Publications by authors named "Yuta Katayama"

54 Publications

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation.

Transplant Cell Ther 2021 May 12. Epub 2021 May 12.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.
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http://dx.doi.org/10.1016/j.jtct.2021.05.003DOI Listing
May 2021

Impact of the combination of donor age and HLA disparity on the outcomes of unrelated bone marrow transplantation.

Bone Marrow Transplant 2021 May 14. Epub 2021 May 14.

Department of Hematology and Oncology, Kyoto University, Kyoto, Japan.

Impact of donor age considering HLA disparity on hematopoietic cell transplantation (HCT) outcomes has not been fully evaluated. We evaluated 8486 patients who received unrelated bone marrow transplantation (UR-BMT) from 8/8 or 7/8 HLA-matched donors. Compared to 8/8 HLA-matched younger donors (<40 years), 8/8 HLA-matched older donors (subdistribution hazard ratio [SHR], 1.16; 95% CI, 0.97-1.38) and 7/8 HLA-matched younger donors (SHR, 1.33; 95% CI, 1.11-1.58) were associated with increased risk of grade III-IV acute graft-versus-host disease (aGVHD). 7/8 HLA-matched older donors had further increased risk (SHR, 2.00; 95% CI, 1.68-2.38) due to interaction between donor age and HLA disparity (p for interaction = 0.038). Progression-free survival (PFS) after UR-BMT with 8/8 HLA-matched younger donors was comparable to that after UR-BMT with 8/8 HLA-matched older donors, whereas UR-BMT with 7/8 HLA-matched younger or older donors was significantly associated with lower PFS than UR-BMT with 8/8 HLA-matched younger donors (younger donor; HR, 1.12; 95% CI, 1.04-1.21, older donor; HR, 1.28; 95% CI, 1.17-1.40; p for interaction = 0.079). In conclusion, adverse effect of increased donor age requires attention, especially in HLA-mismatched UR-BMT due to interaction between donor age and HLA disparity. Intensive aGVHD prophylaxis may be required to improve outcomes after HCT with mismatched older donors.
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http://dx.doi.org/10.1038/s41409-021-01289-8DOI Listing
May 2021

Elevation of Early Plasma Biomarkers in Patients with Clinical Risk Factors Predicts Increased Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 May 12. Epub 2021 May 12.

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.

Early prediction of nonrelapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on the results of laboratory tests is challenging. Thus, there is a need to evaluate biomarkers for prediction of NRM, a major problem that offsets the advantages of allo-HSCT. We tested the validity and efficacy of 2 plasma biomarkers, ST2 and Reg3α, based on the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm, for early prediction of NRM in Japanese patients who underwent allo-HSCT. We conducted a multicenter retrospective study to analyze the clinical data of 112 patients with hematopoietic malignancies who underwent allo-HSCT. Patient blood samples on day 7 after allo-HSCT were obtained from 6 hospitals. The plasma concentrations of ST2 and Reg3α were used to calculate a 6-month NRM risk score. Based on the scores determined in this study, we identified 64 low-risk patients and 48 high-risk patients for the 6-month NRM. The cumulative incidence of 6-month NRM was 29.2% in the high-risk group and 10.9% in the low-risk group (P < .05). The cumulative incidence of relapse mortality was similar in the high-risk and low-risk patients. The biomarker score was predictive in patients with an unrelated donor, an HLA-mismatched donor, high/very high Disease Risk Index, and Hematopoietic Cell Transplantation Comorbidity Index >0. Multivariate analysis identified high biomarker probability as a significant predictor of NRM. The MAGIC algorithm based on blood samples obtained at 7 days after allo-HSCT can identify individuals at high risk for NRM among patients with clinical risk factors for NRM in a Japanese cohort.
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http://dx.doi.org/10.1016/j.jtct.2021.04.025DOI Listing
May 2021

The autism-associated protein CHD8 is required for cerebellar development and motor function.

Cell Rep 2021 Apr;35(1):108932

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. Electronic address:

Mutations in the gene encoding the chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have long been thought to be related to ASD pathogenesis, it has remained largely unknown whether dysfunction of CHD8 in the cerebellum contributes to ASD phenotypes. We here show that cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 in mice impairs the proliferation and differentiation of these cells as well as gives rise to cerebellar hypoplasia and a motor coordination defect, but not to ASD-like behavioral abnormalities. CHD8 is found to regulate the expression of neuronal genes in GNPs. It also binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in these cells. Our results have thus uncovered a key role for CHD8 in cerebellar development, with important implications for understanding the contribution of this brain region to ASD pathogenesis.
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http://dx.doi.org/10.1016/j.celrep.2021.108932DOI Listing
April 2021

Impact of event-free survival status after stem cell transplantation on subsequent survival of patients with lymphoma.

Blood Adv 2021 03;5(5):1412-1424

Department of Oncology and Hematology, Shimane University Hospital, Izumo, Japan.

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period-matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2020003735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948259PMC
March 2021

The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells.

Cell Rep 2021 Feb;34(5):108688

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Electronic address:

Chromodomain helicase DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin-remodeling factor that is encoded by the most frequently mutated gene in individuals with autism spectrum disorder. CHD8 is expressed not only in neural tissues but also in many other organs; however, its functions are largely unknown. Here, we show that CHD8 is highly expressed in and maintains the stemness of hematopoietic stem cells (HSCs). Conditional deletion of Chd8 specifically in mouse bone marrow induces cell cycle arrest, apoptosis, and a differentiation block in HSCs in association with upregulation of the expression of p53 target genes. A colony formation assay and bone marrow transplantation reveal that CHD8 deficiency also compromises the stemness of HSCs. Furthermore, additional ablation of p53 rescues the impaired stem cell function and differentiation block of CHD8-deficient HSCs. Our results thus suggest that the CHD8-p53 axis plays a key role in regulation of the stemness and differentiation of HSCs.
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http://dx.doi.org/10.1016/j.celrep.2021.108688DOI Listing
February 2021

Effect of cytomegalovirus reactivation with or without acute graft-versus-host disease on the risk of nonrelapse mortality.

Clin Infect Dis 2020 Dec 20. Epub 2020 Dec 20.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

Background: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied.

Methods: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a pre-emptive strategy for CMVR between 2008 and 2017.

Results: The cumulative incidences of grade II-IV acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (HR [hazard ratio], 1.59, 95% CI, 1.24-2.05, P < 0.001) and with G24GVHD (HR, 1.34, 95% CI, 1.06-1.70, P = 0.014), but the interaction between G24GVHD and CMVR was not significant (P = 0.326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics.

Conclusions: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.
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http://dx.doi.org/10.1093/cid/ciaa1871DOI Listing
December 2020

Relapse of acute myeloid leukemia after allogeneic hematopoietic cell transplantation: clinical features and outcomes.

Bone Marrow Transplant 2021 May 2;56(5):1126-1133. Epub 2020 Dec 2.

The Jikei University School of Medicine, Tokyo, Japan.

Posttransplant relapse represents the greatest obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML). This study investigated clinical features and outcomes of posttransplant relapse of AML based on data for 1265 patients with AML suffering relapse after allogeneic HCT conducted during complete remission (CR). Relapse occurred at a median of 6.1 months. The incidence rate of relapse peaked at 29.0 per 100 patient-years during the first 3-6 months period post transplant, after which the rate declined over time, and after 3 years remained consistently at less than 1 per 100 patient-years. The probability of overall survival (OS) after posttransplant relapse was 19% at 2 years, with 68% of deaths being attributed to leukemia. The interval from transplantation to relapse was identified as the strongest indicator for OS. Donor lymphocyte infusion (DLI) and second allogeneic HCT (HCT2) were administered to 152 (12%) and 481 (38%) patients, respectively. Landmark analyses showed some signs of survival benefit when these procedures were performed during CR, but no benefit was gained when performed during non-CR. Our findings clarify clinical features of posttransplant relapse of AML, and indicate the urgent need for developing effective bridging to cellular therapies.
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http://dx.doi.org/10.1038/s41409-020-01163-zDOI Listing
May 2021

Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain.

Mol Brain 2020 11 23;13(1):160. Epub 2020 Nov 23.

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan.

CHD8 encodes a chromatin-remodeling factor and is one of the most recurrently mutated genes in individuals with autism spectrum disorder (ASD). Although we have recently shown that mice heterozygous for Chd8 mutation manifest myelination defects and ASD-like behaviors, the detailed mechanisms underlying ASD pathogenesis have remained unclear. Here we performed diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rsfMRI) in oligodendrocyte lineage-specific Chd8 heterozygous mutant mice. DTI revealed that ablation of Chd8 specifically in oligodendrocytes of mice was associated with microstructural changes of specific brain regions including the cortex and striatum. The extent of these changes in white matter including the corpus callosum and fornix was correlated with total contact time in the reciprocal social interaction test. Analysis with rsfMRI revealed changes in functional brain connectivity in the mutant mice, and the extent of such changes in the cortex, hippocampus, and amygdala was also correlated with the change in social interaction. Our results thus suggest that changes in brain microstructure and functional connectivity induced by oligodendrocyte dysfunction might underlie altered social interaction in mice with oligodendrocyte-specific CHD8 haploinsufficiency.
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http://dx.doi.org/10.1186/s13041-020-00699-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686671PMC
November 2020

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

Effect of allogeneic HCT from unrelated donors in AML patients with intermediate- or poor-risk cytogenetics: a retrospective study from the Japanese Society for HCT.

Ann Hematol 2020 Dec 17;99(12):2927-2937. Epub 2020 Sep 17.

Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.

This study aimed to analyze the factors associated with outcomes of bone marrow transplantation (UR-BMT) or cord blood stem cell transplantation from unrelated donors (UR-CBT). We assessed the time from diagnosis to transplantation among acute myeloid leukemia (AML) patients with intermediate- or poor-risk cytogenetics to identify the potential clinical efficacy of transplantation. We retrospectively analyzed 5331 patients who received UR-BMT or UR-CBT between 2008 and 2017. Patients were divided into four groups according to time from diagnosis to transplantation: (1) UR-BMT and > 5 months (n = 2353), (2) UR-BMT and ≤ 5 months (n = 379), (3) UR-CBT and > 5 months (n = 1494), and (4) UR-CBT and ≤ 5 months (n = 1106). There was no difference in overall survival (OS) for transplantation at ≤5 months and > 5 months in patients with first complete remission for both UR-BMT and UR-CBT, but OS in patients with primary induction failure (PIF) and transplantation at ≤ 5 months was significantly higher in the UR-CBT group compared with that at >5 months (P < 0.001). Multivariate Cox regression analysis also showed that transplantation at >5 months in patients with PIF was an independent predictor of poorer OS. Therefore, UR-CBT at ≤ 5 months after diagnosis is an alternative option for AML patients with PIF.
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http://dx.doi.org/10.1007/s00277-020-04261-6DOI Listing
December 2020

Effects of Acute and Chronic Graft-versus-myelodysplastic Syndrome on Long-term Outcomes Following Allogeneic Hematopoietic Cell Transplantation.

Clin Cancer Res 2020 12 6;26(24):6483-6493. Epub 2020 Sep 6.

Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Purpose: Potent graft-versus-tumor (GVT) effects associated with graft-versus-host disease (GVHD) might be dependent on hematologic disease type and status. However, the data regarding the impact of GVHD on transplant outcomes for patients with myelodysplastic syndrome (MDS) are limited.

Experimental Design: We retrospectively evaluated the impact of acute and chronic GVHD on transplant outcomes for a large cohort of adult patients with a low-risk ( = 1,193) and high-risk ( = 1,926) MDS treated by first allogeneic hematopoietic cell transplantation between 2001 and 2017.

Results: The multivariate analysis, in which development of GVHD was treated as a time-dependent covariate, showed that acute and chronic GVHD at any grade or severity did not improve overall mortality, relapse, or nonrelapse mortality (NRM) in low-risk MDS. For patients with high-risk MDS, development of limited chronic GVHD was significantly associated with lower overall mortality [HR, 0.66; 95% confidence interval (CI), 0.50-0.86; = 0.002]. This is probably due to that the reduced risk of relapse with grade III-IV acute GVHD (HR, 0.41; 95% CI, 0.25-0.65; = 0.0002), or limited (HR, 0.57; 95% CI, 0.39-0.83; = 0.003) or extensive (HR, 0.56; 95% CI, 0.41-0.77; = 0.0004) chronic GVHD was offset by increased NRM with grade III-IV acute GVHD or extensive chronic GVHD in high-risk MDS.

Conclusions: These data demonstrated a survival benefit of the graft-versus-MDS effect is present only in high-risk MDS patients with limited chronic GVHD..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1104DOI Listing
December 2020

Development of a Patch-Type Flexible Oxygen Partial Pressure Sensor.

IEEE J Transl Eng Health Med 2020 29;8:1400607. Epub 2020 Jun 29.

Graduate School of Fundamental Science and TechnologyKeio UniversityYokohama223-8522Japan.

Oxygen concentration in living organisms is one of the important vital indicators in emergency care and bedside medical settings. However, the oximetry method has limitations: the measurement site is limited to the tissue containing blood and the absolute value of oxygen concentration cannot be measured. To overcome these limitations, in this work, we develop a new oxygen sensor that can directly measure the oxygen particle pressure ([Formula: see text]) on the surface of the body and organs. A light emitting diode (LED) and a photodiode (PD) were embedded in a dimethylpolysiloxane substrate mixed with carbon nanotubes. The effectiveness of the device was evaluated using calibration, bending strain tests, time and frequency response, and finally assessments. The results reveal that the calibration experiment of the fabricated oxygen sensor device showed high sensitivity. The carbon nanotube electrode has a sufficient bending resistance and does not affect the response characteristics of the LED and PD, that is, it does not affect the oxygen measurement. assessment shows that the developed patch-type flexible oxygen sensor can accurately measure [Formula: see text] by attaching it to tissues or organs having irregularities or curved surfaces and actual measurements on rat liver surface demonstrated its feasibility.
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http://dx.doi.org/10.1109/JTEHM.2020.3005477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333882PMC
June 2020

Outcome and Risk Factors for Therapy-Related Myeloid Neoplasms Treated with Allogeneic Stem Cell Transplantation in Japan.

Biol Blood Marrow Transplant 2020 08 19;26(8):1543-1551. Epub 2020 Apr 19.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

This study aimed to investigate allogeneic hematopoietic cell transplantation (HCT) outcomes and risk factors in adult patients with therapy-related myeloid neoplasm (t-MN) using Japanese registry data. Between 2002 and 2012, a total 12,169 adult patients underwent HCT for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML). Of these, 565 with t-MN were identified. The median patient age was 54 years (range, 16 to 80 years). Three hundred and ninety-eight patients had AML, 154 had MDS, and 13 had CMML. Lymphoma and breast cancer were the major previous malignancies. Favorable karyotypes were detected in 84 patients, and poor karyotypes were identified in 235. Two-thirds (66%) of the patients were in nonremission at HCT. Overall survival at 3 years in patients with t-MN was 31% (95% confidence interval [CI], 27% to 35%), equivalent to that in those with secondary MN (32%; 95% CI, 30% to 34%), and 44% in the de novo cohort (95% CI, 43% to 45%). The cumulative incidence of relapse and nonrelapse mortality at 3 years was 40% and 33%, respectively. The outcomes of HCT for t-MN in Japan were comparable to those in large-scale studies in Europe and the United States.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.004DOI Listing
August 2020

Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation.

Blood Adv 2020 03;4(6):1051-1061

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Cytomegalovirus (CMV) infection is a major complication in allogeneic stem cell transplantation. The utility of CMV prophylaxis with letermovir has been reported; however, the specific applications remain unclear. In this study, we retrospectively analyzed large-scale registry data (N = 10 480) to clarify the risk factors for nonrelapse mortality (NRM) in connection with CMV reactivation. First, we identified risk factors for CMV reactivation using multivariate analysis and developed a scoring model. Although the model effectively stratified reactivation risk into 3 groups (43.7% vs 60.9% vs 71.5%; P < .001), the 3-year NRM was significantly higher in patients with CMV reactivation, even in the low (20.9% vs 13.0%, P < .001), intermediate (21.4% vs 15.6%; P < .001), and high (29.3% vs 18.0%; P < .001) reactivation risk groups. Next, survival analysis considering competing risks, time-dependent covariates, and interaction terms for exploring the heterogeneous impact of CMV reactivation on NRM in the training cohort revealed that chronic myeloid leukemia (CML) (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.05-2.96; P = .033), good performance status (PS) (HR, 1.42; 95% CI, 1.04-1.94; P = .028), HLA-matched donor (HR, 1.34; 95% CI, 1.06-1.70; P = .013), and standard-risk disease (HR, 1.28; 95% CI, 1.04-1.58; P = .022) were associated with increased NRM. In the test cohort, CMV reactivation was significantly associated with increased 3-year NRM among patients with 2 to 4 factors (22.1% vs 13.1%; P < .001) but was comparable among patients with 0 or 1 factor (23.2% vs 20.4%; P = .62). We propose that CMV prophylaxis should be determined based on reactivation risk, as well as these other factors.
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http://dx.doi.org/10.1182/bloodadvances.2019000814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094017PMC
March 2020

Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice.

Hum Mol Genet 2020 05;29(8):1274-1291

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.
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http://dx.doi.org/10.1093/hmg/ddaa036DOI Listing
May 2020

Effects of recombinant thrombomodulin on long-term prognosis after allogeneic hematopoietic stem cell transplantation.

Transpl Immunol 2019 12 27;57:101247. Epub 2019 Oct 27.

Kansai Medical University, Japan.

We investigated the effects of early recombinant thrombomodulin (rTM) treatment on long-term prognosis after hematopoietic stem cell transplantation (HSCT). Subjects included 300 patients who underwent allogeneic HSCT (131 in the rTM(+) group and 169 in the rTM(-) group). The control group received heparin or no anti-coagulation therapy. When we examined patients with confirmed complications (day 1-100), the frequencies of acute graft-versus-host disease (aGVHD) and thrombotic microangiopathy (TMA) were significantly lower in the rTM(+) group, while the frequencies of veno-occlusive disease did not show such differences. rTM administration was associated with significant differences in the cumulative incidence of aGVHD (any grade and II-IV grades) and TMA. The cumulative overall survival probability was significantly higher in the rTM(+) group (42.3% versus 26.2%, p = .037). Therefore, some causes of a poor prognosis included aGVHD and TMA. The present findings suggest that rTM plays a preventive role in transplant-related complications, such as aGVHD and TMA, after allogeneic HSCT.
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http://dx.doi.org/10.1016/j.trim.2019.101247DOI Listing
December 2019

Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Poor-Prognosis Cytogenetics in First Complete Remission.

Biol Blood Marrow Transplant 2020 03 25;26(3):463-471. Epub 2019 Sep 25.

Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P = .011 and P = .025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P = .082 and P = .062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.025DOI Listing
March 2020

[Cytomegalovirus infections following allogeneic hematopoietic stem cell transplantation: prophylaxis and treatment].

Rinsho Ketsueki 2019 ;60(6):635-645

Division of Clinical Laboratory, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital.

In patients who undergo hematopoietic stem cell transplantation (HSCT), cytomegalovirus (CMV) infection directly or indirectly increases all-cause and non-relapse mortality rates. Although preemptive therapy suppresses CMV infection, it does not improve non-relapse mortality rates in patients with CMV reactivation compared to patients with no CMV reactivation. According to the World Health Organization International Standards (WHO IS), quantitative polymerase chain reaction has been recently adopted as the global standard for monitoring CMV, and maribavir, brincidofovir, and letermovir have been developed as new antiviral drugs for the treatment of CMV infection. Letermovir, a first-class anti-CMV agent, strongly inhibits the CMV DNA terminase complex, which is required for viral DNA cleavage and packaging. It significantly suppressed CMV infection in a phase III clinical trial, thereby improving the overall survival of patients who undergo HSCT. Vaccines and cell therapies for CMV must be further developed.
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http://dx.doi.org/10.11406/rinketsu.60.635DOI Listing
August 2019

Allogeneic hematopoietic cell transplantation for patients with a history of multiple relapses of acute myeloid leukemia.

Ann Hematol 2019 Sep 15;98(9):2179-2186. Epub 2019 Jun 15.

Jikei University School of Medicine, Tokyo, Japan.

The prognosis of patients with acute myeloid leukemia (AML) is dismal after experiencing multiple relapses. This study retrospectively analyzed outcomes of allogeneic hematopoietic cell transplantation (HCT) for 192 adults with AML in third or subsequent complete remission (CR3+), 300 in second relapse (REL2), and 50 in third or subsequent relapse (REL3+) who were enrolled in a Japanese nationwide transplantation registry. The study population included patients undergoing umbilical cord blood transplantation, but not those undergoing haploidentical HCT. Patients transplanted in CR3+ had better survival than those transplanted in REL2 and REL3+ (48%, 21%, and 12% at 4 years; P < 0.001), and this was due to a reduction in post-transplant relapse (23%, 57%, and 52%; P < 0.001). The corresponding cumulative incidence of non-relapse mortality was 33%, 26%, and 36% (P = 0.022). Multivariate analysis revealed significantly lower relapse and overall mortality for those in CR3+ and significantly lower non-relapse mortality for those in REL2. Hazard ratios (95% confidence intervals) for overall mortality were 2.02 (1.56-2.64) for REL2+ versus CR3+ (P < 0.001) and 2.12 (1.40-3.19) for REL3+ versus CR3+ (P < 0.001). Our analysis demonstrates the curative potential of allogeneic HCT for patients with a history of multiple AML relapses and suggests the potential benefits and risks of reinduction attempt before transplantation, highlighting the need for an individualized approach in determining whether to give reinduction therapy in this setting.
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http://dx.doi.org/10.1007/s00277-019-03736-5DOI Listing
September 2019

Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis.

J Exp Med 2019 04 15;216(4):950-965. Epub 2019 Mar 15.

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.
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http://dx.doi.org/10.1084/jem.20180900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446870PMC
April 2019

Effects of recombinant thrombomodulin therapy and soluble human leukocyte antigen-G levels during hematopoietic stem cell transplantation.

Transpl Immunol 2019 04 10;53:28-33. Epub 2018 Dec 10.

Kansai Medical University, Japan.

Background: Conditioning chemotherapies for hematopoietic stem cell transplantation (HSCT), especially those that include total body irradiation, can result in serious complications such as graft-versus-host disease (GVHD). Human leukocyte antigen G (HLA-G) is a non-classical class I molecule with multiple immunoregulatory functions.

Methods: We measured interleukin (IL)-10, transforming growth factor (TGF)β, and soluble HLA-G (sHLA-G) in HSCT patients and examined the relationship between sHLA-G levels and acute GVHD (aGVHD). Additionally, we investigated the effect of recombinant soluble thrombomodulin (rTM) therapy on sHLA-G levels. Our study cohort included 135 patients who underwent allogeneic HSCT at several institutions in Japan.

Results: Serum levels of IL-10 and TGFβ exhibited no significant changes following HSCT. In contrast, levels of sHLA-G were significantly increased at days 21 and 28 post-HSCT. For patients with confirmed complications, the frequency of aGVHD was significantly lower in those with a > 2.8-fold increase in sHLA-G levels at day 28 relative to day 7 post-HSCT. sHLA-G levels in patients who received rTM therapy were significantly higher at days 21 and 28 post-HSCT compared with those in patients who did not receive rTM therapy.

Conclusion: These data suggest that HLA-G/sHLA-G participate in prevention of GVHD, and that rTM may prevent aGVHD following HSCT by promoting elevation of sHLA-G.
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http://dx.doi.org/10.1016/j.trim.2018.12.001DOI Listing
April 2019

Characterizing vulnerable brain areas and circuits in mouse models of autism: Towards understanding pathogenesis and new therapeutic approaches.

Neurosci Biobehav Rev 2020 03 22;110:77-91. Epub 2018 Nov 22.

Medical Innovation Center Kyoto University Graduate School of Medicine, Japan. Electronic address:

Recent human genetics studies have identified many genetic variants that may be responsible for autism spectrum disorder (ASD). ASD mouse models with genetic modifications mimicking these rare genetic variants have provided invaluable mechanistic insights into the disruption of various biological processes and brain areas/circuitry affected in ASD patients. In this review, we begin by reviewing several mouse models for ASD-associated copy number variations (CNVs) to illustrate how they have been employed to establish causal links between their behavioral phenotypes and the affected genes. We then focus on studies using one of the principal behavioral abnormalities associated with ASD, social behavior, to identify the molecular and circuit-level deficits involved. Finally, we end by discussing other mouse models designed to probe how the disruption of specific biological processes such as autophagy and neurogenesis may contribute to ASD pathogenesis. By achieving a greater understanding of the pathophysiology and pathogenic mechanisms involved in ASD and related disorders, novel therapeutic strategies may be devised for ASD patients in the near future.
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http://dx.doi.org/10.1016/j.neubiorev.2018.08.001DOI Listing
March 2020

Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning.

Leuk Lymphoma 2019 06 20;60(6):1493-1502. Epub 2018 Nov 20.

m Division of Clinical Oncology and Hematology , The Jikei University School of Medicine , Tokyo , Japan.

To evaluate the prognostic impact of melphalan dose and total body irradiation (TBI) use in acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, we retrospectively compared outcomes of patients receiving a higher-dose (120-140 mg/m,  = 379) or lower-dose melphalan (80-110 mg/m,  = 128) with or without TBI of ≤4 Gy. At 3 years, overall survival was 48.9% in the higher-dose group versus 40.3% in the lower-dose group ( = .013). This survival benefit was attributed to lower tumor-related mortality (23.9% vs. 31.7%;  = .049). Non-relapse mortality did not differ (24.8% vs. 23.5%,  = .59). The beneficial effect of a higher-dose melphalan was more evident when combined with TBI in younger patients, those not in complete remission, and those with good performance status. Our findings support the use of a higher-dose melphalan in combination with TBI for reduced-intensity conditioning in physically fit patients.
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http://dx.doi.org/10.1080/10428194.2018.1535115DOI Listing
June 2019

The Autism-Related Protein CHD8 Cooperates with C/EBPβ to Regulate Adipogenesis.

Cell Rep 2018 05;23(7):1988-2000

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Electronic address:

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein β (C/EBPβ) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPβ regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.
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http://dx.doi.org/10.1016/j.celrep.2018.04.050DOI Listing
May 2018

[Acute leukemia recurring as extramedullary tumors of the ovary following allogeneic hematopoietic stem cell transplantation].

Rinsho Ketsueki 2018;59(1):58-63

Division of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital.

The poor prognosis of extramedullary recurrence of acute leukemia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a therapeutic challenge, and thus far no effective treatment method has been established. Here, we report two patients who presented with relapsed leukemia as extramedullary tumor in the ovary following allo-HSCT. Case 1: A 23-year-old female underwent unrelated allogeneic bone marrow transplantation during the second remission of acute myeloid leukemia. After 706 days post-transplant, bilateral ovarian tumors were detected during the pelvic ultrasound, and extramedullary recurrence in the bilateral ovaries was subsequently established on right salpingo-oophorectomy and biopsy of the left ovary. Following completed systemic chemotherapy and total body irradiation, the patient underwent unrelated cord blood transplantation (CBT) and remission was maintained without recurrence for 7 years after second transplantation. Case 2: A 49-year-old female underwent unrelated CBT during the second remission of acute lymphocytic leukemia. At 372 days post-transplant, a pelvic tumor was detected by FDG-PET/CT, and extramedullary recurrence in the right ovary was diagnosed on examination of the resected pelvic mass. Chemotherapy and radiation were performed, but the tumor recurred on day 1,027 and the patient died on day 1,603. Extramedullary recurrence of adult acute leukemia as a mass in the ovary following allo-HSCT has been rarely reported. Therefore, further accumulation of related case reports is desired.
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http://dx.doi.org/10.11406/rinketsu.59.58DOI Listing
February 2019

Gold nanoparticle core-europium(iii) chelate fluorophore-doped silica shell hybrid nanocomposites for the lateral flow immunoassay of human thyroid stimulating hormone with a dual signal readout.

Analyst 2018 Jan 20;143(2):564-570. Epub 2017 Dec 20.

Program in Biotechnology, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, 10330, Thailand.

Hybrid nanocomposite particles composed of a gold core coated with a europium(iii)-chelate fluorophore-doped silica shell ([email protected]) have been synthesized and applied as antibody labels in lateral flow immunoassay (LFIA) devices for the determination of human thyroid stimulating hormone (hTSH). Labeling of monoclonal anti-hTSH antibodies with [email protected] nanocomposites allows for both colorimetric and fluorometric observation of assay results on LFIA devices, relying on visible light absorption due to the localized surface plasmon resonance of the Au-core and the fluorescence emission of the Eu(iii)-chelate-modified shell under UV hand lamp irradiation (365 nm), respectively. The possibility for a dual signal readout provides an attractive alternative for LFIAs: instantaneous naked eye observation of the AuNP colorimetric signal as in conventional LFIAs for hypothyroidism detection, and more sensitive fluorescence detection to assess hyperthyroidism. The limits of detection (LOD) for naked eye observation of LFIA devices are 5 μIU mL and 0.1 μIU mL for the colorimetric and fluorimetric detection, respectively. Using the fluorescence detection scheme in combination with a smartphone and digital color analysis, a quantitative linear relationship between the red intensity and the logarithmic concentration of hTSH was observed (R = 0.988) with an LOD of 0.02 μIU mL. Finally, LFIA devices were effectively applied for detecting hTSH in spiked diluted human serum with recovery values between 100-116%.
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http://dx.doi.org/10.1039/c7an01799eDOI Listing
January 2018

[Philadelphia chromosome-positive acute lymphoblastic leukemia complicated by concomitant Achromobacter xylosoxidans and Corynebacterium striatum bacteremia following allogeneic hematopoietic stem cell transplantation].

Rinsho Ketsueki 2017;58(11):2250-2255

Division of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital.

A 54-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) underwent hematopoietic stem cell transplantation from an HLA-matched sibling. Subsequently, she suffered from chronic graft versus host disease (GvHD) and received medical treatment. Fever developed on day 697 and resulted in a shock state at 10 h after the visit. Achromobacter xylosoxidans was detected in the initial blood culture on day 699. General conditions exacerbated even after the start of meropenem hydrate (MEPM, Meropen) administration, with Corynebacterium striatum detected as an additional species in the initial blood culture on day 701. Although vancomycin hydrochloride (VCM, Vancomycin) was administered, the conditions did not improve. She died on day 702. Between January 2012 and December 2016, A. xylosoxidans was detected only in nine cases in our hospital, which included five with hematological malignancies and only one (present) with sepsis. At the same time, Corynebacterium species were detected in blood cultures from 39 cases in our hospital, which included 31 with hematological malignancies. Some reports on drug-resistant A. xylosoxidans and C. striatum have been published. Infections with these species may become fatal when complicated by sepsis in immunocompromised patients with hematological malignancies. More cases should be accumulated for detailed investigation.
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http://dx.doi.org/10.11406/rinketsu.58.2250DOI Listing
March 2018

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation.

N Engl J Med 2017 12 6;377(25):2433-2444. Epub 2017 Dec 6.

From the Dana-Farber Cancer Institute and Brigham and Women's Hospital (F.M.M.) and Tufts Medical Center and Tufts University School of Medicine (D.R.S.), Boston; Karolinska University Hospital and Karolinska Institutet, Stockholm (P.L.); University of Texas M.D. Anderson Cancer Center, Houston (R.F.C.); Universitaire Ziekenhuizen Leuven, Leuven, Belgium (J.M.); City of Hope National Medical Center, Duarte (S.S.D.), and Stanford University School of Medicine, Palo Alto (J.B.) - both in California; Hospital Universitario Puerta de Hierro-Majadahonda, Madrid (R.F.D.); Juravinski Hospital and Cancer Center, McMaster University, Hamilton, ON, Canada (S.H.); Universitätsklinikum Würzburg, Würzburg, Germany (A.J.U., H.E.); Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima (Y. Katayama), and Saitama Medical Center, Jichi Medical University, Saitama (Y. Kanda) - both in Japan; University of Chicago, Chicago (K.M.M.); Fred Hutchinson Cancer Research Center, Seattle (M.B.); Perelman School of Medicine at the University of Pennsylvania, Philadelphia (E.A.B.); and Merck, Kenilworth, NJ (M.J.D., V.L.T., H.W., Y.M., N.A.K., R.Y.L., C.B.).

Background: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex.

Methods: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation.

Results: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.

Conclusions: Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).
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http://dx.doi.org/10.1056/NEJMoa1706640DOI Listing
December 2017

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders.

Neuropsychopharmacology 2018 02 4;43(3):459-468. Epub 2017 Aug 4.

Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.
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http://dx.doi.org/10.1038/npp.2017.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770757PMC
February 2018