Language：English   Publishing type：Research paper (scientific journal)  

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.

DOI： 10.1007/s12185-024-03837-6

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Language：English   Publisher：(一社)日本血液学会  

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Mixed-phenotype acute leukemia (MPAL) with FLT3-TKD mutations is a rare and challenging subtype of leukemia. Effective management strategies are crucial for improving patient outcomes. A 31-year-old man with FLT3-TKD-mutated MPAL achieved hematological remission through the JALSG ALL202-O protocol and gilteritinib, followed by cord blood transplantation (CBT). Post-transplant complications included adenovirus-induced hemorrhagic cystitis, managed with bladder irrigation and ribavirin, and engraftment failure, necessitating a second CBT on Day 35. Subsequent adenoviral conjunctivitis resolved with vidarabine. The patient achieved neutrophil engraftment by Day 76 and was discharged on Day 173 without relapse. This case highlights the importance of vigilant supportive care and tailored therapy in managing MPAL with FLT3 mutations, especially in the context of post-transplant complications.

DOI： 10.1002/jha2.956

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Language：English   Publishing type：Research paper (scientific journal)  

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

DOI： 10.1007/s00277-024-05800-1

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(有)科学評論社  

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Acute myeloid leukemia (AML) is a hematological malignancy that frequently relapses, even if remission is achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective AML immunotherapy owing to the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and their therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 AML cases indicated that high expression of CD112 is associated with shorter survival than low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhances the expression of cytotoxicity-related genes, thus overcoming TIGIT inhibitory activity. Between CD155 and CD112, CD112 is an especially important target for NK cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also revealed that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, the modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, these results suggest the potential of the expression levels of these molecules as prognostic markers in AML.

DOI： 10.3324/haematol.2023.282915

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Authorship：Last author   Language：Japanese  

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BACKGROUND: No accurate prognostic tool is available for patients with cancer who spend their final days at home. In this study, we examined whether performance status (PS) and the palliative prognostic index (PPI), a well-known prognostic tool in palliative care units, could be used to predict prognosis in the home care setting at the time of intervention by home physicians. SUBJECTS AND METHODS: Using medical records, we conducted a retrospective analysis of 132 patients who were referred to the Home Clinic Naginoki for home care for terminal stages of carcinoma in situ. Based on the status at the time of the first visit, the PPI-Low group was defined as those scoring six or below and the PPI-High group as those scoring greater than six. RESULTS: The PPI-high group had a significantly poorer prognosis within 21 days than the PPI-low group (21-day-OS; Low 71.4% vs. High 13.2%; p<0.001). The Eastern Cooperative Oncology Group (ECOG) PS alone predicted better prognosis in the group with PS of one or two (21-day survival 90.1%), and the PPI score further significantly stratified the prognosis for patients with PS three or four, with a trend toward poor prognosis (p ≤ 0.005). CONCLUSION: ECOG PS 1 or 2 has a favorable prognosis and that using PPI in ECOG PS 3 or 4 leads to a more accurate prognosis prediction. PPI evaluated during the hospital-based treatment of patients with terminal cancer can also be used to predict prognosis if the patient is transitioned to a home care environment.

DOI： 10.1272/jnms.JNMS.2024_91-107

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01540&link_issn=&doc_id=20231204210001&doc_link_id=10.11406%2Frinketsu.64.1395&url=https%3A%2F%2Fdoi.org%2F10.11406%2Frinketsu.64.1395&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01540&link_issn=&doc_id=20231204210001&doc_link_id=10.11406%2Frinketsu.64.1395&url=https%3A%2F%2Fdoi.org%2F10.11406%2Frinketsu.64.1395&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.xcrm.2023.101114

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although rather favorable probabilities of return to work have been reported after allogeneic hematopoietic cell transplantation (allo-HCT), survivors often have difficulty continuing to work because of their immunocompromised status and diverse late effects after allo-HCT. We evaluated the incidence of and risk factors for recurrent sick leave in allo-HCT survivors after they initially returned to work. METHODS: We targeted allo-HCT survivors who were employed at diagnosis, aged 20-64 at survey, and survived for ≥ 2 years without relapse. Of the 1904 survivors who were informed of the study, 1148 returned the questionnaire (60%), and 1048 eligible participants were included in the overall analysis. In the present study that considered recurrent sick leave after return to work, we targeted 896 participants who returned to work at least once after allo-HCT. Participants stated if they had recurrent sick leave after returning to work and its reasons, as well as associated patient-, HCT/HCT center-, and work-related factors and clinical events after allo-HCT. A logistic regression analysis was conducted to explore correlated factors for recurrent sick leave. RESULTS: In survivors who returned to work, 30% required recurrent sick leave. The most frequent causes of recurrent leave were physical issues (72%), and analysis of free descriptions demonstrated that these were mainly associated with graft-versus-host disease, infection, or readmission. Other reasons included work-related issues such as gap between physical and working conditions. Multivariate analysis showed that cord blood transplantation, longer employment duration, and counseling from healthcare professionals were associated with a lower risk of recurrent leave. Readmission, immunosuppressant use, and symptoms involving the respiratory system, gut, and joints and muscles were associated with a higher risk. CONCLUSIONS: Our results drawn from a large cohort study should help healthcare professionals identify and assist at-risk patients. Multi-professional teams that provide continuous support and effective communication with the workplace are necessary to improve long-term outcomes after allo-HCT. IMPLICATIONS FOR CANCER SURVIVORS: In order to continue working after the initial return to work, it is important to receive counseling from healthcare professionals and obtain reasonable accommodation from workplace.

DOI： 10.1007/s11764-022-01250-8

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We previously showed that cell-surface CD86 expressed on multiple myeloma (MM) cells contributed to not only tumor growth but also antitumor cytotoxic T-lymphocyte responses mediated by induction of IL-10-producing CD4+ T cells. The soluble form of CD86 (sCD86) was also detected in serum from patients with MM. Thus, to determine whether sCD86 levels are a useful prognostic factor, we investigated the association of serum sCD86 levels with disease progression and prognosis in 103 newly diagnosed patients with MM. Serum sCD86 was detected in 71% of the patients with MM but was only rarely detected in patients with monoclonal gammopathy of undetermined significance and healthy controls, and the level was significantly increased in patients with advanced-stage MM. When we examined differences in clinical characteristics according to the level of serum sCD86, those in the high (≥2.18 ng/mL, n = 38) group exhibited more aggressive clinical characteristics, with shorter overall survival times compared with those in the low (<2.18 ng/mL, n = 65) group. On the other hand, it was difficult to stratify the patients with MM into different risk groups based on the expression levels of cell-surface CD86. The levels of serum sCD86 were significantly correlated with the expression levels of the messenger RNA (mRNA) transcripts of CD86 variant 3, which lack exon 6, resulting in a truncated transmembrane region, and its variant transcripts were upregulated in the high group. Thus, our findings suggest that sCD86 can be easily measured in peripheral blood samples and is a useful prognostic marker in patients with MM.

DOI： 10.1016/j.exphem.2023.01.006

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Treatment-free remission (TFR) is a new goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) to treatment with tyrosine kinase inhibitors (TKIs). However, optimal conditions for successful TFR in patients treated with second-generation (2G)-TKIs are not fully defined. In this D-FREE study, treatment discontinuation was attempted in newly diagnosed CML-CP patients treated with the 2G-TKI dasatinib who achieved BCR-ABL1 levels of ≤ 0.0032% (MR4.5) on the international scale (BCR-ABL1IS) and maintained these levels for exactly 1 year. Of the 173 patients who received dasatinib induction therapy for up to 2 years, 123 completed and 60 (48.8%) reached MR 4.5. Among the first 21 patients who maintained MR4.5 for 1 year and discontinued dasatinib, 17 experienced molecular relapse defined as loss of major molecular response (BCR-ABL1IS > 0.1%) confirmed once, or loss of MR4 (BCR-ABL1IS > 0.01%) confirmed on 2 consecutive assessments. The estimated molecular relapse-free survival rate was 16.7% at 12 months. This study was prematurely terminated according to the protocol's safety monitoring criteria. The conclusion was that sustained DMR for just 1 year is insufficient for TFR in CML-CP patients receiving dasatinib for less than a total of 3 years of treatment.

DOI： 10.1007/s12185-023-03549-3

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor is recommended as an initial treatment for young patients. However, immunosuppressive therapy (IST) with cyclosporine and anti-thymocyte globulin may be a viable option even when an HLA-identical sibling donor is available. METHODS: We constructed a Markov model to simulate the 10-year clinical course of patients aged 21-40 years with newly diagnosed severe aplastic anemia. Immediate BMT and IST were compared as an initial treatment assuming the availability of an HLA-identical sibling donor. Transition probabilities after treatment were determined based on a registry data analysis for BMT and a long-term prospective study for IST. RESULTS: Quality-adjusted life years (QALYs) after treatment selection were 6.77 for BMT and 6.74 for IST. One-way sensitivity analysis revealed that the utility for being alive without GVHD after BMT, that for being alive with partial response after IST, and the response rate after initial IST strongly affected the results. CONCLUSIONS: BMT and IST produced similar QALY for young patients with severe aplastic anemia. An estimation of the response rate to the initial IST may enable an individualized comparison between BMT and IST.

DOI： 10.1007/s12185-022-03530-6

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Language：English   Publishing type：Research paper (scientific journal)  

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p <0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co-occurrence of an internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 mutations (triple-mutations) were independent factors predicting poor prognosis related to OS, with NPM1 mutations being an independent factor for favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple-mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple-mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p <0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

DOI： 10.1111/cas.15720

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Language：English   Publishing type：Research paper (scientific journal)  

Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient' s death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.

DOI： 10.1272/jnms.JNMS.2023_90-105

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AIM: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. METHODS: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m2 on day -7, ETP 200 mg/m2 on days -6, -5, -4, -3 and Ara-C 2 g/m2 on day -4 -3, and MEL 140 mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. RESULTS: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. CONCLUSION: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

DOI： 10.1111/ajco.13780

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Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor as standard therapy for ALK-rearranged non-small cell lung cancer (NSCLC). Hemolytic anemia is considered as a rare but significant adverse event with alectinib. Here, we report a case of a 73-year-old female with lung adenocarcinoma, harbouring an ALK fusion gene, who received alectinib as second-line therapy and developed gradually progressive grade 4 (6.4 g/dL) drug-induced hemolytic anemia (DIHA) after complete response. We discontinued alectinib and performed a blood transfusion for the severe anemia. The anemia improved with no recurrence of lung adenocarcinoma over 10 months. Regular hematologic monitoring and the possibility of DIHA should be considered in case of progressive hemolytic anemia during alectinib treatment.

DOI： 10.2147/OTT.S398375

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Myelofibrosis (MF) is a chronic myeloproliferative tumor with a poor prognosis that not only impairs the quality of life because of splenomegaly and debilitating systemic symptoms but also has a high acute myeloid leukemia progression rate. Ruxolitinib, a JAK inhibitor, enhances systemic symptoms in MF and prolongs survival; however, it is not effective in suppressing bone marrow fibrosis and leukemia progression, and allogeneic hematopoietic stem cell transplantation remains needed for treatment. As a result, many new drugs for MF are presently being developed. Many similar drugs have been demonstrated to enhance therapeutic effectiveness if combined with ruxolitinib, particularly BCL-2/BCL-XL inhibitors, bromodomain and extra-terminal domain inhibitors, and human double-minute homolog 2 inhibitors, to improve bone marrow fibrosis. This study provides an overview of drugs currently employed in clinical trials being performed in Japan.

DOI： 10.11406/rinketsu.64.1298

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

INTRODUCTION: Accurate detection of myeloproliferative neoplasms (MPN)-associated gene mutations is necessary to correctly diagnose MPN. However, conventional gene testing has various limitations, including the requirement of skilled technicians, cumbersome experimental procedures, and turnaround time of several days. The gene analyzer i-densy IS-5320 allows gene testing using the quenching probe-Tm method. Specifically, pretreatment of samples including DNA extraction, amplification and detection of genes, and analysis of results are performed in a fully automatic manner after samples and test reagents are added into this system, which is compact and can be easily installed in a laboratory. The aim of this study is to investigate the sensitivity and specificity associated with the simultaneous detection of MPN-associated gene mutations. METHODS: We conducted an analysis of MPN-associated genes using i-densy IS-5320. We analyzed 384 samples (171 JAK2 V617F mutations, 10 JAK2 exon12 mutations, 104 CALR mutations, and 26 MPL mutations) that had been examined using conventional approaches such as allele-specific polymerase chain reaction (PCR), droplet digital PCR, and the direct sequencing method. RESULTS: The detection accuracy of JAK2 V617F, JAK2 exon 12, CALR, and MPL was 100.0% (383/383), 99.7% (383/384), 100.0% (370/370), and 99.7% (377/378), respectively. There was a strong positive correlation between the JAK2 V617F allele burden measured using conventional methods and i-densy IS-5320 (r = .989). CONCLUSION: Overall, i-densy IS-5320 exhibited good accuracy in terms of analyzing MPN-associated genes; thus, it can serve as a replacement for conventional methods of MPN-associated gene testing.

DOI： 10.1111/ijlh.13938

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ijlh.13938

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A pregnant woman with severe aplastic anemia was managed using biweekly red blood cell transfusion and oral eltrombopag olamine administration during pregnancy. She was diagnosed with preeclampsia at 35 weeks of gestation. The severity of aplastic anemia is very important for predicting the course of pregnancy.

DOI： 10.1002/ccr3.6789

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-022-03328-6

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Other Link： https://link.springer.com/article/10.1007/s12185-022-03328-6/fulltext.html

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Essential thrombocythemia (ET) and polycythemia vera (PV), are common Philadelphia-negative myeloproliferative neoplasms (MPN). Patients with MPN have a high rate of cardiovascular complications and often have acquired JAK2V617F and CALR genetic mutations. In this study, we aimed to analyze vascular endothelial function in patients with MPN.We evaluated 27 outpatients, including 10 patients diagnosed with MPN, flow-mediated dilatation (FMD), and nitroglycerin-mediated dilation (NMD), between September 2014 and August 2016. We measured serum adiponectin, which protects vascular endothelial function, and serum asymmetric dimethyl arginine (ADMA), which inhibits the production of adiponectin. The presence or absence of JAK2V617F and CALR mutations was evaluated in patients with MPN.Venous thrombosis was observed more frequently in patients with MPN than in those without. Seven MPN patients were diagnosed with PV, and 3 MPN patients were diagnosed with ET. JAK2V617F and CALR mutations were found in 5 and 3 MPN patients, respectively. FMD was significantly lower in JAK2V617F-positive MPN patients than in JAK2V617F-negative MPN patients, although NMD, adiponectin, and ADMA were similar in both groups. Adiponectin levels were higher and ADMA levels were lower in CALR-positive MPN patients than in CALR-negative MPN patients. There was no difference in FMD and NMD prevalence between the 2 groups. Furthermore, we had 3 representative MPN patients who were complicated with coronary spasm, possibly caused by MPN-related endothelial dysfunction.We found that patients with MPN presented with endothelial dysfunction, which was related to the presence of genetic mutations and was sometimes associated with cardiovascular disease.

DOI： 10.1536/ihj.22-003

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10−13) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.

DOI： 10.1038/s41588-022-01090-3

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Language：English   Publisher：(一社)日本骨髄腫学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41588-022-01036-9

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Other Link： https://www.nature.com/articles/s41588-022-01036-9

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Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

DOI： 10.1111/ajco.13674

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No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10−15). Subsequent fine-mapping analysis indicated that rs11065828 in CUX2 is the causal variant for colorectal polyps. We found that known colorectal cancer-susceptible SNPs were also associated with colorectal polyps. The genetic correlation between colorectal cancer and polyps is very high (r = 0.98 and p value = 0.0006). We additionally identified 14 significant loci of colorectal polyps and three significant loci of colorectal cancer by applying the multi-trait analysis of GWAS of colorectal cancer and colorectal polyps. We showed very similar germline polygenic features, which gives us the additional insight into potential cancers at polygenic levels for patients with polyps who are followed up at outpatients’ clinic; thus, close observation and polypectomy is critical to prevent colorectal cancers.

DOI： 10.1038/s10038-021-00980-4

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Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

DOI： 10.3390/cancers14010248.

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BACKGROUND: Headache is frequently reported as a neurological manifestation of myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythaemia. This study sought to clarify the clinical characteristics and response to treatment of headaches in patients with MPNs. METHODS: We prospectively studied 137 patients with MPNs. The following information was gathered to assess the features of headache at baseline and at follow-up (>6 months): (1) average duration of headache attacks, (2) number of headache days per month, (3) numerical rating scale (NRS), (4) Headache Impact Test-6 (HIT-6), and (5) Migraine Disability Assessment (MIDAS). We compared those parameters for headaches between the baseline and follow-up interviews according to the management. RESULTS: Thirty-seven (27.0%) patients had headache. The prevalence of headaches gradually decreased with increasing age (Age ≤ 49 years: 61.0%, 50-59 years: 38.5%, 60-69 years: 17.2%, 70-79 years: 5.1%, and ≥80 years: 0.0%, P < 0.001). Multiple logistic regression analysis showed that younger age, but not platelet counts or the JAK2 V617F mutation, was independently associated with headaches (Odds Ratios 2.004, 95% confidence intervals 1.293-3.108, P = 0.002). Scintillating scotomas were present in 22 (59.5%) of 37 patients with headaches, while four patients developed sudden headaches that lasted for only 0-10 min. Follow-up interviews were available for 31 (83.8%) of 37 patients with headaches. Twenty-one (67.7%) patients were treated with low-dose aspirin (100 mg once daily) [low-dose aspirin alone: n = 9; combined cytoreductive therapy: n = 12] for headache management. All parameters for headache [average duration of headache attacks, number of headache days per month, NRS score, HIT-6 score, and MIDAS score (all P < 0.001)] were significantly improved at follow-up in patients taking low-dose aspirin. However, there were no significant differences in these parameters of headaches in patients who did not receive low-dose aspirin. CONCLUSION: Headaches is common in patients with MPNs, particularly in younger patients. MPN-related headaches may be managed by using low-dose aspirin and controlling MPNs.

DOI： 10.3389/fneur.2022.1051093

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Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy accompanied by impaired differentiation and autonomous proliferation of hematopoietic stem cells. Standard induction therapy results in first complete remission among 70% of patients with AML; however, approximately half of these patients relapse and become refractory. Allogeneic hematopoietic cell transplantation is a useful treatment for relapsed and refractory cases. However, transplantation-related mortality is approximately 20%, which is not a low value, and quality of life after transplantation decreases. Therefore, there is a need to stratify the prognosis of each patient and implement this treatment appropriately. Owing to recent advances in genome analysis technology, many gene mutations involved in onset and recurrence of AML have been discovered. These abnormalities and mutations not only have clinical application as prognostic factors and minimal residual disease markers, but they may also contribute to novel molecular targeted drug development. Many new drugs such as first-generation FMS-like tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 and 2 (IDH1/2), and B cell lymphoma 2 (BCL2) inhibitors have been developed in the West. In addition, the second-generation FLT3 inhibitors gilteritinib and quizartinib were developed in Japan, and treatment outcomes for patients with AML have improved. However, there is still a large disparity in drug availability between the West, and Japan. As a result, treatment guidelines in the West cannot be applied in the clinical setting in Japan. In this study, we assessed the molecular target drug treatment by gene diagnosis for treatment of AML patients.

DOI： 10.1272/jnms.JNMS.2022_89-313

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.

DOI： 10.1038/s41467-021-23134-8

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Primary thyroid lymphoma (PTL) is a rare disease frequently arising against a background of autoimmune thyroiditis. It has recently been reported that the inactivation of the NF-κB negative regulator A20 by deletion and/or mutation could be involved in the pathogenesis of subsets of B-cell lymphomas. This study investigated the clinicopathologic characteristics and A20 mutation in PTL.We analyzed the characteristics of 45 PTL patients (14 men and 31 women), with a median age of 71 (range, 35-90) years. A20 mutations were analyzed in DNA extracted from 20 samples consisting of 19 tumor tissues and 1 sample from Hashimoto's thyroiditis.Thirty-five patients (82%) had a history of Hashimoto's thyroiditis and 29 (64%) had diffuse large B-cell lymphoma (DLBCL), presenting with larger tumors including bulky mass, elevated soluble interleukin-2 receptor levels, and longer history of Hashimoto's thyroiditis compared with mucosa-associated lymphoid tissue (MALT) lymphoma patients (n=16). A20 mutations were identified in 3 of 19 PTL patients (16%), 2 of 10 (20%) with DLBCL, and 1 of 9 (11%) with MALT lymphoma. Interestingly, all patients with A20 mutations had Hashimoto's thyroiditis. Furthe

DOI： 10.1272/jnms.JNMS.2022_89-305

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human dise

DOI： 10.1038/s41588-021-00931-x

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Language：English   Publisher：(一社)日本血液学会  

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Language：Japanese   Publisher：科学評論社  

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

DOI： 10.1182/bloodadvances.2021004292

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Language：Japanese  

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Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15–1.36; P = 1.8 × 10−7), including sepsis (HR 2.68; 95% CI = 2.25–3.19; P = 3.1 × 10−28), pneumonia (HR 1.76; 95% CI = 1.53–2.03; P = 2.3 × 10−15), digestive system infections (HR 1.51; 95% CI = 1.32–1.73; P = 2.2 × 10−9) and genitourinary infections (HR 1.25; 95% CI = 1.11–1.41; P = 3.7 × 10−4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

DOI： 10.1038/s41591-021-01371-0

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Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed.This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 10 CD34-positive cells/kg (range: 0.3-47.4 × 10 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 10 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed.The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 10/μL; range: 1.60-47.4 × 10 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment.The presence of promyelocy

DOI： 10.1272/jnms.JNMS.2021_88-104

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Language：Japanese   Publisher：一般社団法人 日本血液学会  

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Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for refractory hematological malignancies. However, there are many treatment-related complications, including organ disorders, graft-versus-host disease (GVHD), and infectious diseases. Furthermore, there are many unclear points regarding central nervous system (CNS) complications, and the prognosis in patients with CNS complications is extremely poor. We herein report a 49-year-old woman who developed CNS-GVHD after a second transplantation for therapy-related myelodysplastic syndrome. CNS-GVHD in this case was refractory to all treatments, including steroids, and progressed. We also present a review of the literature about the symptoms, diagnosis, and treatment of CNS-GVHD.

DOI： 10.2169/internalmedicine.6351-20

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Language：Japanese   Publisher：一般社団法人 日本造血細胞移植学会  

<p> 急性骨髄性白血病（acute myeloid leukemia，AML）は，近年の遺伝子変異解析技術の進歩によってその発症や再発に関与をする多くの遺伝子変異が発見された。こうしたゲノム解析の結果は予後因子や微少残存病変マーカーとして臨床応用をされるだけでなく新規の分子標的薬創薬に貢献をしている。実際に欧米からは第一世代FLT3阻害薬，IDH1/2阻害薬，BCL2阻害薬など多くの新規薬剤が登場をし，本邦からも第二世代FLT3阻害薬のGilteritinibやQuizartinibの登場でAMLの治療成績が向上しつつある。しかし欧米とのドラッグラグが依然として大きく，欧米の治療ガイドラインを本邦の実臨床にあてはめることはできない。そこで本稿では現在の本邦でのAMLの実臨床において遺伝子診断によるAMLの予後層別化や同種造血幹細胞移植の適応を概説する。</p>

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVES: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. METHODS: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. RESULTS: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. CONCLUSIONS: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.

DOI： 10.1016/j.ijid.2020.08.081

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Publisher：Cold Spring Harbor Laboratory  

<title>Abstract</title>Current genome-wide association studies (GWASs) do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype GWASs (diseases, biomarkers, and medication usage) in BioBank Japan (<italic>n</italic>=179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (<italic>n</italic>_total=628,000) identified ∼5,000 novel loci, which improved the resolution of genomic map of human traits. This atlas elucidated landscape of pleiotropy as represented by MHC locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically-informed subtyping of similar diseases (e.g., allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

DOI： 10.1101/2020.10.23.20213652

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

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

DOI： 10.1007/s00277-020-04290-1

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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

DOI： 10.1007/s12185-020-02894-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 x 10(-9)). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.Genome-wide analysis in 212,453 Japanese individuals identifies loci associated with 42 diseases. Comparative analysis with European populations identifies East Asian-specific associations.

DOI： 10.1038/s41588-020-0640-3

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Other Link： http://www.nature.com/articles/s41588-020-0640-3

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

BACKGROUND: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. METHODS: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. RESULTS: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. CONCLUSION: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.

DOI： 10.1272/jnms.jnms.2020_87-404

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV) and essential thrombocythemia (ET) have an increased risk of ischemic stroke. However, little is known about brain morphological changes and the cerebral vasculature in MPNs. The aim of the present study is to clarify the prevalence rates of brain infarcts (BIs) on magnetic resonance imaging (MRI) and to assess the detailed clinical and MRI characteristics in those patients. METHODS: We prospectively enrolled patients with MPNs who underwent brain MRI between September 2017 and June 2019. BI patterns were characterized by the numbers and locations of BIs on MRI. RESULTS: A total of 101 patients were included in the present study. BIs were observed in 23 patients (23%). Multiple logistic regression analysis showed that age > 60 years (odds ratio (OR) 7.34, 95% confidence interval (CI) 1.08-49.7, p = .041) and history of thrombosis (OR 40.6, 95% CI 7.97-207, p < .0001) were independently associated with BIs, but not the JAK2V617F mutation. Of the 23 patients with BIs, eight patients (35%) had multiple territorial infarcts, and large vessel involvement was identified in five patients (22%). Two patients had thrombus formation in large vessels. CONCLUSIONS: Among patients with MPNs who underwent MRI, BIs were observed in 23% of patients followed up in our center. Older age and thrombosis history were independently associated with BIs. Some patients with MPNs may present with distinctive MRI findings including multiple territorial infarcts and thrombus formation in large vessels.

DOI： 10.1016/j.jns.2020.116990

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-020-02865-2

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: A cryptic form of dyskeratosis congenita (cDKC) has a gradual onset without the characteristic physical findings of DKC. cDKC is distinguished from other forms of bone marrow failure (BMF) through analysis of telomere shortening and gene mutations. Mutations in the telomerase reverse transcriptase (TERT) and telomere RNA component (TERC) genes have been detected in most Japanese cDKC patients. Therefore, we investigated the impact of each TERT and TERC mutation on telomerase activity. METHODS: TERT and TERC mutants observed in DKC or cDKC patients were transfected into Saos-2 or VA13+TERT (TERT-expressing VA13 cells) cells to measure telomerase activity. RESULTS: Telomerase activity in cells expressing a mutant detected in cDKC patients was significantly lower (P < .0001) than in cells expressing the wild-type genes. In addition, some TERT mutations seen in cDKC (p.P632R, p.T726M) caused weaker (P = .0013) suppression of telomerase activity than others (p.G106W and p.G682D). In contrast, telomerase activity in cells expressing a TERT or TERC mutant detected in DKC patients did not significantly differ from cells expressing the wild-type genes. CONCLUSION: These findings suggest that TERT and TERC mutations detected in cDKC patients could potentially contribute to the pathogenesis of cDKC by blocking telomerase activity. However, TERT and TERC mutations detected in DKC patients did not affect telomerase activities, which means studying the telomerase activity of mutants are not always useful for the diagnosis of DKC.

DOI： 10.1111/ijlh.13176

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS: We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS: In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION: A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

DOI： 10.1200/JCO.19.01916

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s12185-019-02801-z

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

BACKGROUND: Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed. METHODS: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 106 CD34-positive cells/kg (range: 0.3-47.4 × 106 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 106 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed. RESULTS: The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 106/μL; range: 1.60-47.4 × 106 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment. CONCLUSION: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.

DOI： 10.1272/jnms.jnms.2021_88-104

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is a key predictive factor for the prognosis of acute myeloid leukemia (AML). We compared the detection sensitivity of fragment analysis with that of PCR-electrophoresis using MV4-11 (FLT3-ITD) and NKM-1 (FLT3-wild type) cell lines. DNA of these cells was mixed at different ratios and subjected to PCR-electrophoresis or fragment analysis. PCR-electrophoresis was found to have an FLT3-ITD allelic ratio (AR) detection limit of 0.034-0.072. Visual inspection of the PCR-electrophoresis revealed a lower detection sensitivity than that of fragment analysis. Therefore, it is essential to conduct fragment analysis when screening for FLT3-ITD.

DOI： 10.1016/j.lrr.2020.100198

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BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

DOI： 10.1159/000504354

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DOI： 10.1272/jnms.JNMS.2020_87-102

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Language：Japanese   Publisher：(一社)日本頭痛学会  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

The prognostic significance of FLT3-tyrosine kinase domain (TKD) mutations remains unknown. To investigate the prognostic impact of FLT3-TKD, 676 de novo acute myeloid leukemia (AML), we retrospectively analyzed cases and conducted a review of the literature. Of the 676 de novo AML cases, 34 (5.0%) were FLT3-TKD-positive; both FLT3-TKD and FLT3-ITD were noted in only two cases (0.3%). Although no significant differences in relapse-free survival (RFS) were noted, FLT3-TKD-positive cases showed better prognoses than FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.152). For overall survival (OS), although FLT3-TKD-positive cases showed prognoses similar to those for FLT3-WT cases, their prognoses were significantly better than those of FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.032). Moreover, the 5-year OS for FLT3-TKD-positive cases was 46.1%, indicating that this as an intermediate prognosis group. Although no reports from Asia have indicated a frequency of FLT3-TKD-positive cases > 10%, several reports from Europe and the United States have indicated frequencies > 10%. This suggests the possibility that FLT3-TKD-positive cases are less common in Asia than in Europe and the United States. We anticipate that in the future, the appearance of targeting agents, such as FLT3 inhibitors, will improve the prognosis of FLT3-TKD-positive AML relative to that of FLT3-WT AML.

DOI： 10.1007/s12185-019-02720-z

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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DOI： 10.1111/ped.13859

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INTRODUCTION: Acute myelogenous leukemia (AML) in elderly patients is associated with an increased incidence of complications and treatment-related toxicity because of the frequency of comorbid disease and age-related deterioration in organ function. Despite advances in AML treatment in recent years, elderly patients have experienced limited benefit, and their outcomes remain poor. This study aimed to perform a comprehensive gene mutation analysis in elderly AML patients and identify gene mutations that could serve as prognostic factors. METHODS: An analysis of gene mutations was performed for 281 AML patients, including 98 elderly patients aged 65 years or above. RESULTS: Compared to younger AML patients, elderly patients showed a higher frequency of the following gene mutations: TP53 (P = 0.026), PTPN11 (P = 0.006), RUNX1 (P = 0.024), TET2 (P = 0.002), and ASXL1 (P = 0.023). The complete remission rate was significantly lower in DNMT3A mutation-positive cases (4.26%, P = 0.011) and TP53 mutation-positive cases (2.13%, P = 0.031) than in negative cases. The overall survival rate was significantly poorer in cases with FLT3-ITD (P = 0.003), DNMT3A (P = 0.033), or TP53 mutation (P < 0.001). Conversely, cases with PTPN11 mutation (P = 0.014) had a significantly more favorable prognosis. In multivariate analysis, FLT3-ITD (P = 0.011) and TP53 mutation positivity (P = 0.002) were independent poor prognostic factors, as were a performance status of 3 or above (P < 0.001) and poor cytogenetic prognosis (P = 0.001). In contrast, PTPN11 mutation positivity (P = 0.023) was an independent favorable prognosis factor. CONCLUSION: Analysis of gene mutations in elderly AML patients is very important, not only for establishing prognosis, but also for introducing appropriate molecular-targeted treatments.

DOI： 10.1111/ijlh.13025

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Language：Japanese   Publisher：医学図書出版(株)  

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In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.

DOI： 10.1182/bloodadvances.2018019398

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An 11q23 abnormality presents in approximately 5% of adults with acute myeloid leukemia (AML) and is associated with adverse outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). To evaluate the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality, we retrospectively analyzed the Japanese registration data of 322 adult AML patients with 11q23 abnormality who had received allo-HCT between 1990 and 2014. In total, the disease status at HCT was first complete remission (CR1) in 159 (49%) patients. The probability of overall survival and the cumulative incidence of relapse at 3 years were 44 and 44%, respectively. In the multivariate analysis, disease status beyond CR1 at the time of HCT was significantly associated with a higher overall mortality and relapse. The 11q23 fusion partner did not have a significant impact on survival. We also evaluated the prognostic value of minimal residual disease (MRD) status at HCT on transplant outcomes among hematological CR patients. MRD status at HCT was the significant prognostic indicator for hematological relapse and survival. These data suggested that allo-HCT offered a curative option for adult AML with 11q23 abnormality. Pretransplant MRD status was the significant prognostic indicator for relapse and survival in CR patients.

DOI： 10.1007/s00277-018-3419-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.

DOI： 10.1007/s12185-018-2510-7

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In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)-positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation-positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut-positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival [OS], 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival [RFS] P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut-positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.

DOI： 10.1182/bloodadvances.2018020305

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Language：English   Publisher：(一社)日本小児血液・がん学会  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Inc.  

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P = 0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P = 0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P = 0.0038, P = 0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor.

DOI： 10.1002/gcc.22542

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc  

DOI： 10.1016/j.ekir.2017.12.013

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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We analyzed the clinical responses to thyrosine kinase inhibitors (TKIs) and the molecular and cytogenetic characteristics of 18 chronic myeloid leukemia (CML) patients with 3-way chromosomal translocations. The patients were 14 men and 4 women, aged 23–75 years (median 57 years). The Sokal risk was low in 12 patients, intermediate in 4 patients, and high in 2 patients. Newly identified translocation breakpoints were seen in 7 of the 18 patients. Three patients had the same breakpoints of t(9
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11)(q34
q11.2
q23). The best responses to TKIs were partial cytogenic response (PCyR) in 2 patients, complete cytogenic response (CCyR) in 3 patients, molecular response (MR) 3.0 in 7 patients, MR 4.0 in 3 patients, and MR 4.5 or higher in 3 patients. A total of 66.7% of patients did not achieve MR 4.0 or higher. In 3 patients in whom TKIs resulted in MR 4.5 or higher for more than 2 years, TKI treatment was discontinued. However, all of them exhibited a loss of MR3.0, at 2, 6, and 20 months after the discontinuation of treatment, respectively, and TKI treatment needed to be restarted. According to Kaplan-Meier survival curve analysis, the overall survival (OS) was 100 months in 56% of the patients. The 60-months cumulative incidences of CCyR, MR3.0, MR4.0 and MR4.5 were 88.9%, 72.2%, 33.3%, and 16.7%, respectively. In the 11 analyzable patients, the BCR-ABL1 mRNA subtype was e14a2 type in 4 patients and e13a2 type in 7 patients.

DOI： 10.1016/j.leukres.2018.01.005

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%). TP53 gene deletion was observed in 3.1% of 358 cases. All cases had monoallelic deletion with TP53 gene mutation on the opposite allele. Multivariate analysis demonstrated that TP53 gene mutation in the DNA binding domain and outside the DNA binding domain was an independent poor prognostic factor for overall survival and relapse-free survival among the total cohort and it is also an unfavorable prognostic factor in FLT3-ITD-negative AML cases aged 70 years or below with intermediate cytogenetic prognosis. In stratified treatment, full-length search for TP53 gene mutation is therefore very important.

DOI： 10.1007/s00277-017-3143-2

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High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML. However, the clinical features of adult AML with PRDM16 expression remain unclear. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of MECOM (also known as EVI1). We investigated PRDM16 expression in 151 AML patients, with 47 (31%) exhibiting high PRDM16 expression (PRDM16/ABL1 ratio &gt;= 0.010). High PRDM16 expression significantly correlated with DNMT3A (43% vs. 15%, P&lt;0.001) and NPM1 (43% vs. 21%, P=0.010) mutations and partial tandem duplication of KMT2A (22% vs. 1%, P&lt;0.001). Remarkably, high-PRDM16-expression patients were frequent in the noncomplete remission group (48% vs. 21%, P=0.002). Overall survival (OS) was significantly worse in high-PRDM16-expression patients than in low-PRDM16-expression patients (5-year OS, 18% vs. 34%; P=0.002). This trend was observed more clearly among patients aged &lt;65 years (5-year OS, 21% vs. 50%; P=0.001), particularly in FLT3-ITD-negative patients in the intermediate cytogenetic risk group (5-year OS, 25% vs. 59%; P=0.009). These results suggest that high PRDM16 expression is a significant predictive marker for poor prognosis in adult AML patients, similar to pediatric AML patients.

DOI： 10.1002/gcc.22483

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p &lt; 0.001, OS: p &lt; 0.001). Moreover, stratified analysis of the chromosomal abnormalities t(8;21)(q22;q22) and inv(16)(p13.1q22), t(16;16)(p13.1;q22) showed that D816 mutation was associated with a significantly worse prognosis. In a further multivariate analysis of RFS and OS, D816 mutation was found to be an independent risk factor for significantly poorer prognosis. In the present study, we were able to establish that, of all KIT mutations, D816 mutation alone is an unfavorable prognostic factor.

DOI： 10.1007/s00277-017-3074-y

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

In core-binding factor acute myeloid leukemia (CBF-AML), there have been conflicting reports regarding the status as an unfavorable prognostic factor of mutation in the KIT gene, the significance of which remains unclear. We previously reported that prognoses differ between the KIT D816V and N822K mutations. In the present study, we compared in vitro the cell-proliferative and anti-apoptotic ability of D816V and N822K. We transduced these KIT mutations into the interleukin-3-dependent cell line TF-1 (TF-1 KITD816V, TF-1 KITN822K).When these KIT mutations were transduced into TF-1 cells, the cells acquired a proliferative ability independent of growth factor, which was significantly higher in TF-1 KITD816V than in TF-1 KITN822K (p = 0.022). When Ara-C was added in the absence of growth factor, Annexin V assay revealed that TF-1 KITD816V was associated with a significantly lower proportion of apoptotic cells than TF-1 KITN822K (p &lt; 0.001). Regarding signal transduction pathways, both KIT D816V and KIT N822K underwent autophosphorylation in the absence of growth factor. This was followed in KIT D816V by downstream activation of the SRC family kinase pathway in addition to the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and in KIT N822K by downstream activation of the mitogen-activated protein kinase (MAPK) pathway in addition to the JAK/STAT pathway. These findings establish that D816V and N822K mutations are situated closely on the KIT receptor activation loop, but D816V has greater cell-proliferative and anti-apoptotic ability than N822K. Copyright (C) 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2017.05.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Acute lymphoblastic leukemias (ALL) positive for KMT2A/ AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNF alpha, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-alpha. InKMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNF alpha by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. (C)2017 AACR.

DOI： 10.1158/0008-5472.CAN-16-2974

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n = 9963) or allogeneic (n = 3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/ MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P &lt; 0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P = 0.04) or secondary malignancies (Po0.001) and receiving cord blood stem cell (P = 0.03) or involved field radiotherapy (P = 0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

DOI： 10.1038/bmt.2017.52

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Purpose: Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making.
Methods: We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).
Results: We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants.
Conclusion: Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.

DOI： 10.1038/gim.2016.197

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Other Link： http://search.jamas.or.jp/link/ui/2017209721

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

DOI： 10.1038/bmt.2016.255

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DOI： 10.1111/1346-8138.13441

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/1346-8138.13441

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<p>Acute myeloid leukemia (AML) is a heterogeneous disease, the onset of which involves a variety of chromosomal abnormalities and gene mutations. In recent years, the use of next-generation sequencers has facilitated intensive exploration of gene mutations resulting in the discovery of many AML-related gene mutations, and in clarifying the clonal evolution process of relapse. Epigenetic regulatory gene mutations have occurred in pre-leukemic cells with normal differentiation potential, and the acquisition of numerous genetic mutations was found to be strongly associated with AML onset, with further co-mutations contributing to clonal diversity and leading to the generation of treatment-resistant clones. As a result of these fruitful findings, the gene mutations of AML are becoming useful as not only prognostic factors but also the targets of molecular medicines such as FLT3 and IDH inhibitors. Most notably, several guidelines have proposed a prognostic classification that groups FLT3ITD, NPM1 mutation, and CEBPA mutation together under conventional chromosomal aberrations. This review outlines recent findings pertaining to the gene mutations in AML.</p>

DOI： 10.11406/rinketsu.57.2535

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DOI： 10.1002/pbc.26030

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DOI： 10.1007/s11604-016-0564-0

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DOI： 10.1007/s00330-016-4573-2

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In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P&lt;0.0001) and in patients with intermediate cytogenetic risk (P&lt;0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged &lt;= 70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia.

DOI： 10.3324/haematol.2016.143073

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We performed a decision analysis comparing allogeneic hematopoietic cell transplantation (allo-HCT) versus chemotherapy in first complete remission for patients with cytogenetically intermediate-risk acute myeloid leukemia, depending on the presence or absence of FLT3-internal tandem duplication (ITD), nucleophosmin (NPM1), and CCAAT/enhancer binding protein alpha (CEBPA) mutations. Adjusted means of the patient reported EQ-5D index were used as quality-of-life (QOL) estimates. In 332 patients for which FLT3-ITD status was available, FLT3-ITD was present in 60. In 272 patients without FLT3-ITD, NPM1 mutations were present in 83. CEBPA biallelic mutations were detected in 53 patients. For patients harboring FLT3-ITD, allo-HCT improved life expectancy (LE) (52 versus 32 months during 10-year observation) and QOL-adjusted life expectancy (QALE, 36 versus 21). Monte-Carlo simulation identified allo-HCT as the favored strategy in 100% of simulations. In patients without FLT3-ITD, allo-HCT improved LE/QALE with or without NPM1 mutations. However, sensitivity analyses showed that the results were not robust enough. For patients harboring CEBPA biallelic mutations, chemotherapy was favored (LE, 53 versus 84; QALE, 37 versus 59), whereas, for patients with monoallelic mutations or wild-type CEBPA, allo-HCT was favored (LE, 68 versus 54; QALE, 48 versus 37). Sensitivity analyses did not change the results in either group. In conclusion, based on a Markov decision analysis, allo-HCT was a favored postremission strategy in patients with FLT3-ITD, and chemotherapy was favored in patients with biallelic CEBPA mutations. A prospective study is warranted to determine the value of allo-HCT, especially in FLT3-ITD negative patients. (C) 2016 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2016.03.015

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We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versushost disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×104/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBVpositive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBVrelated LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

DOI： 10.1272/jnms.83.35

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versushost disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×104/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBVpositive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBVrelated LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

DOI： 10.1272/jnms.83.35

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P = 0.0006) and cumulative incidence of relapse (CIR) significantly higher (P = 0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged. 65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P = 0.0010; CIR: P = 0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P = 0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P = 0.0002. CIR: P &lt; 0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

DOI： 10.1038/leu.2015.288

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The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET.
Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F-positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK246/1 haplotype was significantly higher among patients with JAK2V617F, JAK2Ex12del, or MAL mutations, whereas no significant difference was found among CALR mutation-positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F-positive patients.
Our findings suggest that JAK2V617F-positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2015.11.002

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Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>Acute myeloid leukemia (AML) is a heterogeneous disease, the onset of which involves a variety of chromosomal abnormalities and gene mutations. In recent years, the use of next-generation sequencers has facilitated intensive exploration of gene mutations resulting in the discovery of many AML-related gene mutations, and in clarifying the clonal evolution process of relapse. Epigenetic regulatory gene mutations have occurred in pre-leukemic cells with normal differentiation potential, and the acquisition of numerous genetic mutations was found to be strongly associated with AML onset, with further co-mutations contributing to clonal diversity and leading to the generation of treatment-resistant clones. As a result of these fruitful findings, the gene mutations of AML are becoming useful as not only prognostic factors but also the targets of molecular medicines such as FLT3 and IDH inhibitors. Most notably, several guidelines have proposed a prognostic classification that groups FLT3ITD, NPM1 mutation, and CEBPA mutation together under conventional chromosomal aberrations. This review outlines recent findings pertaining to the gene mutations in AML.</p>

DOI： 10.11406/rinketsu.57.2535

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Other Link： http://search.jamas.or.jp/link/ui/2017213844

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AstonJournals  

Although the prognosis of acute promyelocytic leukemia (APL) are favorable because of disease-specific drugs, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), early death due to fatal intracranial hemorrhage has been observed in many cases. The aim of this study is to examine the relationship between the treatment and intracranial hemorrhage complication in APL patients.46 patients diagnosed of APL during a period from 2000 to 2014 in our hospital were examined. The distribution of fatal intracranial hemorrhage (FICH) risk score in the 46 APL patients showed 23.9%, 58.6% and 17.3% for low, intermediate, and high categories, respectively. Among the 46 patients, 5 patients developed intracranial hemorrhage before remission, including 4 patients who developed such hemorrhage after chemotherapy and ATRA administration, and 1 patient who developed intracranial hemorrhage before treatment. All of the 5 patients were included in the high risk group of FICH score, including 1 patient who died and 3 patients who had serious paralysis. These hemorrhage tended to expand for several days because of progression of disseminated intravascular coagulation (DIC) accompanied by tumor lysis syndrome after chemotherapy. Based on this experience, we firstly provided single administration of ATRA for 5 days to a patient with intracranial hemorrhage and then added chemotherapy after improvement of DIC. As a result, we could lead remission with no expansion of intracranial hemorrhage. In most of induction therapy protocols for APL, patients with high white blood cell counts are recommended to receive combination of chemotherapy and ATRA with a focus on ATRA syndrome, but the risk of fatal intracranial hemorrhage is not reflected in the treatment regimen. Such a complication may be prevented using initial single administration of ATRA followed by concomitant chemotherapy after treatment for DIC in patients with a high-risk FICH score.

DOI： 10.4172/0974-8369.1000262

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Other Link： http://search.jamas.or.jp/link/ui/2016153383

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective In hematological malignancy patients, the complication of acute respiratory failure often reaches a degree of severity that necessitates mechanical ventilation. The objective of the present study was to investigate the therapeutic outcomes of mechanical ventilation in hematological malignancy patients with respiratory failure and to analyze the factors that are associated with successful treatment in order to identify the issues that should be addressed in the future.
Methods The present study was a retrospective analysis of 71 hematological malignancy patients with non-cardiogenic acute respiratory failure who were treated with mechanical ventilation at Nippon Medical School Hospital between 2003 and 2014.
Results Twenty-six patients (36.6%) were treated with mechanical ventilation in an intensive care unit (ICU). Non-invasive positive pressure ventilation (NPPV) was applied in 29 cases (40.8%). The rate of successful mechanical ventilation treatment with NPPV alone was 13.8%. The rate of endotracheal extubation was 17.7%. A univariate analysis revealed that the following factors were associated with the successful extubation of patients who received invasive mechanical ventilation: respiratory management in an ICU (p=0.012); remission of the hematological disease (p=0.011); female gender (p=0.048); low levels of accompanying non-respiratory organ failure (p=0.041); and the non-use of extracorporeal circulation (p=0.005). A subsequent multivariate analysis revealed that respiratory management in an ICU was the only variable associated with successful extubation (p=0.030).
Conclusion The outcomes of hematological malignancy patients who receive mechanical ventilation treatment for respiratory failure are very poor. Respiratory management in an ICU environment may be useful in improving the therapeutic outcomes of such patients.

DOI： 10.2169/internalmedicine.55.5822

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Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-a)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-a) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-a). In single-point sampling strategies, the AUC(0-a) predicted based on C-6 (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0-a) = 2556.5 C-6 + 320.9 (r (2) = 0.929, P &lt; 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-a), suggesting that this time-point is acceptable for busulfan monitoring.

DOI： 10.1007/s12185-015-1853-6

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DOI： 10.1245/s10434-015-4494-3

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DOI： 10.1245/s10434-015-4494-3

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Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

DOI： 10.1182/blood-2015-05-646240

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Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.

DOI： 10.1007/s12185-015-1861-6

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Pseudomonas oryzihabitans (formerly Flavimonas oryzihabitans) is a glucose non-fermentative, Gram-negative bacillus which is rarely isolated from human specimens. When isolated, it is on very rare occasion as a causative pathogen of catheter-related bloodstream infection in an immunocompromised patient. Herein, we describe two hematological malignancy patients suspected to have P. oryzihabitans bacteremia. We also review cases with bacteremia due to this pathogen and its microbiological characteristics.

DOI： 10.1016/j.jiac.2015.06.005

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Pseudomonas oryzihabitans (formerly Flavimonas oryzihabitans) is a glucose non-fermentative, Gram-negative bacillus which is rarely isolated from human specimens. When isolated, it is on very rare occasion as a causative pathogen of catheter-related bloodstream infection in an immunocompromised patient. Herein, we describe two hematological malignancy patients suspected to have P. oryzihabitans bacteremia. We also review cases with bacteremia due to this pathogen and its microbiological characteristics. (C) 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2015.06.005

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DOI： 10.11406/rinketsu.56.939

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Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P &lt; .01), and tumor-related mortality was lower (HR, 0.50; P &lt; .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

DOI： 10.1182/blood-2015-04-642652

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DOI： 10.1128/IAI.02968-14

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We have previously demonstrated conjugation of Escherichia coli into vacuoles of the protozoal ciliate (Tetrahymena thermophila). This indicated a possible role of ciliates in evoking bacterial quorum sensing, directly connecting bacterial survival via accumulation in the ciliate vacuoles. We therefore assessed if ciliates promoted bacterial autoinducer (AI)-2 accumulation with vacuole formation, which controls quorum sensing. E. coli AI-2 accumulation was significantly enhanced in the supernatants of a mixed culture of ciliates and bacteria, likely depending on ciliate density rather than bacterial concentration. As expected, AI-2 production was significantly correlated with vacuole formation. The experiment with E. coli luxS mutants showed that ciliates failed to enhance bacterial AI-2 accumulation, denying a nonspecific phenomenon. Fluorescence microscopy revealed accumulation of fragmented bacteria in ciliate vacuoles, and, more importantly, expulsion of the vacuoles containing disrupted bacteria into the culture supernatant. There was no increase in the expression of luxS (encoding AI-2) or ydgG (a transporter for controlling bacterial export of AI-2). We conclude that ciliates promote bacterial AI-2 accumulation in a mixed culture, via accumulation of disrupted bacteria in ciliate vacuoles followed by expulsion of the vacuoles, independently of luxS or ydgG gene induction. This is believed to be the first demonstration of a relationship between E. coli AI-2 dynamics and ciliates. In the natural environment, ciliate biotopes may provide a survival advantage to bacteria inhabiting such biotopes, via evoking quorum sensing.

DOI： 10.2323/jgam.61.203

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DOI： 10.3324/haematol.2014.114504

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DOI： 10.1111/jgh.12571

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DOI： 10.1183/09031936.00051314

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial.
Patients and methods Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups.
Results There were 56 men and 60 women, median age 60 years (range, 28-71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P = 0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin.
Conclusion In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients. (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

DOI： 10.1097/MEG.0000000000000105

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Mixed-lineage leukemia (MLL)/AF4-positive ALL is associated with a poor prognosis even after allogeneic hematopoietic SCT (allo-HSCT). We reported previously that MLL/AF4-positive ALL shows resistance to TNF-alpha, which is the main factor in the GVL effect, by upregulation of S100A6 expression followed by interference with the p53-caspase 8-caspase 3 pathway in vitro. We examined whether inhibition of S100A6 can induce an effective GVL effect on MLL/AF4-positive ALL in a mouse model. MLL/AF4-positive ALL cell lines (SEM) transduced with lentiviral vectors expressing both S100A6 siRNA and luciferase (SEM-Luc-S100A6 siRNA) were produced. SEM-Luc-S100A6 siRNA cells and SEM-Luc-control siRNA cells were injected into groups of five SCID mice (1 Chi 10(7)/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8 Chi 10(7) human PBMCs. SEM-Luc-S100A6 siRNA-injected mice showed significantly longer survival periods than SEM-Luc-control siRNA-injected mice (P = 0.002). SEM-Luc-S100A6 siRNA-injected mice showed significantly slower tumor growth than those injected with SEM-Luc-control siRNA (P &lt; 0.0001). These results suggested that inhibition of S100A6 may be a promising therapeutic target for MLL/AF4-positive ALL in combination with allo-HSCT.

DOI： 10.1038/bmt.2014.18

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DOI： 10.1530/EJE-13-0741

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DOI： 10.1183/09031936.00149113

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Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 (FLT3) and rat sarcoma viral oncogene homolog (RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3-ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain (FLT3-TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-a (40%) mutations. However, epigenetics-modifying gene (DNMT3a, TET2 and IDH1/2) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3-ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them (P = 0.001). Moreover, the high frequency of FLT3-ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations (P&lt;0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3-ITD, leading to resistance to therapy and relapse.

DOI： 10.1038/leu.2012.317

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Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin α (PSMα), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSMα gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSMα expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSMα comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSMα, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property. © 2013 Kaito et al.

DOI： 10.1371/journal.ppat.1003269

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Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin alpha (PSM alpha), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSM alpha gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSM alpha expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSM alpha comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSM alpha, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property.

DOI： 10.1371/journal.ppat.1003269

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Introduction: A case of mucosa-associated lymphoid tissue (MALT) lymphoma, the most frequent of the various conjunctival lymphoproliferative disorders, in which the initial biopsy was inconclusive but the second biopsy provided a definitive diagnosis, is reported. Case Report: A 26-year-old woman with a 3-month history of bilateral conjunctival swelling was referred by a local physician for suspected MALT lymphoma. A salmon-pink elastic swelling was found to involve both eyes and to extend from the lower palpebral conjunctiva to the bulbar conjunctiva. Tonsillar swelling was also found, and ophthalmologic (left eye) and otolaryngologic biopsies were therefore performed simultaneously under general anesthesia. The otolaryngologic diagnosis was chronic tonsillitis. Light microscope examination of the conjunctival tissue showed proliferation of lymphocytes and small aggregates of small to medium-sized atypical lymphocytes. On immunohistochemical studies, atypical lymphocytes were positive for CD20 and CD79a, but differentiation to plasmacytes was not prominent, and neither Dutcher bodies nor evidence of immunoglobulin light chain restriction was found. The results were not incompatible with MALT lymphoma but were not definitive. A second biopsy of the right eye was therefore performed 3 months later. Staining with hematoxylin and eosin showed proliferation of small lymphocytes and monocytoid B cells and differentiation to plasmacytes. The hyperplastic cells were positive for CD19, CD79a, and CD20, and their cytoplasm were positive for Bcl-2 and slightly positive for Bcl-6. Cells positive for CD38 were noted where differentiation to plasmacytes and immunoglobulin light chain κ restriction was evident on immunohistochemical studies and in situ hybridization. The Ki-67-positivity rate was approximately 5%. The results of paraffin-embedded tissue section fluorescence in situ hybridization were negative for MALT-1 (18q21). A diagnosis of MALT lymphoma was made, and treatment with rituximab was started. Discussion: Few findings lead directly to a definitive diagnosis of MALT lymphoma, and its differential diagnosis from benign lymphoproliferative disorders is difficult. In the present case definitive diagnosis was possible only after a second biopsy. This case suggests repeated biopsy may be necessary when a single biopsy is not definitive.

DOI： 10.1272/jnms.80.475

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Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-alpha and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-alpha, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL. (Blood. 2012; 119(1): 64-71)

DOI： 10.1182/blood-2011-05-354050

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DOI： 10.3960/jslrt.52.145

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Pure red cell aplasia (PRCA) and Evans syndrome following allogeneic hematopoietic stem cell transplantation (HSCT) from a blood type-matched donor are very rare. A 29-year-old Japanese woman with hematologic remission of Philadelphia chromosomepositive acute lymphoblastic leukemia underwent bone marrow transplantation from a blood type-matched, HLA 6/6 ― matched, unrelated donor in May 2008. Her clinical course after transplantation was favorable, and allowed for a gradual reduction in tacrolimus dosage. However, 12 months after transplantation, she developed PRCA related to allogeneic HSCT. The patientʼs PRCA was alleviated by stopping the dosage reduction for the immunosuppressive therapy and by continued administration of lowdose tacrolimus. Three months after the PRCA diagnosis, the patient developed Evans syndrome, so prednisolone (PSL) treatment was initiated. PSL treatment effectively treated the Evans syndrome, as was evident by the absence of cythemolysis two months later, and no relapse has occurred even after the PSL dose was reduced and then terminated. The fact that PRCA onset in this case occurred after blood type-matched allogeneic HSCT, during the late grafting phase, and in combination with Evans syndrome, suggests that the pathogenic mechanism may differ from that of previously reported cases of PRCA following blood type-incompatible allogeneic HSCT.

DOI： 10.7889/hct.1.24

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Mixed-lineage leukemia (MLL)-AFF1 (MLL-AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo- HSCT on MLL-AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL-AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL-AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53-caspase 8-caspase 3 pathway were observed only in MLL-AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53-caspase 8-caspase 3 pathway of MLL-AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL-AFF1 transgenic mice. These results suggest that MLL-AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53-caspase 8-caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL-AFF1-positive ALL in combination with allo-HSCT. © 2011 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/bcj.2011.37

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Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P = 0.355), but was a factor when using MB-PCR (P = 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P = 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML. Leukemia (2011) 25, 1423-1432; doi: 10.1038/leu.2011.104; published online 24 May 2011

DOI： 10.1038/leu.2011.104

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Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.

DOI： 10.1111/j.1440-1827.2011.02704.x

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Recently, RCSD1 was identified as a novel gene fusion partner of the ABL1 gene. The RCSD1 gene, located at 1q23, is involved in t(1;9)(q23;q34) translocation in acute B lymphoblastic leukemia. Here we describe RCSD1-ABL1-positive B-cell acute lymphoblastic leukemia (ALL) followed by rapid clonal evolution exhibiting three rare reciprocal translocations. We performed breakpoint analysis of the transcript expressed by the RCSD1-ABL1 fusion gene. RT-PCR and sequence analyses detected transcription of a single RCSD1-ABL1 fusion gene variant, which had breakpoints in exon 3 of RCSD1 and exon 4 of ABL1. The RCSD1 portion of the RCSD1-ABL1 fusion transcript consists of exons 1, 2, and 3. Tyrosine kinase inhibitors, imatinib and dasatinib, coadministered with dexamethasone achieved transient clinical effects in the present RCSD1-ABL1-positive ALL. However, leukemic cells rapidly became refractory to this treatment following the subsequent development of three additional reciprocal chromosomal translocations, t(5;16)(q33;q24), dic(18;20)(p11.2;q11.2) and t(10;19) (q24;p13.3). The present RCSD1-ABL1-positive ALL may represent a state of high chromosomal instability.

DOI： 10.1007/s12185-011-0910-z

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DOI： 10.1038/leu.2011.15

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DOI： 10.1111/j.1600-0609.2010.01554.x

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The F region downstream of the mecI gene in the SCCmec element in hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) contains two bidirectionally overlapping open reading frames (ORFs), the fudoh ORF and the psm-mec ORF. The psm-mec ORF encodes a cytolysin, phenol-soluble modulin (PSM)-mec. Transformation of the F region into the Newman strain, which is a methicillin-sensitive S. aureus (MSSA) strain, or into the MW2 (USA400) and FRP3757 (USA300) strains, which are community-acquired MRSA (CA-MRSA) strains that lack the F region, attenuated their virulence in a mouse systemic infection model. Introducing the F region to these strains suppressed colony-spreading activity and PSM alpha production, and promoted biofilm formation. By producing mutations into the psm-mec ORF, we revealed that (i) both the transcription and translation products of the psm-mec ORF suppressed colony-spreading activity and promoted biofilm formation; and (ii) the transcription product of the psm-mec ORF, but not its translation product, decreased PSM alpha production. These findings suggest that both the psm-mec transcript, acting as a regulatory RNA, and the PSM-mec protein encoded by the gene on the mobile genetic element SCCmec regulate the virulence of Staphylococcus aureus.

DOI： 10.1371/journal.ppat.1001267

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CHOP therapy combined with rituximab (R-CHOP) is currently a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, relapse is detected despite R-CHOP in approximately 30% of patients. Treatment results should be further improved. Previously, second- and third-generation therapies such as MACOP-B, m-BACOD, and ProMACE-CytaBOM were performed to improve the results of DLBCL treatment. However, dose intensity (DI) enhancement increased treatment-associated toxicity, and the treatment results did not improve. Recently, the entity of the relative dose intensity (RDI) was proposed as an index of the intensity of chemotherapy. In this method, the ratio of actual DI to the DI designed per specific period is numerically evaluated. The purpose of calculating the RDI is to achieve chemotherapy as scheduled while maintaining the DI, and not to improve the DI. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. In this paper, we review DI and RDI in studies of DLBCL, and revisit the significance of these indicators.

DOI： 10.3960/jslrt.51.1

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CHOP-like regimen combined with rituximab is a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). The relative dose intensity (RDI) was proposed as an index of the dose and administration interval of agents. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. However, few studies regarding RDI have reviewed patients receiving combination therapy with CHOP and rituximab. We investigated the influence of RDI maintenance, involving combination therapy with rituximab, on therapeutic effects in patients with DLBCL. We retrospectively examined 152 DLBCL patients who were treated with CHOP-like regimen combined with rituximab in whom the RDI could be followed up. Multivariate analysis revealed that international prognosis index (IPI) high intermediate-high (HI-H) (p = 0.005) and RDI of less than 70% (p = 0.007) were independent prognostic factors for low progression free survival. Concerning overall survival, IPI HI-H (p = 0.027) and an RDI of less than 70% (p = 0.002) were involved in an unfavorable prognosis. In addition, age over 60 years (p = 0.003), R-THPCOP (p = 0.034), or the presence of febrile neutropenia (p = 0.004) made RDI maintenance difficult, and prophylactic G-CSF therapy (p = 0.026) was useful for maintaining the RDI. Maintaining the RDI is important even in the era of rituximab-combined chemotherapy for DLBCL.

DOI： 10.1007/s00277-010-0956-7

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DOI： 10.1111/j.1365-2141.2010.08278.x

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DOI： 10.11406/rinketsu.51.646

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DOI： 10.11406/rinketsu.51.508

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We report here a rare case of EBV-related post-transplantation lymphoproliferative disorder (PTLD) localized to the skin. The patient was a 64-year-old man diagnosed with angioimmunoblastic T cell lymphoma (AITL). He underwent cord blood transplantation with a reduced intensity conditioning regimen during partial remission after chemotherapy. On day 70 after transplantation, subcutaneous tumors developed near the left scapula and in the left upper arm. Pathological examination of the skin tumor revealed that this tumor was composed of diffuse large centroblast-like cells, the majority of which were CD20 positive, CD 79a positive, CD30 positive and Epstein-Barr virus (EBV) latency-associated RNA (EBER) positive, and EBV-DNA was also detected in tumor cells. At that time, real-time polymerase chain reaction documented no evidence of the EBV genome in his blood. Chimerism analysis revealed that the tumor cells were derived from donor cells, which led to the diagnosis of EBV-related PTLD. For treatment, in addition to decreasing the dose of tacrolimus, we administered rituximab and local irradiation to skin lesions, which led to disappearance of the tumors followed by continued complete remission.

DOI： 10.11406/rinketsu.51.138

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Stem cell transplantation (SCT) is a useful treatment for hematological malignancies, but it is limited to younger patients because of its high treatment-related mortality. Fludarabine (Flu), a novel anticancer agent with potent immunosuppressive activity, used as a conditioning regimen (reduced intensity transplantation
RIST), can decrease treatment-related mortality, as recently reported. However, the best drug combination and the best timing for RIST remain unknown. We herein report the SCT outcomes of 36 patients undergoing Flu treatment at our institution since December 2002 and retrospectively analyze the results. RIST conditioning with Flu was well-tolerated. No severe toxicity related conditioning regimens was observed in our patients, even though there were 10 patients with a history of autologous (n=5) or allogeneic stem cell transplantation (n=5). Hematological engraftment was found in 33 patients. The median times for reconstitution of WBCs, RBCs, and platelets were 16 days, 27.5 days and 34 days, respectively. Stable complete donor chimerism after SCT was present in all patients with WBC engraftment, and no patients experienced late rejection. Thirty-two patients were evaluated for acute graft versus host disease (aGVHD). Nine patients had no aGVHD. The incidence of grade I/II and III/IV aGVHD was 78% and 22%, respectively. Skin lesions were the major sites of involvement. Gut involvement was present in 9 patients. All 4 patients with grade IV GVHD had stage four hepatic GVHD. Twenty-two patients were analyzed for chronic GVHD (cGVHD). Twelve patients had no cGVHD, 6 had limited type and 4 had extended type. The overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in all patients over 7 years were found to be 41.7%, 20.1%, and 34.6%, respectively. Induction failures were present in 5 cases of AML and 1 case of NHL. Disease progression was the primary cause of death, which occurred in 12 of 21 patients. Six patients died of grade IV GVHD (n=2) or complicated fungal infection contracted during the GVHD treatment (n=4). One patient died of secondary MSD, which originated from donor hematopoietic cells. Two patients died of cerebral bleeding and cardiac rapture, respectively. We found that the patients' state on SCT was the most important factor in long-term survival. The OS of standard risk and high risk patients with hematological malignancies were 75% and 30.3%. We concluded that stem cell transplantation using a non-myeloablative conditioning regimen with Flu was a useful therapeutic approach for patients with hematological malignancies.

DOI： 10.1272/jnms.77.254

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Heparinized human whole blood from 16 adult volunteers was stimulated with achievable blood concentrations of trastuzumab and rituximab at 37A degrees C for 4 h, then CCL20, IL8, and beta-actin mRNA were quantified. The fold increase of beta-actin was all less than 1.5, and heat aggregated IgG induced both IL8 and CCL20 mRNA in all cases, suggesting that the assay was performed appropriately. Rituximab reduced the levels of CCL20 mRNA in approximately 1/3 of subjects, whereas 50 mu g/ml trastuzumab induced IL8 and CCL20 mRNA in more than half of subjects. Although the results do not directly indicate the toxicity of antibody medicines, the individual variation found under physiological ex vivo condition will be an interesting clinical research model for drug safety analysis.

DOI： 10.1007/s10637-009-9223-y

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Other Link： http://search.jamas.or.jp/link/ui/2009248291

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective. Concerning MLL-AF4 leukemogenesis, previous mouse models suggest that the tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Fms-like tyrosine kinase 3 (Flt3) gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of mixed lineage leukemia (MLL.), we investigated synergistic leukemogenesis effects of the two genes in vitro.
Materials and Methods. In a mouse interleukin-3 (IL-3)-dependent cell line, 32Dc, expression of MLL-AF4 and mutant Flt3 was induced using a lentiviral vector. We analyzed apoptosis induction in the absence of IL-3 and the granulocyte colony-stimulating factor related induction of differentiation, gene expression profiling, and the mechanism involved in the synergistic effects of MLL-AF4 and Flt3-TKD.
Results. Neither Flt3-expressing 32Dc (32Dc(Flt3-TKD)) nor MLL-AF4-expressing 32Dc (32Dc(MLL-AF4)) acquired IL-3-independent proliferative capacity in semisolid/liquid media. However, Flt3-TKD+MLL-AF4-expressing 32Dc (32Dc(Ftl3-TKD+MLL-AF4)) acquired a non - IL-3-dependent proliferative capacity by inhibiting apoptosis in the two media. The 32Dc(FIt3-TKD) and 32Dc(MLL-AF4) cells differentiated into granulocytes in the presence of granulocyte colony-stimulating factor. However, in the 32Dc(Flt3-TKD+MLL-AF4) cells, there was no differentiation. Subsequently, we performed gene expression profiling. The enhancement of Hox genes expression was not identified. However, expression of S100A6 was synergistically enhanced in the presence of both MLL-AF4 and Flt3-TKD genes. Moreover, anti-S100A6 small interfering RNA downregulated leukemic proliferation.
Conclusion. We conclude that their synergistic enhancement of S100A6 expression plays an important role in MLL-AF4-associated leukemogenesis. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2009.02.007

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The 11q23 abnormalities are frequent cytogenetic abnormalities found in some adult and pediatric cases of primary acute leukemia (AL), and also in the majority of patients with secondary AL after previous treatment with DNA topoisomerase II inhibitors. According to the WHO classification, AL with 11q23 abnormalities involving the Mixed-Lineage-Leukemia (MLL) gene composes one category of recurring genetic abnormalities. Over 60 chromosome partners of 11q23 have been reported to date, and 33 of the presumptive gene partners of 11q23 have been cloned and analyzed at the molecular level. 11q23/MLL abnormalities have been widely recognized as an important prognosis factor in AL. Recent studies showed that the prognosis of AL with 11q23/MLL is dependent on 11q23 fusion partner, and that the prognosis of AL with 11q23/MLL according to the 11q23 fusion partner is different between adults and children. The present article summarizes the current status of prognosis and treatment of AL with 11q23/MLL according to the fusion partner especially in adult, in which prognosis analysis has not be fully established due to a small number of cases, compared with infant cases. © 2009 Bentham Science Publishers Ltd.

DOI： 10.2174/157339409788982205

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Background/Aims Secondary hemophagocytic syndrome (hemophagocytic lymphohistiocytosis, HLH) follows viral infection, malignant disorders, and autoimmune disease. Criteria for HLH diagnosis, which were proposed in 2004, include hypertriglyceridemia. However, some studies reported the absence of hypertriglyceridemia in patients with secondary HLH, differing from those with primary HLH.
Subjects and Methods In this study, we investigated the presence or absence of hypertriglyceridemia in 28 patients who were diagnosed with secondary HLH between 1997 and 2007 retrospectively. There were no patients undergoing treatment for those with a history of hyperlipidemia.
Results The subjects consisted of 14 patients with lymphoma-associated HLH, 11 with virus-associated HLH, 2 with autoimmune disease-associated HLH, and 1 with post transplantation HLH. In 19 patients (68%), hypertriglyceridemia was noted on diagnosis or during the disease period (mean: 242 mg/dL). Furthermore, the triglyceride (TG) level decreased with the treatment-related amelioration of HLH (mean level before and after treatment: 297 and 136 mg/dL, respectively, p=0.0001).
Conclusion These results suggest that the TG level is useful for diagnosing HLH and evaluating the treatment response. TG measurement is simple and inexpensive; therefore, this parameter can be determined several times to evaluate the treatment response.

DOI： 10.2169/internalmedicine.48.1677

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background Itraconazole (ITCZ) oral solution (-os) is more effective than ITCZ capsule for fungal infection. However, some patients refuse it due to unpleasant taste. Objectives The aim of this study was to evaluation the influence of ITCZ-os dilution with distilled water (DW) or simple syrup on the pharmacokinetics property of ITCZ and it's metabolite and on taste. Methods Each of 12 healthy male volunteers were enrolled in 2 independent studies. ITCZ-os was diluted with same amount of DW or simple syrup at dispensation and single dosed as 200 mg of ITCZ. Pharmacokinetics of ITCZ+DW and ITCZ+syrup were compared with ITCZ-os using cross over design. Results C max and AUC 0→24 of ICTZ, OH-ITCZ and actives diluted with DW or syrup were bioequivalent with ITCZ-os. The score of bitter was slightly improved in ITCZ+DW and significantly improved in ITCZ+syrup (p=0.005 and p=0.001, respectively). Conclusions Dilution of ITCZ-os with DW or syrup had no affect on pharmacokinetics property. The dilution with syrup will be helpful for compliance who felt unpleasant taste.

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Staphylococcus aureus colonies can spread on soft agar plates. We compared colony spreading of clinically isolated methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). All MSSA strains showed colony spreading, but most MRSA strains (73%) carrying SCCmec type-II showed little colony spreading. Deletion of the entire SCCmec type-II region from these MRSA strains restored colony spreading. Introduction of a novel gene, fudoh, carried by SCCmec type-II into Newman strain suppressed colony spreading. MRSA strains with high spreading ability (27%) had no fudoh or a point-mutated fudoh that did not suppress colony spreading. The fudoh-transformed Newman strain had decreased exotoxin production and attenuated virulence in mice. Most community-acquired MRSA strains carried SCCmec type-IV, which does not include fudoh, and showed high colony spreading ability. These findings suggest that fudoh in the SCCmec type-II region suppresses colony spreading and exotoxin production, and is involved in S. aureus pathogenesis.

DOI： 10.1371/journal.pone.0003921

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Although core-binding factor acute myeloid leukemia (CBF-AML) is generally considered to be a low-risk form of AML, the survival rate is still 50% to 60%. To evaluate the effectiveness of autologous stem cell transplantation (ASCT) with a PCR-negative graft we analyzed a series of consecutive CBF-AML patients. Between 1997 and 2006, 18 patients aged &lt;60 years were referred under a diagnosis of CBF-AML. Peripheral blood stem cells (PBSC) were collected after a second or further course of postremission therapy. When &gt;2.0 x 10(6)/kg CD34-positive cells with minimal residual disease (MRD) undetectable by nested polymerase chain reaction (PCR) had been collected, ASCT was performed with busulfan, etoposide, and cytarabine combined with granulocyte colony-stimulating factor. Event-free survival (EFS) and complications of ASCT were then assessed. Fourteen of the 18 patients received ASCT The median observation period was 4.4 years. The 5-year EFS was 93% for ASCT patients, despite the presence of adverse factors. In 8 of 10 patients who had detectable MRD in the bone marrow before ASCT MRD became undetectable after ASCT Neutrophils recovered promptly within 2 weeks, but platelets recovered relatively slowly. Half of the patients suffered from varicella zoster virus infection. Although I case of myelodysplastic syndrome occurred, there was no case of relapse. ASCT with a PCR-negative graft was associated with excellent EFS. For patients with CBF-AML, especially with adverse factors or remnant MRD in the bone marrow, this strategy is the treatment of choice.

DOI： 10.1016/j.bbmt.2008.08.012

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/bmt.2008.200

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

J-GLOBAL

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/sj.leu.2405029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

As the incidence of bone-marrow failure syndromes (BMFS) is 2-3x higher in East Asia than in the West, we examined peripheral blood or marrow cells of 100 Japanese patients for possible pathogenic mutations in the two main components of the telomere-synthesizing enzyme telomerase (hTERC RNA and hTERT protein) that have recently been implicated in the disease pathogenesis. We analyzed samples collected from 34 patients with acquired aplastic anemia (AA), 66 patients with myelodysplastic syndromes (MDS) and 120 healthy controls. In addition to two polymorphic germ-line sequence changes (n-771A/G and n-714 C insertion) in the promoter region of hTERC and eleven hTERT polymorphisms that were identified in both patients and healthy individuals, we found a novel germ-line C323T mutation in the hTERC RNA in an MDS patient only. This heterozygous C323T mutation abolished telomerase enzymatic activity and functioned in a haploinsufficiency manner to modulate telomerase activity in cells. In summary, this study reports a novel telomerase natural variant that abolishes telomerase function, which may lead to telomere shortening and marrow hypocellularity in patients with BMFS. This study also highlights the rarity of genetic alterations in BMFS patients in Japan, which suggests that other factors may play a more prominent role in the disease pathogenesis in East Asia. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcmd.2007.08.002

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Other Link： http://search.jamas.or.jp/link/ui/2008126349

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

To clarify the clinical features of adult patients with acute leukemia (AL) with 11q23 abnormalities, we performed a retrospective analysis of data from 58 adult Japanese patients: 51 with acute myeloid leukemia (AML), and 7 with acute lymphoblastic leukemia (ALL). The incidences according to fusion partners in AML were: t(9;11), 31.3%; t(11;19), 27.4%; t(6;11), 21.5%. The incidence of patients with t(11;19) was higher than those in the US and Europe, and the incidence of t(4;11) was lower than that in childhood. The results indicated the poor prognosis of AML with 11q23 abnormalities regardless of the fusion partners. AML patients with 11q23 aged &lt; 60 years in the first CR who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed a more favorable outcome than those treated without allo-HSCT, although the differences were not statistically significant (P = 0.322 for DFS, P = 0.138 for OS). This result suggests that treatment strategies including allo-HSCT may be considered in the first CR in cases of AML with 11q23 abnormalities. However, further studies involving a large number of cases are required to assess the effect of allo-HSCT on adult AL with 11q23 abnormalities.

DOI： 10.1007/s12185-008-0034-2

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DOI： 10.1038/sj.leu.2404953

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DOI： 10.1038/bmt.2008.200

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Dyskeratosis congenita (DKC) is a bone marrow failure (BMF) with characteristic physical anomalies, and is typically diagnosed in childhood. Some forms of DKC are known to be caused by mutations occurring in DKC1, telomerase RNA component (TERC), and telomerase reverse transcriptase (TERT). These genes are the main constituents of the telomerase complex that plays a role in replicating telomeres and stabilizing them against shortening. Mutations in these genes could shorten telomeres and impair the proliferative capacity of hematopoietic stem cells, eventually causing DKC. Recently, mutations in TERC and TERT have been reported in some cases of aplastic anemia (AA) and myelodysplastic syndrome (MDS). These cases are considered to be atypical forms of DKC that develop slowly in adulthood without characteristic physical anomalies. Genetic tests are essential in diagnosing this late-presenting DKC and determining the appropriate treatment. This article reviews mutations in the telomerase complex and their connections with DKC and bone marrow failures.

DOI： 10.1272/jnms.74.202

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