Masahiro Takeuchi - Academia.edu (original) (raw)

Papers by Masahiro Takeuchi

International journal of molecular sciences, 2014

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoie... more We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with...

Histopathology, Jan 25, 2014

Pulmonary adenosquamous carcinoma (ASC) is more aggressive than adenocarcinoma (AC) and squamous ... more Pulmonary adenosquamous carcinoma (ASC) is more aggressive than adenocarcinoma (AC) and squamous cell carcinoma (SCC). The genetic features and biomarkers of ASC are not well known. Here, we attempted to identify potential therapeutic markers for ASC. Surgically resected ASC samples from 65 patients were analysed. We examined the expression of β III-tubulin, thymidylate synthase, breast cancer susceptibility gene 1 and ribonucleotide reductase M1 (RRM1); identified mutations in epidermal growth factor receptor (EGFR), KRAS, BRAF and HER2; and detected ALK, ROS1 and RET rearrangements. Gene amplification and expression of EGFR, human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor-1 and MET were also examined. β III-Tubulin showed the highest expression (P = 0.002), and its expression was more frequent in the AC than in the SCC component (P = 0.013). RRM1 expression was more frequent in the SCC component (P = 0.046). EGFR and KRAS mutations were detected ...

Internal medicine (Tokyo, Japan), 2014

Myeloid sarcoma (MS) is an extramedullary myeloid tumor that sometimes presents with antedating s... more Myeloid sarcoma (MS) is an extramedullary myeloid tumor that sometimes presents with antedating systemic leukemia, leading physicians to the misdiagnosis of lymphoma. CD25 is expressed in 13% of patients with acute myeloid leukemia (AML), and its expression is associated with FLT3-ITD mutations, an elevated serum soluble interleukin 2 receptor (sIL-2R) level and a lower survival rate. However, there are no reports concerning the relationship between MS and the CD25 expression. We herein report a case of AML accompanied by thoracic epidural MS with a high CD25 expression, the FLT3-ITD mutation and an extremely elevated serum sIL-2R level in a 59-year-old man who presented with paraplegia.

Leukemia research reports, 2013

Extramedullary blast crisis of chronic myelogenous leukemia (CML) is defined as the development o... more Extramedullary blast crisis of chronic myelogenous leukemia (CML) is defined as the development of extramedullary disease caused by the infiltration of blasts regardless of proliferation of blasts in the bone marrow. The onset of extramedullary blast crisis in the newly diagnosed patients is known to be extremely rare. Here, we present a case of extramedullary blast crisis of CML as an initial presentation in a 17-year-old female presenting with pain in the left femur tumor. This case was treated successfully with dasatinib and allogeneic hematopoietic stem cell transplantation, with achievement of long-term remission.

Journal of Cancer Research and Clinical Oncology, 2008

Purpose There is some unknown reason Ewing family of tumors (EFTs) is much less common on Asia a... more Purpose There is some unknown reason Ewing family of tumors (EFTs) is much less common on Asia and Africa than in the Western Caucasian population. This study analyzed the prediction of response and prognostic factors for Ewing family of tumors (EFTs) in an Asian population with a low incidence. Methods We retrospectively reviewed 94 patients with EFTs between 1978 and 2006. Fifteen

Experimental & Molecular Medicine, 2014

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular... more LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-a and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

Many patients with myeloid malignancies are ineligible for conventional allogeneic he-matopoietic... more Many patients with myeloid malignancies are ineligible for conventional allogeneic he-matopoietic stem cell transplantation allo-HSCT with myeloablative conditioning because of their age, medical problems, or the lack of a suitable HLA-identical related donor. The outcome of 9 patients with myeloid malignancies who underwent allo-HSCT following fludarabine-and busulfan-based reduced intensity conditioning RIC from unrelated or mismatched related donor is herein described. Six patients received bone marrow from an unrelated donor, two re-ceived a serologically mismatched related allograft, and one received serologically mismatched unrelated cord blood. All patients demonstrated successfully engraftment at a median of 15 days and showed complete donor chimerism of 95% on day 28. One patient developed grade 3 regimen-related toxicity. Grade II to IV acute graft-versus-host disease GVHD and exten-sive type chronic GVHD developed in 6 and 4 patients, respectively. Of the two patients who...

Nature, 1996

MANY cytokines signal through different cell-surface receptors to activate the transcription fact... more MANY cytokines signal through different cell-surface receptors to activate the transcription factor NF-kappaB (ref. 1). Members of the TRAF protein family have been implicated in the activation of NF-kappaB by the tumour-necrosis factor (TNF)-receptor superfamily2-5. Here we report the identification of a new TRAF family member, designated TRAF6. When overexpressed in human 293 cells, TRAF6 activates NF-kappaB. A dominant-negative mutant

Transplant Infectious Disease, 2013

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation... more Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo-SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus-6-associated post-transplantation acute limbic encephalitis (HHV-6 PALE) after allo-SCT. A 45-year-old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus-mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV-6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV-6 PALE, and close monitoring of serum sodium levels in high-risk patients for HHV-6 PALE is necessary for immediate diagnosis and treatment initiation.

Respirology, 2007

The aim of this study was to develop a simple prediction model for the underlying diagnosis of so... more The aim of this study was to develop a simple prediction model for the underlying diagnosis of solitary pulmonary nodules (SPN) based on clinical characteristics and thin-section CT findings. Retrospective analysis was carried out on 452 patients with SPN (113 benign and 339 malignant) smaller than 30 mm, who underwent thin-section CT followed by surgical resection and histological diagnosis. The clinical characteristics were collected from medical records, and radiographic characteristics from thin-section CT findings. The prediction model was determined using multivariate logistic analysis. The prediction model was validated in 148 consecutive patients with undiagnosed SPN, and the diagnostic accuracy of the model was compared with that of an experienced chest radiologist. The prediction model comprised the level of serum CRP, the level of carcinoembryonic antigen, the presence or absence of calcification, spiculation and CT bronchus sign. The areas under the receiver-operating characteristic curve in training and validation sets were 0.966 and 0.840, respectively. The diagnostic accuracies of the prediction model and the experienced chest radiologist for the validation set were 0.858 and 0.905, respectively. The simple prediction model consisted of two biochemical and three radiographic characteristics. The diagnostic accuracy of an experienced chest radiologist was higher compared with the prediction model.

Proceedings of the National Academy of Sciences, 1996

The two cell surface receptors for tumor necrosis factor (TNF) interact with a number of intracel... more The two cell surface receptors for tumor necrosis factor (TNF) interact with a number of intracellular signal transducing proteins. The association of TRADD, a 34-kDa cytoplasmic protein containing a C-terminal death domain, with aggregated TNF receptor 1 (TNF-R1) through their respective death domains leads to NF-kappa B activation and programmed cell death. In contrast, TNF receptor 2 (TNF-R2) interacts with the TNF receptor associated factors 2/1 (TRAF2/TRAF1) heterocomplex, which mediates the recruitment of two cellular inhibitor of apoptosis proteins (c-IAP1 and c-IAP2) to TNF-R2. Here we show that the TNF-R2 signal transducers TRAF2 and c-IAP1 are a part of the TNF-R1 signaling complex. The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD, and is independent of TNF-R2. These data establish the physiological involvement of TRAF2 and c-IAP1 in TNF-R1 signaling and help provide a molecular explanation for both the overlapping and distinct signals generated by the two TNF receptors.

Leukemia & Lymphoma, 2014

Leukemia, 2008

qualitative and quantitative FC analysis, is a highly reliable marker for MLL diagnosis, more tha... more qualitative and quantitative FC analysis, is a highly reliable marker for MLL diagnosis, more than the absence of CD10. By collecting immunophenotypic NG2 data from 1461 B-ALL patients using both qualitative and quantitative methods, we tested FC performances according to GS response: sensitivity, specificity, predictive values and accuracy for both approaches produced comparable results with no significant differences in MLL diagnosis. Quantitative and qualitative FC produced five and six discordant results, respectively, compared to GS outcomes. Two out of five patients were considered negative by quantitative FC because of the low number of NG2-positive blast cells, enough to suspect MLL rearrangements by qualitative FC. This acknowledgment reduces the number of discordant cases to three in a comprehensive cohort of 1461 specimens. These findings suggest that the most accurate immunophenotyping approach to diagnose MLL rearrangements is given by the evaluation of both FC methods on NG2 antigen data combining subjective procedures (gating processes by qualitative FC) and objective measures (MESF values by quantitative FC). Moreover, taking into account that FC is undoubtedly a fast, cheap and easy technique compared to molecular diagnostics, our results support the introduction of immunophenotyping as a fundamental tool in the diagnosis of leukemias and the reliability of NG2 antigen as an accurate marker for MLL diagnosis. Immunophenotypic NG2 criterion for the diagnosis of MLL rearrangements provides a simple method with sufficient sensitivity and specificity to be applied for upfront clinical use in low-income countries.

The Lancet Oncology, 2008

Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good re... more Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

Journal of Biological Chemistry, 2013

A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from ... more A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit(+) Lin(-) cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit(+) Lin(-) cells of lr11(-/-) mice was reduced by hypoxia much more than of lr11(+/+) animals. sLR11 induced the adhesion of U937 and c-Kit(+) Lin(-) cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1α, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1α-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1α binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche.

International Journal of Hematology, 2014

Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph(+)MPAL) is a rare type of acu... more Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph(+)MPAL) is a rare type of acute leukemia having myeloid and lymphoid features. In the present study, we describe the successful treatment of a 71-year-old Japanese female patient with Ph(+)MPAL by the alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutations. The patient survived in her third complete remission (CR) for over 4 years. In her first CR, the patient was treated with multiple-agent chemotherapy and underwent maintenance therapy with imatinib and monthly vincristine and prednisolone (VP). At the first relapse, an examination of the bone marrow revealed a transformation into acute lymphoblastic leukemia and an F317L mutation in BCR-ABL1 gene, which responded preferentially to nilotinib over dasatinib. She achieved second CR, and nilotinib with VP therapy was selected for maintenance treatment. At second relapse, BCR-ABL1 mutational analysis revealed Y253H mutation instead of F317L mutation, resulting in resistance to nilotinib. The patient achieved third CR with dasatinib and VP therapy, and maintained CR with this treatment. This suggests that appropriate alternation of TKIs may contribute to long-term survival in elderly patients with Ph(+)MPAL.

International Journal of Hematology, 2013

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disease... more Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behçet&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations. Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.

Hypertension Research, 2008

The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nep... more The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study previously showed that treatment with telmisartan, an angiotensin II receptor blocker, effectively reduced the transition from incipient to overt nephropathy in Japanese type 2 diabetic patients. However, that large study included both normotensive and hypertensive patients. In the present post hoc analysis, we aimed to assess whether or not telmisartan elicits beneficial effects on the progression of microalbuminuria in normotensive patients. We randomized 163 microalbuminuric (urinary albumin-to-creatinine ratio: UACR of 100 to 300 mg/g creatinine) normotensive type 2 diabetic patients to treatment with telmisartan (40 or 80 mg once daily) or placebo over 52 weeks. The patients treated with either dose of telmisartan showed lower transition rates from microalbuminuria to overt nephropathy compared to the placebo group. In addition, more patients on telmisartan reverted to normoalbuminuria (UACR&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;30 mg/g creatinine): 15.5% of the 40 mg group, 19.6% of the 80 mg group, and 1.9% of the placebo group. In normotensive patients treated with telmisartan, changes in UACR were not significantly correlated with changes in blood pressure. Side effects did not differ among the groups. The present study demonstrates that telmisartan prevents the progression of microalbuminuria (in some cases induces remission of albuminuria) in normotensive Japanese patients with type 2 diabetes. Telmisartan is shown to be safe and well tolerated in these patients.

Leukemia & lymphoma, 2012

Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity c... more Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute GVHD grades II-IV and chronic GVHD were 29% and 48%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplantation was measured in 31 out of 34 patients (91%) surviving beyond day +100. Seventeen patients achieved >90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with ≤90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, P=0.002), and better long-term PFS and OS (P=0.002 and 0.05 respectively). Donor T-cell engraftment of >90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.