Publications by authors named "Takeshi Sugio"

25 Publications

  • Page 1 of 1

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Kyushu University Hospital, Japan.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.
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http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
October 2021

Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway.

Digestion 2021 Jul 22:1-10. Epub 2021 Jul 22.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.

Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.

Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.

Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
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http://dx.doi.org/10.1159/000518103DOI Listing
July 2021

Targeting leukemia-specific dependence on the de novo purine synthesis pathway.

Leukemia 2021 Aug 3. Epub 2021 Aug 3.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan.

Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
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http://dx.doi.org/10.1038/s41375-021-01369-0DOI Listing
August 2021

Platelet decrease and efficacy of platelet-rich plasma return following peripheral blood stem cell apheresis.

J Clin Apher 2021 Oct 16;36(5):687-696. Epub 2021 Jun 16.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Background: Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis.

Methods: We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis.

Results: In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 10 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 10 /L, respectively), whereas severe platelet decrease (<50 × 10 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 10 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings.

Conclusion: Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.
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http://dx.doi.org/10.1002/jca.21917DOI Listing
October 2021

Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study.

Ann Hematol 2021 Jan 5;100(1):197-208. Epub 2020 Nov 5.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
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http://dx.doi.org/10.1007/s00277-020-04310-0DOI Listing
January 2021

Increasing Diluent Volume Decreases Bendamustine-Induced Venous Irritation without Reducing the Therapeutic Efficacy.

Biol Pharm Bull 2020 ;43(3):488-492

Department of Pharmacy, Kyushu University Hospital.

The intravenous injection of bendamustine often induces venous irritation, which reduces patients' QOL. We previously reported that the dilution of the final volume of bendamustine from 250 to 500 mL significantly decreased the incidence of venous irritation. However, the influence of this change on the therapeutic efficacy of bendamustine remains unclear. Therefore, the aim of this study was to evaluate the efficacy and safety profiles of bendamustine at different dilutions of the final volume, comparing with the correspondences of previous studies. Thirty-four patients, who received a total of 161 courses of bendamustine and rituximab chemotherapy, were included in this study. The overall response rate of this regimen was 94.1% in this study, which was comparable to that reported in the BRB study (94.2%, a phase II study of bendamustine plus rituximab therapy in Japanese patients). Additionally, the median progression-free survival was not inferior to that reported in the BRB study. Bendamustine-induced venous irritation was observed in 17.6% of the patients during the first treatment cycle administered at a final volume of 500 mL, and was found to be lower than that observed in the control, where bendamustine was administered at a final volume of 250 mL (85.7%). These results suggest that diluting bendamustine to 500 mL, but not to 250 mL, reduces the incidence of venous irritation without a negative impact on its therapeutic efficacy; thus, this simple strategy may be beneficial to ensure efficacy and safety in patients receiving regimens including bendamustine.
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http://dx.doi.org/10.1248/bpb.b19-00826DOI Listing
September 2020

Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation.

Ann Hematol 2019 Nov 18;98(11):2579-2591. Epub 2019 Oct 18.

Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m on day 1, 7 mg/m on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.
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http://dx.doi.org/10.1007/s00277-019-03801-zDOI Listing
November 2019

Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 08 6;25(8):1576-1585. Epub 2019 Apr 6.

Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan. Electronic address:

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.
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http://dx.doi.org/10.1016/j.bbmt.2019.04.006DOI Listing
August 2019

Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma.

Ann Hematol 2019 May 7;98(5):1197-1207. Epub 2019 Feb 7.

Department of Pathology, Kurume University, School of Medicine, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan.

The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.
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http://dx.doi.org/10.1007/s00277-019-03628-8DOI Listing
May 2019

Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis.

Am J Surg Pathol 2018 11;42(11):1466-1471

Departments of Pathology.

GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2-IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression-free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL.
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http://dx.doi.org/10.1097/PAS.0000000000000969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266301PMC
November 2018

Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS.

Blood Adv 2018 09;2(17):2242-2252

Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.
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http://dx.doi.org/10.1182/bloodadvances.2018018754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134219PMC
September 2018

Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Biol Blood Marrow Transplant 2018 11 15;24(11):2302-2309. Epub 2018 Jun 15.

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Electronic address:

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.002DOI Listing
November 2018

Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma.

Oncotarget 2018 Jan 11;9(2):1717-1725. Epub 2017 Dec 11.

Department of Pathology, Kurume University, School of Medicine, Kurume, Japan.

Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <120 g/l, elevated lactate dehydrogenase level, and high-risk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL ( < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.
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http://dx.doi.org/10.18632/oncotarget.23138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788593PMC
January 2018

Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma.

Ann Hematol 2018 Feb 2;97(2):359-360. Epub 2017 Oct 2.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1007/s00277-017-3146-zDOI Listing
February 2018

Identification of unipotent megakaryocyte progenitors in human hematopoiesis.

Blood 2017 06 23;129(25):3332-3343. Epub 2017 Mar 23.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and.

The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34CD38IL-3RαCD45RA common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41 CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.
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http://dx.doi.org/10.1182/blood-2016-09-741611DOI Listing
June 2017

Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study.

Rinsho Ketsueki 2016 ;57(12):2475-2480

Department of Hematology, Hamanomachi Hospital.

In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.
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http://dx.doi.org/10.11406/rinketsu.57.2475DOI Listing
March 2017

Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2016 09 21;22(9):1608-1614. Epub 2016 May 21.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.
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http://dx.doi.org/10.1016/j.bbmt.2016.05.017DOI Listing
September 2016

[Herpes simplex virus type 2 fulminant hepatitis after umbilical cord blood transplantation for acute myeloid leukemia].

Rinsho Ketsueki 2014 Jun;55(6):682-6

Department of Hematology, Toranomon Hopital.

This report describes a 41-year-old patient, who developed herpes simplex virus type 2 (HSV-2)-hepatitis after umbilical cord blood transplantation (CBT). The patient had received allogeneic bone marrow transplantation from an unrelated donor for acute myeloid leukemia (AML) not in remission. AML relapsed 18 months after the first transplantation, and CBT was performed. AML relapsed again 5 months later and the patient was given chemotherapy. Although there was no active chronic graft-versus-host disease, liver dysfunction appeared, and one week later, progressed to acute liver failure. Viral screening of blood by PCR including hepatitis B and C viruses, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, herpes simplex virus type 1 and HSV-2 revealed elevation of HSV-2 (2.34 × 10⁴ copies/ml). We diagnosed the patient as having HSV-2 acute hepatitis, and initiated treatment with antiviral drugs (acyclovir, foscarnet) and plasma exchange. However, liver functions deteriorated rapidly, and the patient died on day 6 after the onset of acute liver failure. Although HSV hepatitis is very rare after allogeneic stem cell transplantation, it is rapidly progressive and associated with a high mortality rate. Thus, early diagnosis with prompt antiviral intervention is recommended.
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June 2014

Differences between actual and imagined usage of chopsticks: an fMRI study.

Cortex 2007 Apr;43(3):301-7

Graduate School of Informatics, Kyoto University, Kyoto, Japan.

We examined neural basis underlying tool-use behavior to discuss whether or not the usage of a well-learned tool has a specific route. Regional cerebral blood flow was measured in healthy Japanese subjects using functional magnetic resonance imaging (fMRI) during object pick-up using chopsticks, object pick-up using the hand, pantomiming the use of chopsticks, imagining the use of chopsticks, and imagining the use of the hand. First, the left inferior parietal lobule (IPL) was found to selectively contribute to tasks requiring explicit retrieval of tool-related hand movements that were pantomiming task and imagery task. This finding provides supporting evidence for the ideomotor apraxia (IMA) model proposed by Buxbaum (2001). However, departing from Buxbaum's (2001) proposal, the actual use of a well-learned tool displays distinct processing routes to those for pantomime and imagining. A comparison of these tasks revealed that activation in the lateral part of the right cerebellum increased during execution of tool-use, and this activity was considered to reflect the internal model for tools proposed by Imamizu et al. (2000, 2003).
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http://dx.doi.org/10.1016/s0010-9452(08)70456-8DOI Listing
April 2007

Neural correlates of state estimation in visually guided movements: an event-related fMRI study.

Cortex 2007 Apr;43(3):289-300

Graduate School of Informatics, Kyoto University, Kyoto, Japan.

State estimation of self-movement, based on both motor commands and sensory feedback, has been suggested as essential to human movement control to compensate for inherent feedback delays in sensorimotor loops. The present study investigated the neural basis for state estimation of human movement using event-related functional magnetic resonance imaging (fMRI). Participants traced visually presented curves with a computer mouse, and an artificial delay was introduced to visual feedback. Motor performance and brain activities during movements were measured. Experiment 1 investigated brain activations that were significantly correlated with visual feedback delay and motor error by parametrically manipulating visual feedback delay. Activation of the right posterior parietal cortex (PPC) was positively correlated with motor error, whereas activation of the right temporo-parietal junction (TPJ) was observed only in the group with a smaller increase in motor error with increased visual feedback delay. Experiment 2 involved parametric analysis of motor performance while controlling mouse movement speed during the task. Activity in the right TPJ showed a significant positive correlation with motor performance under the delayed visual feedback condition. In addition, activity of the PPC was greater when motor error was presented visually. These results suggest that the PPC plays a significant role in evaluating visuomotor prediction error, while the TPJ is involved in state estimation of self-movement during visually guided movements.
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http://dx.doi.org/10.1016/s0010-9452(08)70455-6DOI Listing
April 2007

Separating brain regions involved in internally guided and visual feedback control of moving effectors: an event-related fMRI study.

Neuroimage 2006 Oct 24;32(4):1760-70. Epub 2006 Jul 24.

Graduate School of Informatics, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto 606-8501, Japan.

Online visual information of moving effectors plays important roles in visually guided movements. The present study used event-related functional resonance imaging to temporally separate neural activity associated with internally guided and visual feedback control of moving effectors. Using a cursor controlled by a computer mouse, participants traced curved lines on a screen. During this movement, vision of the moving cursor was occluded after tracing had begun and then was restored after variable intervals. The results showed that when visual feedback was unavailable, bilateral activation was significantly greater in the basal ganglia, thalamus, premotor cortex and mesial motor areas, peaking at the presupplementary motor area (pre-SMA). In contrast, when visual feedback was available, significantly greater activation was observed bilaterally in the posterior parietal cortex (PPC) and cerebellum and in the middle and inferior frontal gyri and occipito-temporal cortex in the right hemisphere. Pre-SMA activity was significantly negatively correlated with tracing error when visual feedback was unavailable. In contrast, right PPC activation showed a significant positive correlation with tracing error after visual feedback became available. These findings suggest that the pre-SMA is involved in internally guided movements in the absence of visual feedback, and that the PPC is related to visual feedback control by evaluating online visuomotor error. The current study clarifies the different functional roles of fronto-parietal and cerebellum circuits subserving visually guided movements regarding visual feedback control of effectors.
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http://dx.doi.org/10.1016/j.neuroimage.2006.05.012DOI Listing
October 2006

Temporal relationship between action and visual outcome modulates brain activation: an fMRI study.

Magn Reson Med Sci 2005 ;4(3):115-21

Department of Psychology, Showa Women's University, Setagaya, Tokyo, Japan.

Monitoring the visual outcome of our actions is critical to our visuo-motor behavior. To investigate the neural basis of monitoring visual change produced by self-movement, we examined the temporal relationship between manual depression of a button and visual feedback on activation of the brain. Six neurologically normal subjects participated in 3 experiments (synchronous, delayed, and visual [control]). Magnetic resonance (MR) images of their brains were acquired during the experiments using a scanner operating at 3T. In the synchronous experiment, subjects pressed a button at self-paced intervals and received synchronous visual stimuli in response. In the delayed experiment, visual stimuli were presented with a delay after subjects pressed a button at self-paced intervals. In the control experiment (visual experiment), subjects did not press the button, but viewed visual stimuli generated by a computer at random intervals. In the synchronous experiment, activation in the cerebellum and right parietal lobe was stronger than in the delayed experiment, whereas activation in the primary visual cortex was weaker than in the delayed and visual experiments. These results suggest that visual outcomes produced synchronously with action are processed in the cerebellum and the parietal area for the organization of optimal motor behavior, rather than in the primary visual area that is known to process the visual properties of external objects. The cerebellar signal related to visuo-motor contingency may modulate the cortical processing of visual input that is synchronous with action.
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http://dx.doi.org/10.2463/mrms.4.115DOI Listing
June 2006

Neural correlates of semantic effects on grasping familiar objects.

Neuroreport 2003 Dec;14(18):2297-301

Department of Intelligence Science and Technology, Graduate School of Informatics, Kyoto University, Japan.

This study used event-related fMRI to explore the neural basis of semantic involvement when performing a visually guided grasping movement. Three types of object images were presented in random order: familiar objects with handles (FH+) familiar objects without handles (FH-) and geometrical objects with a handle-like part (GH+). Subjects were then instructed to configure an appropriate hand shape for grasping the object. Common activations were found for all event types when contrasted with baseline. Activation of the anterior part of the rostral cingulate motor area was detected for only the FH+ condition and these results imply that the appropriate selection of multiple motor schemata took place in this region.
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http://dx.doi.org/10.1097/00001756-200312190-00002DOI Listing
December 2003
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