Hokkaido, Japan, in 2019 and 2020, respectively. YEZV is phylogenetically grouped with Sulina virus detected in Ixodes ricinus ticks in Romania. YEZV infection has been confirmed in seven patients from 2014-2020, four of whom were co-infected with Borrelia spp. Antibodies to YEZV are found in wild deer and raccoons, and YEZV RNAs have been detected in ticks from Hokkaido. In this work, we demonstrate that YEZV is highly likely to be the causative pathogen of febrile illness, representing the first report of an endemic infection associated with an orthonairovirus potentially transmitted by ticks in Japan.
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http://dx.doi.org/10.1038/s41467-021-25857-0DOI Listing
September 2021

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.

Blood Adv 2021 Aug 27. Epub 2021 Aug 27.

National Cancer Center Hospital, Tokyo.

Mutations of CCAAT/enhancer binding protein alpha (CEBPAmu) are found in 10-15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not appear to improve prognosis. We investigated the CEBPAmu for prognosis in 1028 AML patients, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (p<0.001), better overall survival (OS; p<0.001) and a lower risk of relapse (p<0.001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients, OS: p=0.008; the cumulative incidence of relapse (CIR): p=0.063. patients aged ≤70 years and with intermediate-risk karyotype, OS: p=0.008; CIR: p=0.026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio: 0.3287; p<0.001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA mutated AML.
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http://dx.doi.org/10.1182/bloodadvances.2021004292DOI Listing
August 2021

Laboratory diffracted x-ray blinking to monitor picometer motions of protein molecules and application to crystalline materials.

Struct Dyn 2021 Jul 8;8(4):044302. Epub 2021 Jul 8.

AIST-UTokyo Advanced Operando Measurement Technology Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Kashiwa 277-0882, Japan.

In recent years, real-time observations of molecules have been required to understand their behavior and function. To date, we have reported two different time-resolved observation methods: diffracted x-ray tracking and diffracted x-ray blinking (DXB). The former monitors the motion of diffracted spots derived from nanocrystals labeled onto target molecules, and the latter measures the fluctuation of the diffraction intensity that is highly correlated with the target molecular motion. However, these reports use a synchrotron x-ray source because of its high average flux, resulting in a high time resolution. Here, we used a laboratory x-ray source and DXB to measure the internal molecular dynamics of three different systems. The samples studied were bovine serum albumin (BSA) pinned onto a substrate, antifreeze protein (AFP) crystallized as a single crystal, and poly{2-(perfluorooctyl)ethyl acrylate} (PCFA) polymer between polyimide sheets. It was found that not only BSA but also AFP and PCFA molecules move in the systems. In addition, the molecular motion of AFP molecules was observed to increase with decreasing temperature. The rotational diffusion coefficients (D) of BSA, AFP, and PCFA were estimated to be 0.73 pm/s, 0.65 pm/s, and 3.29 pm/s, respectively. Surprisingly, the D of the PCFA polymer was found to be the highest among the three samples. This is the first report that measures the molecular motion of a single protein crystal and polymer by using DXB with a laboratory x-ray source. This technique can be applied to any kind of crystal and crystalline polymer and provides atomic-order molecular information.
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http://dx.doi.org/10.1063/4.0000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270646PMC
July 2021

The safety and efficacy of the long-acting neuraminidase inhibitor laninamivir octanoate hydrate for Inhalation Suspension Set in children under the age of 5 in a post-marketing surveillance.

J Infect Chemother 2021 Oct 2;27(10):1436-1446. Epub 2021 Jul 2.

Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Introduction: We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug.

Methods: Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert.

Results: Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0-39.0) h in type A virus (785 patients), 45.0 (34.0-56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials.

Conclusion: The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses.
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http://dx.doi.org/10.1016/j.jiac.2021.06.004DOI Listing
October 2021

Case of slowly progressive type 1 diabetes mellitus with drastically reduced insulin secretory capacity after immune checkpoint inhibitor treatment for advanced renal cell carcinoma.

Diabetol Int 2021 Apr 24;12(2):234-240. Epub 2020 Aug 24.

Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-cho Tennoujiku, Osaka, 543-0035 Japan.

We encountered a 55-year-old Japanese man with advanced renal cell carcinoma and slowly progressive type 1 diabetes mellitus (SPT1DM), whose insulin secretory capacity was drastically reduced for a brief period after only one cycle of immune checkpoint inhibitor (ICI) treatment. The patient had been diagnosed with type 2 diabetes at the age of 53 years and was treated using oral hypoglycemic agents. However, 2 years later, he was diagnosed with SPT1DM and autoimmune thyroiditis, based on the presence of anti-glutamic acid decarboxylase antibodies (GADA) and thyroid autoantibodies, which was accompanied by advanced renal cell carcinoma. At that time, his insulin secretory capacity was preserved (CPR 2.36 ng/mL), and good glycemic control was maintained using only medical nutrition therapy (HbA1c 6.3%). He subsequently developed destructive thyroiditis approximately 2 weeks after the first cycle of ICI treatment using nivolumab (a programmed cell death-1 inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen-4 inhibitor) for advanced renal cell carcinoma. Three weeks later, his plasma glucose level markedly increased, and we detected absolute insulin deficiency and hypothyroidism. Human leukocyte antigen (HLA) analysis revealed haplotypes indicating susceptibility to type 1 diabetes mellitus (T1DM) or autoimmune thyroiditis (HLA genotype, DRB1-DQB1 *09:01-*03:03/*08:03-*06:01). He showed a good antitumor response and is currently receiving permanent insulin therapy and levothyroxine replacement with the ICI treatment. Based on this case and the available literature, patients with preexisting islet autoantibodies or SPT1DM/LADA, plus a genetic predisposition to T1DM, may have an extremely high risk of developing ICI-related T1DM for a brief period after starting ICI treatment.
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http://dx.doi.org/10.1007/s13340-020-00459-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943686PMC
April 2021

Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.

Intern Med 2021 15;60(6):905-910. Epub 2021 Mar 15.

Department of Diabetes and Endocrinology, Osaka Police Hospital, Japan.

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
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http://dx.doi.org/10.2169/internalmedicine.5578-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024957PMC
April 2021

[Overview].

Authors:
Hiroki Yamaguchi

Rinsho Ketsueki 2021 ;62(2):99-100

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http://dx.doi.org/10.11406/rinketsu.62.99DOI Listing
May 2021

Cross β-alkylation of primary alcohols catalysed by DMF-stabilized iridium nanoparticles.

Org Biomol Chem 2021 03;19(9):1950-1954

Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan. [email protected] kansai-u.ac.jp.

A simple method for the cross β-alkylation of linear alcohols with benzyl alcohols in the presence of DMF-stabilized iridium nanoparticles was developed. The nanoparticles were prepared in one-step and thoroughly characterized. Furthermore, the optimum reaction conditions have a wide substrate scope and excellent product selectivity.
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http://dx.doi.org/10.1039/d1ob00045dDOI Listing
March 2021

Usability assessment of drug-linking laboratory data listed on prescriptions for outpatients of chiba university hospital.

Sci Rep 2021 01 18;11(1):1715. Epub 2021 Jan 18.

Division of Pharmacy, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku Chiba-shi, Chiba, 260-8677, Japan.

To evaluate the impact of pharmacotherapy on efficacy and safety by providing laboratory data information linked to medicines on outpatient prescriptions from the hospital to the community pharmacy. Beginning on October 28, 2014, standardized laboratory data and drug-linking laboratory data were included with outpatient prescriptions at our hospital. We have created a database of drug-linking laboratory data for all drugs that can be prescribed in Japan. We counted the number of prescription inquiries related to laboratory data from community pharmacies, including those leading to prescription changes. Before laboratory data were listed on outpatient prescriptions, 4 prescription inquiries from community pharmacies per year were related to laboratory data. After our hospital started to list laboratory data, this number rose to 643, 576, 563, and 847 in the first, second, third, and fourth year (P < .05). Of these, 132, 143, 152, and 224 inquiries resulted in prescription changes. Listing laboratory data on outpatient prescriptions avoided 153 contraindications and 84 exacerbations of adverse drug reactions in four years by a prescription inquiry that had never been done before. The efficacy and safety of pharmacotherapy can be improved by listing relevant laboratory data on outpatient prescriptions.
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http://dx.doi.org/10.1038/s41598-021-81344-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814059PMC
January 2021

Rapidly Progressed Distal Arch Aneurysm with Distal Open Stent Graft-Induced New Entry Caused by "Spring-Back" Force.

Ann Vasc Dis 2020 Sep;13(3):343-346

Department of Cardiovascular Surgery, Showa University Koto Toyosu Hospital.

The J Graft Open Stent Graft (JOSG) is used for the frozen elephant trunk procedure in Japan. We report a 70-year-old male who developed a rapidly progressing distal arch aneurysm caused by a distal stent graft-induced new entry (DSINE) 7 months after the procedure. The JOSG was originally implanted at the curved part of the distal arch. It created its initial DSINE on the greater curve and rapidly "sprang" back in 2 months. Urgent thoracic endovascular aortic repair fixed this serious complication. We should remember such rapid progression of DSINE by JOSG and treat its initial sign earlier.
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http://dx.doi.org/10.3400/avd.cr.20-00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751074PMC
September 2020

Leucine Dehydrogenase: Structure and Thermostability.

Subcell Biochem 2021 ;96:355-372

AJINOMOTO Co., Inc, 1-1, Suzuki-Cho, Kawasaki-Ku, Kawasaki-Shi, Kanagawa, 210-8681, Japan.

Thermostability is a key factor in the industrial and clinical application of enzymes, and understanding mechanisms of thermostability is valuable for molecular biology and enzyme engineering. In this chapter, we focus on the thermostability of leucine dehydrogenase (LDH, EC 1.4.1.9), an amino acid-metabolizing enzyme that is an NAD-dependent oxidoreductase which catalyzes the deamination of branched-chain l-amino acids (BCAAs). LDH from Geobacillus stearothermophilus (GstLDH) is a highly thermostable enzyme that has already been applied to quantify the concentration of BCAAs in biological specimens. However, the molecular mechanism of its thermostability had been unknown because no high-resolution structure was available. Here, we discuss the thermostability of GstLDH on the basis of its structure determined by cryo-electron microscopy. Sequence comparison with other structurally characterized LDHs (from Lysinibacillus sphaericus and Sporosarcina psychrophila) indicated that non-conserved residues in GstLDH, including Ala94, Tyr127, and the C-terminal region, are crucial for oligomeric stability through intermolecular interactions between protomers. Furthermore, NAD binding to GstLDH increased the thermostability of the enzyme as additional intermolecular interactions formed on cofactor binding. This knowledge is important for further applications and development of amino acid metabolizing enzymes in industrial and clinical fields.
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http://dx.doi.org/10.1007/978-3-030-58971-4_10DOI Listing
February 2021

[Importance of gene mutation analysis as prognostic factor of acute myeloid leukemia].

Authors:
Hiroki Yamaguchi

Rinsho Ketsueki 2020 ;61(9):1160-1165

Department of Hematology, Nippon Medical School.

In acute myeloid leukemia (AML), a number of chromosomal abnormalities and gene mutations associated with onset and recurrence were discovered by the recent progress of genome analysis technology. The founding did not only have clinical application as prognostic factors and minimal residual disease markers but also contributed to novel molecular targeted drug development. Many new drugs, such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor, have been developed in Europe and the United States. In addition, the second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, which significantly improved the treatment outcome of AML. However, there is still a large disparity in drug availability between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to practical use in Japan. This paper presents an outline of the prognosis stratification and indication of allogenic hematopoietic cell transplantation for AML by gene diagnosis in Japan.
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http://dx.doi.org/10.11406/rinketsu.61.1160DOI Listing
January 2021

Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy.

Nephrol Dial Transplant 2021 01;36(1):75-86

Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear.

Methods: Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils.

Results: Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients.

Conclusions: These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
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http://dx.doi.org/10.1093/ndt/gfaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771982PMC
January 2021

Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia.

Ann Hematol 2021 Jan 9;100(1):217-228. Epub 2020 Oct 9.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II-IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P < 0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P = 0.016), but not in UD recipients (HR 1.1, P = 0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants.
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http://dx.doi.org/10.1007/s00277-020-04290-1DOI Listing
January 2021

[Significance of detecting minimal/measurable residual disease utilizing genetic mutations in acute myeloid leukemia].

Authors:
Hiroki Yamaguchi

Rinsho Ketsueki 2020 ;61(8):965-970

Department of Hematology, Nippon Medical School.

Owing to recent advances in genome analysis technology, many chromosomal abnormalities and gene mutations involved in leukemia onset or recurrence have been discovered in acute myeloid leukemia. These findings contribute to not only the clinical usage, such as prognostic factors or minimal/measurable residual disease (MRD) markers, but also to the development of novel molecular-targeted drugs. In this study, the utility of MRD analysis using the NPM1 mutation and prognosis analysis using a highly sensitive KIT mutation detection method will be outlined.
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http://dx.doi.org/10.11406/rinketsu.61.965DOI Listing
October 2020

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia; A subgroup analysis of the CEDMIC trial.

Int J Infect Dis 2020 Nov 3;100:292-297. Epub 2020 Sep 3.

General Medical Research Center, Fukuoka University, Japan.

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings.

Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy.

Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups.

Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.
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http://dx.doi.org/10.1016/j.ijid.2020.08.081DOI Listing
November 2020

Development of a novel formula for estimating the amylose content of starch using japonica milled rice flours based on the iodine absorption curve.

Biosci Biotechnol Biochem 2020 Nov;84(11):2347-2359

Faculty of Applied Life Science, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.

The apparent amylose content (AAC) is usually measured by an iodine colorimetric method using the starch as a sample. Nevertheless, it is time-consuming and labor-intensive to prepare rice starch. Therefore, we compared two methods, starch method and milled rice flour method. The former AACs were higher than the latter and correlated with pasting properties, physical properties and sensory scores better than the latter. Therefore, we developed a novel formula for estimating the AACs of starches from japonica rice cultivars using milled rice flours instead of using rice starch. The correlation coefficients of the new formula were 0.89 for calibration and 0.94 for validation, which showed that this equation can be applied to unknown japonica rice samples, and will lead to easy, rapid, and accurate iodine method to determine rice AACs using milled rice flours instead of starch. Abbreviations: AAC: apparent amylose content; RS: resistant starch; SLC: super-long chain; CD: chain length distribution; RVA: Rapid Visco Analyzer; SB: setback; BD: breakdown; Max.vis: maximum viscosity; Min.vis: minimum viscosity; Pt: pasting temperature; Cons: consistency; Final.vis: Final viscosity; SB/Cons: setback/consistency; Max/Min: maximum viscosity/minimum viscosity; Max/Fin: maximum viscosity/final viscosity.
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http://dx.doi.org/10.1080/09168451.2020.1794786DOI Listing
November 2020

Clinical characteristics and brain MRI findings in myeloproliferative neoplasms.

J Neurol Sci 2020 Sep 19;416:116990. Epub 2020 Jun 19.

Department of Neurology, Nippon Medical School, Tokyo, Japan.

Background: Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV) and essential thrombocythemia (ET) have an increased risk of ischemic stroke. However, little is known about brain morphological changes and the cerebral vasculature in MPNs. The aim of the present study is to clarify the prevalence rates of brain infarcts (BIs) on magnetic resonance imaging (MRI) and to assess the detailed clinical and MRI characteristics in those patients.

Methods: We prospectively enrolled patients with MPNs who underwent brain MRI between September 2017 and June 2019. BI patterns were characterized by the numbers and locations of BIs on MRI.

Results: A total of 101 patients were included in the present study. BIs were observed in 23 patients (23%). Multiple logistic regression analysis showed that age > 60 years (odds ratio (OR) 7.34, 95% confidence interval (CI) 1.08-49.7, p = .041) and history of thrombosis (OR 40.6, 95% CI 7.97-207, p < .0001) were independently associated with BIs, but not the JAK2V617F mutation. Of the 23 patients with BIs, eight patients (35%) had multiple territorial infarcts, and large vessel involvement was identified in five patients (22%). Two patients had thrombus formation in large vessels.

Conclusions: Among patients with MPNs who underwent MRI, BIs were observed in 23% of patients followed up in our center. Older age and thrombosis history were independently associated with BIs. Some patients with MPNs may present with distinctive MRI findings including multiple territorial infarcts and thrombus formation in large vessels.
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http://dx.doi.org/10.1016/j.jns.2020.116990DOI Listing
September 2020

Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

Nat Genet 2020 07 8;52(7):669-679. Epub 2020 Jun 8.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
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http://dx.doi.org/10.1038/s41588-020-0640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968075PMC
July 2020

The prognostic impact of FLT3-ITD, NPM1 and CEBPa in cytogenetically intermediate-risk AML after first relapse.

Int J Hematol 2020 Aug 3;112(2):200-209. Epub 2020 Jun 3.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

We evaluated the impact of FLT3-ITD, NPM1 mutations, and double mutant CEBPa (dmCEBPa) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16-65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed FLT3-ITD, NPM1 mutations and CEBPa using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with dmCEBPa. Patients with FLT3-ITD had significantly worse OS after relapse than those without (19% vs 41%, p = 0.002), while OS was comparable between patients with and without NPM1 mutations (37% vs 34%, p = 0.309). Patients with dmCEBPa had improved OS than those without (61% vs 32%, p = 0.006). By multivariate analysis, FLT3-ITD was independently associated with worse OS after relapse [hazard ratio (HR) 1.99, 95% CI 1.27-3.12, p = 0.003], and dmCEBPa with improved OS (HR 0.40, 95% CI 0.17-0.93, p = 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.
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http://dx.doi.org/10.1007/s12185-020-02894-xDOI Listing
August 2020

[Genetic analysis and targeted therapy for acute myeloid leukemia].

Authors:
Hiroki Yamaguchi

Rinsho Ketsueki 2020 ;61(4):350-357

Department of Hematology, Nippon Medical School.

Several chromosomal abnormalities and gene mutations involved in the onset and recurrence of acute myeloid leukemia (AML) were discovered with the recent progress of genome analysis technology. The founding not only have clinical application as prognostic factors and minimal residual disease markers but also contribute to the novel molecular-targeted drug development. Many new drugs such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor have been developed in Europe and the United States. In addition, second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, and the treatment outcome of AML has been improved. However, a large disparity in the drug availability remains between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to the practical use in Japan. In this paper, molecular-targeted drug treatment by gene diagnosis will be considered for AML in Japan, and the future paradigm shift of gene diagnosis and treatment of AML will be outlined.
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http://dx.doi.org/10.11406/rinketsu.61.350DOI Listing
July 2020

The sensitivity of the -ITD detection method is an important consideration when diagnosing acute myeloid leukemia.

Leuk Res Rep 2020 19;13:100198. Epub 2020 Apr 19.

Department of Hematology, Nippon Medical School, Tokyo, Japan.

-internal tandem duplication (-ITD) is a key predictive factor for the prognosis of acute myeloid leukemia (AML). We compared the detection sensitivity of fragment analysis with that of PCR-electrophoresis using MV4-11 (-ITD) and NKM-1 (-wild type) cell lines. DNA of these cells was mixed at different ratios and subjected to PCR-electrophoresis or fragment analysis. PCR-electrophoresis was found to have an -ITD allelic ratio (AR) detection limit of 0.034-0.072. Visual inspection of the PCR-electrophoresis revealed a lower detection sensitivity than that of fragment analysis. Therefore, it is essential to conduct fragment analysis when screening for -ITD.
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http://dx.doi.org/10.1016/j.lrr.2020.100198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184170PMC
April 2020

Preemptive angioplasty for contralateral leg stenosis following EXCLUDER Iliac Branch Endoprosthesis implantation.

J Surg Case Rep 2020 Jan 22;2020(1):rjz191. Epub 2020 Jan 22.

Department of Cardiovascular Surgery, Showa University Koto Toyosu Hospital, Tokyo, Japan.

The GORE EXCLUDER Iliac Branch Endoprosthesis (IBE) device is designed to seal off a common iliac artery (CIA) aneurysm, preserving the internal iliac artery during endovascular aortic repair. We report the case of an 84-year-old man with isolated saccular right CIA aneurysm (35 mm) and a relatively small terminal aorta (24 mm). The IBE device was successfully placed, and intraoperative angiography revealed no leakage or delay. However, postoperative computed tomography revealed marked compression of the contralateral leg by a bridging component. Although his ankle-brachial index was preserved, its acute occlusion was judged highly possible; we decided to perform preemptive angioplasty. The angiography revealed the stenosis only in the left anterior oblique view, and angioplasty was uneventfully performed. The leg was successfully patent at 1-year follow-up. When compression by IBE and bridging component in the terminal aorta is expected, caution should be preserved at intraoperative angiography following the device deployment.
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http://dx.doi.org/10.1093/jscr/rjz191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115704PMC
January 2020

Presence of Promyelocytes in Peripheral Blood as a Novel Predictor of Optimal Timing for Single-Step Peripheral Blood Stem Cell Collection.

J Nippon Med Sch 2021 Mar 31;88(1):45-53. Epub 2020 Mar 31.

Department of Hematology, Nippon Medical School.

Background: Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed.

Methods: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 10 CD34-positive cells/kg (range: 0.3-47.4 × 10 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 10 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed.

Results: The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 10/μL; range: 1.60-47.4 × 10 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment.

Conclusion: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-104DOI Listing
March 2021

No sex-related difference in achievement of treatment-free remission following treatment with tyrosine kinase inhibitors in chronic myeloid leukemia.

Int J Hematol 2020 Jun 31;111(6):904. Epub 2020 Mar 31.

Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8603, Japan.

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http://dx.doi.org/10.1007/s12185-020-02865-2DOI Listing
June 2020

JSH Practical Guidelines for Hematological Malignancies, 2018: I. Leukemia-1. Acute myeloid leukemia (AML).

Int J Hematol 2020 May 23;111(5):595-613. Epub 2020 Mar 23.

Department of Hematology and Oncology, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.

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http://dx.doi.org/10.1007/s12185-020-02856-3DOI Listing
May 2020

TERT and TERC mutations detected in cryptic dyskeratosis congenita suppress telomerase activity.

Int J Lab Hematol 2020 Jun 9;42(3):316-321. Epub 2020 Mar 9.

Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.

Introduction: A cryptic form of dyskeratosis congenita (cDKC) has a gradual onset without the characteristic physical findings of DKC. cDKC is distinguished from other forms of bone marrow failure (BMF) through analysis of telomere shortening and gene mutations. Mutations in the telomerase reverse transcriptase (TERT) and telomere RNA component (TERC) genes have been detected in most Japanese cDKC patients. Therefore, we investigated the impact of each TERT and TERC mutation on telomerase activity.

Methods: TERT and TERC mutants observed in DKC or cDKC patients were transfected into Saos-2 or VA13+TERT (TERT-expressing VA13 cells) cells to measure telomerase activity.

Results: Telomerase activity in cells expressing a mutant detected in cDKC patients was significantly lower (P < .0001) than in cells expressing the wild-type genes. In addition, some TERT mutations seen in cDKC (p.P632R, p.T726M) caused weaker (P = .0013) suppression of telomerase activity than others (p.G106W and p.G682D). In contrast, telomerase activity in cells expressing a TERT or TERC mutant detected in DKC patients did not significantly differ from cells expressing the wild-type genes.

Conclusion: These findings suggest that TERT and TERC mutations detected in cDKC patients could potentially contribute to the pathogenesis of cDKC by blocking telomerase activity. However, TERT and TERC mutations detected in DKC patients did not affect telomerase activities, which means studying the telomerase activity of mutants are not always useful for the diagnosis of DKC.
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http://dx.doi.org/10.1111/ijlh.13176DOI Listing
June 2020

Measurement of Heat Transfer from Anodic Oxide Film on Aluminum in High Knudsen Number Flows.

Micromachines (Basel) 2020 Feb 25;11(3). Epub 2020 Feb 25.

Department of Micro-Nano Mechanical Science and Engineering, Nagoya University, Nagoya 464-8603, Japan.

The heat transfer in vacuum depends on the gas-surface interaction. In this study, the heat flux from anodic oxide films on aluminum with different anodizing times through a gas confined between two surfaces with different temperatures was studied. We prepared a non-treated surface, a surface with a normal anodizing time of 30 min, and a surface with 90 min, where the formed film would partially dissolve by long time exposure to the solution. The formation of the films was checked by electrical resistance. Scanning electron microscope (SEM) images were obtained for the three sample surfaces. Even though it was difficult to observe the hexagonal cylindrical cell structures on anodic oxide films, the 30 min sample surface was shown to be rough, and it was relatively smooth and powdery for the 90 min sample surface. The heat fluxes from three sample surfaces were measured from the free-molecular to near free-molecular flow regimes, and analyzed to obtain the energy accommodation coefficients. The heat fluxes were well fitted by the fitting curves. The energy accommodation coefficients for both helium and argon increased by anodizing an aluminum sample surface, while they decreased with increasing the anodizing time up to 90 min indicating the dissolution of the film.
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http://dx.doi.org/10.3390/mi11030234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143282PMC
February 2020
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