Publications by authors named "Shinichiro Okamoto"

363 Publications

Phase 1 study of plerixafor in combination with total body irradiation-based myeloablative conditioning for allogeneic hematopoietic stem cell transplantation.

Int J Hematol 2021 Mar 1. Epub 2021 Mar 1.

Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Plerixafor, a CXCR4 inhibitor, has the potential to mobilize leukemic cells, which may contribute to their chemosensitization. This phase 1 study evaluated the safety of myeloablative conditioning combined with plerixafor for allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high-risk leukemia undergoing allogeneic HSCT after total body irradiation (TBI, 12 Gy)-based myeloablative conditioning were eligible; 9 patients were enrolled. The study was performed using a 3 + 3 design with an escalating total dose of plerixafor. Plerixafor was given subcutaneously 8 h before TBI and chemotherapeutic agents. Plerixafor was successfully escalated to the maximum dose (0.72 mg/kg) without dose-limiting toxicities. Underlying diseases were acute myelogenous and lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. As adverse events, plerixafor administration was associated with transient Grades 2-3 diarrhea (n = 7) and abdominal pain (n = 4). In 6 patients, leukemic cell mobilization into the peripheral blood by plerixafor was confirmed by a morphological or molecular method. All patients achieved neutrophil engraftment and 5 were alive in remission at a follow-up after 30-40 months. Plerixafor-combined myeloablative conditioning for allogeneic HSCT was well tolerated. Leukemic-cell mobilization into peripheral blood was observed in half of the patients. Further study is required to evaluate the efficacy and safety of this concept.
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http://dx.doi.org/10.1007/s12185-021-03109-7DOI Listing
March 2021

Airway Pseudomonas aeruginosa density in mechanically ventilated patients: clinical impact and relation to therapeutic efficacy of antibiotics.

Crit Care 2021 02 11;25(1):59. Epub 2021 Feb 11.

Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan.

Background: The bacterial density of Pseudomonas aeruginosa is closely related to its pathogenicity. We evaluated the effect of airway P. aeruginosa density on the clinical course of mechanically ventilated patients and the therapeutic efficacy of antibiotics.

Methods: We retrospectively analyzed data of mechanically ventilated ICU patients with P. aeruginosa isolated from endotracheal aspirates. Patients were divided into three groups according to the peak P. aeruginosa density during ICU stay: low (≤ 10 cfu/mL), moderate (10‒10 cfu/mL), and high (≥ 10 cfu/mL) peak density groups. The relationship between peak P. aeruginosa density and weaning from mechanical ventilation, risk factors for isolation of high peak density of P. aeruginosa, and antibiotic efficacy were investigated using multivariate and propensity score-matched analyses.

Results: Four-hundred-and-sixty-one patients were enrolled. Patients with high peak density of P. aeruginosa had higher inflammation and developed more severe respiratory infections. High peak density of P. aeruginosa was independently associated with few ventilator-free days on day 28 (P < 0.01) and increased ICU mortality (P = 0.047). Risk factors for high peak density of P. aeruginosa were prolonged mechanical ventilation (odd ratio [OR] 3.07 95% confidence interval [CI] 1.35‒6.97), non-antipseudomonal cephalosporins (OR 2.17, 95% CI 1.35‒3.49), hyperglycemia (OR 2.01, 95% CI 1.26‒3.22) during ICU stay, and respiratory diseases (OR 1.9, 95% CI 1.12‒3.23). Isolation of commensal colonizer was associated with lower risks of high peak density of P. aeruginosa (OR 0.43, 95% CI 0.26‒0.73). Propensity score-matched analysis revealed that antibiotic therapy for patients with ventilator-associated tracheobronchitis improved weaning from mechanical ventilation only in the high peak P. aeruginosa group.

Conclusions: Patients with high peak density of P. aeruginosa had worse ventilator outcome and ICU mortality. In patients with ventilator-associated tracheobronchitis, antibiotic therapy was associated with favorable ventilator weaning only in the high peak P. aeruginosa density group, and bacterial density could be a good therapeutic indicator for ventilator-associated tracheobronchitis due to P. aeruginosa.
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http://dx.doi.org/10.1186/s13054-021-03488-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876981PMC
February 2021

Stopping tyrosine kinase inhibitors started after allogeneic HCT in patients with Philadelphia chromosome-positive leukemia.

Bone Marrow Transplant 2021 Jan 8. Epub 2021 Jan 8.

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

For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.
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http://dx.doi.org/10.1038/s41409-020-01206-5DOI Listing
January 2021

OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy.

Cell Rep 2021 Jan;34(1):108579

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
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http://dx.doi.org/10.1016/j.celrep.2020.108579DOI Listing
January 2021

Exclusive labeling of direct and indirect pathway neurons in the mouse neostriatum by an adeno-associated virus vector with Cre/lox system.

STAR Protoc 2021 Mar 18;2(1):100230. Epub 2020 Dec 18.

Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

We developed an adeno-associated virus (AAV) vector-based technique to label mouse neostriatal neurons comprising direct and indirect pathways with different fluorescent proteins and analyze their axonal projections. The AAV vector expresses GFP or RFP in the presence or absence of Cre recombinase and should be useful for labeling two cell populations exclusively dependent on its expression. Here, we describe the AAV vector design, stereotaxic injection of the AAV vector, and a highly sensitive immunoperoxidase method for axon visualization. For complete details on the use and execution of this protocol, please refer to Okamoto et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753197PMC
March 2021

Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

Thorac Cancer 2021 Feb 9;12(3):397-401. Epub 2020 Dec 9.

Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan.

A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor-immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72-year-old man was diagnosed with an advanced pulmonary carcinoid tumor. CT-guided biopsies of lung and scapular tumors confirmed typical carcinoid (PD-L1, 1%-24%) and atypical carcinoid tumors (PD-L1, negative), respectively. Although the primary lung carcinoid tumor showed a partial response, the scapular tumor was significantly enlarged after two cycles of anti-PD-L1 antibody therapy in combination with carboplatin plus etoposide. We performed quantitative pathology imaging analysis with fluorescent multiplex immunohistochemistry. CD8 T cell infiltration was detected in the PD-L1-positive primary lung tumor nest; however, it was mostly restrained in the stroma in a PD-L1-negative metastatic scapular tumor. Treg infiltrations into both tumor nests and stroma were detected in the lung tumor, which were not detected in the metastatic scapular tumor. This study provides the first evidence of coexistence of heterogeneous TIME within a single individual with a pulmonary carcinoid tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors.
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http://dx.doi.org/10.1111/1759-7714.13772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862786PMC
February 2021

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.

Ther Adv Hematol 2020 24;11:2040620720966137. Epub 2020 Oct 24.

Hematology Transplantation, Hôpital Saint-Louis, Paris, France.

Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment.

Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics.

Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time.

Conclusion: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control.

Trial Registration: ClinicalTrials.gov identifier, NCT02946463.
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http://dx.doi.org/10.1177/2040620720966137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592174PMC
October 2020

Establishment of a High-risk MDS/AML Cell Line YCU-AML1 and its Xenograft Model Harboring t(3;3) and Monosomy 7.

Hemasphere 2020 Oct 17;4(5):e469. Epub 2020 Sep 17.

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.

Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with both inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 defines an extremely aggressive myeloid cancer whose molecular pathogenesis and optimal therapeutic strategy still remain unclear. We established a new MDS/AML cell line, YCU-AML1, and its patient-derived xenograft (PDX) model from a high-risk MDS patient who later transformed into AML harboring both t(3;3)(q21;q26.2) and monosomy 7. YCU-AML1 cells propagated in co-culture system with stromal cells in granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent manner. CD34 bone marrow cells derived from our PDX model showed high and low expression. Moreover, mutational profile of our MDS/AML model was consistent with recently published mutational spectrum of myeloid malignancies with inv(3)/t(3;3). These data suggest that YCU-AML1 cells and its MDS/AML model strongly mimics a high-risk human myeloid cancer with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 in terms of both clinical phenotype and molecular basis. We believe our model can be used as a feasible tool to further explore molecular pathogenesis and novel treatment strategy of high-risk MDS/AML with t(3;3)(q21;q26.2) and monosomy 7.
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http://dx.doi.org/10.1097/HS9.0000000000000469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643909PMC
October 2020

Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph B cells but not bone marrow stem/progenitors.

Leuk Lymphoma 2021 Mar 26;62(3):679-687. Epub 2020 Oct 26.

Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were -negative. Moreover, in some patients was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.
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http://dx.doi.org/10.1080/10428194.2020.1837366DOI Listing
March 2021

Clinical Benefits of Preconditioning Intervention in Patients with Relapsed or Refractory Acute Myelogenous Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A Kanto Study of Group for Cell Therapy Multicenter Analysis.

Biol Blood Marrow Transplant 2020 Sep 30. Epub 2020 Sep 30.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P = .035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.025DOI Listing
September 2020

The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.

Cancer Res 2020 10 14;80(20):4439-4450. Epub 2020 Sep 14.

Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3993DOI Listing
October 2020

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

Rinsho Ketsueki 2020 ;61(8):870-873

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.
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http://dx.doi.org/10.11406/rinketsu.61.870DOI Listing
October 2020

Pharmacokinetics of intravenous busulfan as condition for hematopoietic stem cell transplantation: comparison between combinations with cyclophosphamide and fludarabine.

Int J Hematol 2021 Jan 4;113(1):128-133. Epub 2020 Sep 4.

Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Busulfan (Bu) has been used in combination with fludarabine (Flu; BuFlu) or cyclophosphamide (Cy; BuCy) as conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). This multi-institutional prospective study compared pharmacokinetic (PK) parameters of Bu between BuFlu and BuCy. Plasma Bu concentrations were measured by high-performance liquid chromatography at the first dose of the first and fourth days of intravenous Bu administrations (total of 16 doses of 0.8 mg/kg). Thirty-seven patients were evaluable (BuFlu, N = 18; BuCy, N = 19). The median age was significantly higher in BuFlu. In BuFlu, the median area under the blood concentration-time curve of Bu on the fourth day was 1183 μmol min/L (range 808-1509), which was significantly higher than that on the first day [1095 μmol min/L (range 822-1453), P < 0.01]. In contrast, such differences were not observed in BuCy. Consistently, there was a significant decrease in the clearance of Bu on the fourth day as compared with the first day in BuFlu. These results suggest that the PK of Bu was altered during the co-administration of Flu, which was not the case with Cy. A large-scale study is required to evaluate the significance of the differences in the PK of Bu between the conditionings on HSCT outcomes.
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http://dx.doi.org/10.1007/s12185-020-02990-yDOI Listing
January 2021

Overlapping Projections of Neighboring Direct and Indirect Pathway Neostriatal Neurons to Globus Pallidus External Segment.

iScience 2020 Aug 6:101409. Epub 2020 Aug 6.

Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address:

Indirect pathway medium-sized spiny neurons (iMSNs) in the neostriatum are well known to project to the external segment of the globus pallidus (GPe). Although direct MSNs (dMSNs) also send axon collaterals to the GPe, it remains unclear how dMSNs and iMSNs converge within the GPe. Here, we selectively labeled neighboring dMSNs and iMSNs with green and red fluorescent proteins using an adeno-associated virus vector and examined axonal projections of dMSNs and iMSNs to the GPe in mice. Both dMSNs and iMSNs formed two axonal arborizations displaying topographical projections in the dorsoventral and mediolateral planes. iMSNs displayed a wider and denser axon distribution, which included that of dMSNs. Density peaks of dMSN and iMSN axons almost overlapped, revealing convergence of dMSN axons in the center of iMSN projection fields. These overlapping projections suggest that dMSNs and iMSNs may work cooperatively via interactions within the GPe.
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http://dx.doi.org/10.1016/j.isci.2020.101409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520896PMC
August 2020

Use of unapproved or off-label drugs in Japan for the treatment of graft-versus-host disease and post-transplant viral infection.

Int J Hematol 2020 Dec 1;112(6):841-850. Epub 2020 Sep 1.

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

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.
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http://dx.doi.org/10.1007/s12185-020-02972-0DOI Listing
December 2020

Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients.

Int J Hematol 2020 Oct 31;112(4):466-476. Epub 2020 Aug 31.

Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.
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http://dx.doi.org/10.1007/s12185-020-02934-6DOI Listing
October 2020

Interleukin-6-producing Intravascular Large B-cell Lymphoma with Lymphadenopathy Mimicking the Histology of Multicentric Castleman Disease.

Intern Med 2020 Dec 4;59(23):3061-3065. Epub 2020 Aug 4.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Japan.

An inguinal lymph node biopsy of a woman with a one-month history of a progressive fever, fatigue, dyspnea, skin rash, and lymphadenopathy revealed a well-preserved basic structure, hyperplastic germinal centers, and an interfollicular region containing polyclonal plasma cell sheets, suggesting plasma cell-type multicentric Castleman disease (MCD). We initiated prednisolone and anti-interleukin (IL)-6 antibody (tocilizumab), without success. A biopsy specimen re-evaluation detected CD20-positive atypical large B cells infiltrating the small vessels within and around the lymph node and its capsule. We diagnosed her with intravascular large B-cell lymphoma (IVLBCL). Lymphoma cells were weakly positive for IL-6 by immunohistochemical staining. IL-6 from lymphoma cells may have caused the MCD-like presentation as a paraneoplastic etiology. Malignant lymphoma should be excluded before diagnosing MCD.
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http://dx.doi.org/10.2169/internalmedicine.5046-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759707PMC
December 2020

Real-World Issues and Potential Solutions in Hematopoietic Cell Transplantation during the COVID-19 Pandemic: Perspectives from the Worldwide Network for Blood and Marrow Transplantation and Center for International Blood and Marrow Transplant Research Health Services and International Studies Committee.

Biol Blood Marrow Transplant 2020 12 24;26(12):2181-2189. Epub 2020 Jul 24.

Department of Adult Hematology and Stem Cell Transplant, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers and the recognition of the variability in practice worldwide, the Worldwide Network for Blood and Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research's (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT, including diagnostics for SARS-CoV-2 in HCT recipient, pre- and post-HCT management, donor issues, medical tourism, and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplantation activity in those patients who urgently require it, albeit with extreme caution. This shared knowledge may be of value to the HCT community in the absence of high-quality evidence-based medicine. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380217PMC
December 2020

Clinical characteristics and outcomes of duodenal-type follicular lymphoma.

Leuk Lymphoma 2020 12 22;61(13):3266-3268. Epub 2020 Jul 22.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1080/10428194.2020.1795162DOI Listing
December 2020

Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia conducted in Japan during the past quarter century.

Ann Hematol 2020 Jun 4;99(6):1351-1360. Epub 2020 May 4.

The Jikei University School of Medicine, Tokyo, Japan.

Acute myeloid leukemia (AML) represents the most common indication for allogeneic hematopoietic cell transplantation (HCT). This study aimed to address the implementation status of allogeneic HCT for adults with AML in Japan and to provide a comprehensive overview of post-transplant outcomes. For this purpose, we analyzed data of 15,186 patients undergoing allogeneic HCT between 1992 and 2016 who were consecutively reported to the Japanese nationwide transplantation registry. The constant increase in the annual number of transplantations was clearly attributable to the growth of unrelated transplantation, and umbilical cord blood transplantation currently accounts for one-third of all allogeneic HCTs. The proportion of older patients has increased steadily since 2000, approximately, in parallel with the introduction of reduced-intensity conditioning. The probability of overall survival (OS) was estimated at 41% (95% confidence interval (CI), 40-42%) for the entire cohort, 56% (95% CI, 55-57%) for patients transplanted in complete remission (CR), and 22% (95% CI, 21-23%) for those transplanted in non-CR. Multivariate analysis identified age, sex, performance status, disease status, cytogenetic risk, donor type, graft source, sex mismatch between the donor and the recipient, and year of transplantation as factors significantly associated with OS. These findings represent the real-world data in Japan, showing the changes in transplantation practice and a detailed estimation of post-transplant outcomes.
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http://dx.doi.org/10.1007/s00277-020-04051-0DOI Listing
June 2020

Health-related quality of life in peripheral blood stem cell donors and bone marrow donors: a prospective study in Japan.

Int J Hematol 2020 Jun 14;111(6):840-850. Epub 2020 Mar 14.

Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Understanding of the impact of stem cell donation on donors' health-related quality of life (HRQOL) remains limited. A prospective observational study of eligible unrelated donors enrolled in the Japan Marrow Donor Program was conducted to compare HRQOL and adverse events (AEs) between peripheral blood stem cell (PBSC) and bone marrow (BM) donors. In total, 107 PBSC donors and 108 BM donors were enrolled. HRQOL scores for physical status were significantly lower in BM donors 1 week post-harvest (P < 0.001), but there were no significant differences between the two groups at baseline or 3 months post-harvest. PBSC donors were more likely to experience AEs before harvest (P < 0.001). However, at harvest, moderate-to-severe AEs were more common in BM donors (P = 0.001). After harvest, all grades of AEs were significantly higher in BM donors (P < 0.001). Among BM donors, a lower total physical score at baseline [odds ratio (OR) 1.21], female sex [OR 2.71], and young donors (OR 3.08) were risk factors for moderate-to-severe AEs at harvest, while among PBSC donors, only female sex (OR 4.86) was a risk factor. Our findings show better HRQOL during PBSC donation. These data help support decision-making by potential donors.
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http://dx.doi.org/10.1007/s12185-020-02852-7DOI Listing
June 2020

Disseminated Mycobacterium massiliense infection in a patient with myelodysplastic syndrome undergoing allogeneic bone marrow transplantation.

Transpl Infect Dis 2020 Jun 19;22(3):e13278. Epub 2020 May 19.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Nontuberculous mycobacteria are ubiquitous in water and soil, and the subset of rapidly growing mycobacteria species can cause severe infections in immunocompromised patients. Solid organ or hematopoietic stem cell transplantation (HSCT) recipients are known to be susceptible to infection by nontuberculous mycobacteria. The nontuberculous mycobacteria species Mycobacterium massiliense (M massiliense) has been classified as a rapidly growing mycobacteria and recognized as a pathogen causing lung and soft tissue infections in humans. However, there have been only a few reported cases of M massiliense infection after solid organ transplantation and HSCT. We herein report another case of M massiliense infection after allogeneic HSCT, which manifested as soft tissue infection, lung infection, and bacteremia.
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http://dx.doi.org/10.1111/tid.13278DOI Listing
June 2020

In vivo expansion of functional human hematopoietic stem progenitor cells by butyzamide.

Int J Hematol 2020 May 12;111(5):739-741. Epub 2020 Mar 12.

Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.

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http://dx.doi.org/10.1007/s12185-020-02849-2DOI Listing
May 2020

Treatment outcomes of chronic-phase chronic myeloid leukemia with resistance and/or intolerance to a 1st-line tyrosine kinase inhibitor in Japan: the results of the New TARGET study 2nd-line.

Int J Hematol 2020 Jun 9;111(6):812-825. Epub 2020 Mar 9.

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

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22-88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.
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http://dx.doi.org/10.1007/s12185-020-02843-8DOI Listing
June 2020

Successful Treatment of End-stage Renal Disease in a Patient With Chronic Myeloid Leukemia by Kidney Transplantation and Tyrosine Kinase Inhibitors: A Case Report.

Transplant Proc 2020 Mar 3;52(2):604-607. Epub 2020 Feb 3.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Consensus regarding kidney transplantation feasibility in patients with chronic myeloid leukemia (CML) well controlled by tyrosine kinase inhibitors has not yet been achieved. Here, we report a patient with CML well controlled by tyrosine kinase inhibitors who developed end-stage renal disease during treatment and underwent kidney transplantation. CML activity has been carefully and successfully controlled for 4 years post-transplant. Very cautious dose adjustment and temporary cessation of nilotinib were required because kidney function fluctuated in reference to the doses of nilotinib.
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http://dx.doi.org/10.1016/j.transproceed.2019.10.035DOI Listing
March 2020

Outcomes and Prognostic Factors for Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A KSGCT Multicenter Analysis.

Biol Blood Marrow Transplant 2020 05 18;26(5):998-1004. Epub 2020 Jan 18.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 10/μL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P < .001). This scoring system may be useful in identifying the patient population for which allogeneic HCT is least beneficial in advanced stages of ALL.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.007DOI Listing
May 2020

Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic phase: the D-NewS Study of the Kanto CML Study Group.

Int J Hematol 2020 Mar 1;111(3):401-408. Epub 2020 Jan 1.

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

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.
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http://dx.doi.org/10.1007/s12185-019-02801-zDOI Listing
March 2020

Allogeneic hematopoietic stem cell transplantation for aplastic anemia with pre-transplant conditioning using fludarabine, reduced-dose cyclophosphamide, and low-dose thymoglobulin: A KSGCT prospective study.

Am J Hematol 2020 03 19;95(3):251-257. Epub 2019 Dec 19.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

The optimal pre-transplant conditioning for aplastic anemia (AA) remains unclear. We performed a prospective study on allogeneic transplantation from a related or unrelated donor for adult patients with AA. We assessed whether reduced-dose cyclophosphamide (CY) could decrease toxicity while maintaining engraftment, and low-dose thymoglobulin could safely prevent graft-vs-host disease (GVHD). The pre-transplant conditioning regimen consisted of fludarabine 120 mg/m , CY 100 mg/kg, and thymoglobulin 2.5 mg/kg with or without 2 Gy of total body irradiation. Twenty-seven patients with a median age of 36 years were analyzed. Sixteen patients received graft from related donors. The stem cell source was bone marrow in 26 patients. All of the patients but one, who died early, achieved neutrophil engraftment at a median of 19 days. Mixed chimerism was observed in six and five patients at days 30 and 90, respectively. Only one patient experienced secondary engraftment failure with complete donor-type chimerism. None of the patients developed severe acute GVHD. The cumulative incidence of chronic GVHD was 37.7% at 1 year. The overall survival rate was 96.3% at 1 year and 3 years. A high EB virus-DNA load was detected in one patient at days 60. No one developed EBV-lymphoproliferative disorder within a year. The results suggest that the conditioning regimen in this study was safe and effective. However, relatively high incidence of chronic GVHD needs further improvement.
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http://dx.doi.org/10.1002/ajh.25693DOI Listing
March 2020

Seasonal changes in indoor airborne fungal concentration in a hematology ward.

J Infect Chemother 2020 Apr 30;26(4):363-366. Epub 2019 Nov 30.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Invasive fungal disease (IFD) is an important infectious complication of hematological disorders, especially in hematopoietic stem cell transplantation recipients. Evidences suggest seasonal and/or geographical variations in the airborne fungal counts and a relationship between those counts and the incidence of IFD. We evaluated the concentrations of indoor airborne fungi quantitated over the course of one year in a hematology ward in Japan. In January, April, July, and October, fixed volumes of air samples were obtained by an air sampler in a hematology ward not equipped with a high-efficiency particulate air filter and incubated in fugal cultures. Samples were also obtained from a protective environment in the same ward and were evaluated. The number of fungal colonies per 50 L of sampled air was highest in October (median 2.25 (range, 0.2-7.0)), which was significantly higher than those in the other three months (0.1 (range, 0-1.0) in January; 0 (0-0) in April; 0.55 (0-2.5) in July; P < 0.01)). Commonly identified pathogens included Penicillium and Cladosrporium species, but Aspergillus species was detected only in July and October samples. These results suggest a seasonal variation in indoor airborne fungal concentrations in Japan, which could affect the epidemiology of IFD.
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http://dx.doi.org/10.1016/j.jiac.2019.10.020DOI Listing
April 2020