• Transcription factors in the development of myeloid cells
  Tomohiko TAMURA, Shin-ichi KOIZUMI, Daisuke KUROTAKI
  2015 Volume 56 Issue 10 Pages 1861-1870
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1861
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  Hematopoietic stem cells give rise to various blood cell types with diverse functions, although these different cell types harbor essentially identical genome sequences. The basis for this cell type diversity is the establishment of specific gene expression patterns through transcription factor regulation. Transcription factors recognize and bind to specific nucleotide sequences in target genes and recruit chromatin modifiers to alter the epigenetic status of these genes, thereby controlling their expression. Dysregulation of these processes can cause diseases such as leukemia. Due to rapid advances in high-throughput experimental techniques including chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-seq, the study of transcription factors is now entering a new era. In this review, we update the current knowledge of developmental pathways in myeloid cells, particularly mononuclear phagocytes (i.e., monocytes/macrophages and dendritic cells), and the transcription factors known to be required for their development. We subsequently provide an overview of the cooperative and antagonistic mechanisms by which the myeloid transcription factors regulate their target genes, with an emphasis on chromatin biology.

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• Recent progress in leukemic stem cell research for childhood leukemia
  Mariko EGUCHI, Minenori EGUCHI-ISHIMAE, Eiichi ISHII
  2015 Volume 56 Issue 10 Pages 1871-1881
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1871
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  Leukemic stem cells (LSCs) were originally identified in acute myeloid leukemia (AML) cases by using xenograft models, as a distinct cell population that can initiate leukemia in immunodeficient mice. Since then, many efforts have been made to clarify the identities of LSCs and other cancer stem cells in various cancer types, to both understand their biology and determine the most suitable targets for anti-cancer therapies. LSCs were identified as existing in the immature CD34⁺CD38^- leukemic population in most AML cases, and these cells were found to share some features with normal hematopoietic stem cells. On the other hand, recent studies have shown that in childhood acute lymphoblastic leukemia (ALL), LSCs exist among B-lineage-committed progenitors expressing CD19. In contrast to AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in childhood ALL is better explained by a stochastic model. In B-precursor ALL, LSCs form via acquisition of additional genetic change(s) in CD19⁺ B-lineage progenitor cells with self-renewing capacity. These LSCs possess a growth advantage and the capacity to produce progeny with the same ability as the LSCs. Identification of genetic and cellular targets in leukemic transformation is necessary to develop improved anti-cancer therapies.

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• Metabolic regulation of stem cells
  Keiyo TAKUBO
  2015 Volume 56 Issue 10 Pages 1882-1887
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1882
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  Stem cells activate various metabolic programs and acquire ATP and metabolites to maintain self-renewal and multi-differentiation capacities. Pluripotent stem cells and hematopoietic stem cells have recently been shown to have specific metabolic features different from those of differentiated cells. These metabolic features themselves drive stem cell-specific characteristics. Thus, integrative understandings of metabolic regulation of stem cells are essential for the development of technologies for ex vivo expansion of stem cells, efficient induction of differentiated cells from stem cells and targeted therapies aimed at controlling and eliminating tumor-initiating cells.

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• The hematopoietic stem cell niche
  Yuya KUNISAKI
  2015 Volume 56 Issue 10 Pages 1888-1893
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1888
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  Somatic stem cells self-renew to maintain tissue homeostasis for the lifetime of organisms through tightly controlled proliferation and differentiation. Hematopoietic stem cells (HSCs) are essentially required for hematopoietic homeostasis. Therefore, they not only ensure lifelong replenishment of all blood lineages, but also maintain a constant pool. Cell cycle quiescence is a critical feature contributing to stem cell maintenance. Recent studies have highlighted the importance of bone marrow (BM) microenvironments that regulate HSC functions (HSC niches). In the HSC field, there has been considerable interest and debate regarding whether or not quiescence and proliferation of HSCs is regulated by distinct niches. Previous reports suggest that quiescent HSCs reside near osteoblasts in the BM whereas actively cycling HSCs are found near sinusoids. However, this popular concept has not been supported by rigorous analyses. To gain more insight into the spatial localization of HSCs, we have developed a whole-mount staining technique that allows precise measurements of 3D distances of HSCs from structures and allows computational simulation to define the significance of these interactions. This novel approach has allowed us to uncover two distinct types of vessels associated with quiescent and proliferating HSCs and to underscore the importance of arteriolar vessels for stem cell quiescence. We will discuss the crosstalk between the two hematopoietic and mesenchymal stem cells with a review of the recent literature.

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• Diagnosis and treatment of hemolytic anemia
  Toyomi KAMESAKI
  2015 Volume 56 Issue 10 Pages 1894-1902
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1894
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  Hemolytic anemia is defined as anemia due to a reduction of the RBC lifespan to less than the normal range of approximately 120 days. Patients with anemia and jaundice are often suspected to have hemolysis. Herein, different causes of hemolysis and the diagnostic algorithm are reviewed. Currently, there is no generic treatment for hemolytic anemia. Appropriate management of a patient with hemolytic anemia requires determination of the underlying cause. Treatments for the different causes of hemolytic anemia are also reviewed.

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• Iron dysregulation and anemias
  Katsuya IKUTA
  2015 Volume 56 Issue 10 Pages 1903-1913
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1903
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  Most iron in the body is utilized as a component of hemoglobin that delivers oxygen to the entire body. Under normal conditions, the iron balance is tightly regulated. However, iron dysregulation does occasionally occur; total iron content reductions cause iron deficiency anemia and overexpression of the iron regulatory peptide hepcidin disturbs iron utilization resulting in anemia of chronic disease. Conversely, the presence of anemia may ultimately lead to iron overload; for example, thalassemia, a common hereditary anemia worldwide, often requires transfusion, but long-term transfusions cause iron accumulation that leads to organ damage and other poor outcomes. On the other hand, there is a possibility that iron overload itself can cause anemia; iron chelation therapy for the post-transfusion iron overload observed in myelodysplastic syndrome or aplastic anemia improves dependency on transfusions in some cases. These observations reflect the extremely close relationship between anemias and iron metabolism.

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• Diagnosis and management of inherited bone marrow failure syndrome
  Miharu YABE, Hiromasa YABE
  2015 Volume 56 Issue 10 Pages 1914-1921
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1914
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  The inherited bone marrow failure syndromes (IBMFS) are rare disorders in which there is usually some form of bone marrow failure and typical changes in physical appearance, associated with a family history of the same disorder. Patients with IBMFS have a very high risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. The latest technology applied to the molecular pathogenesis of these disorders has led to identification of specific genetic mutations and now facilitates determining the appropriate diagnosis and management of afflicted patients. In this section, we describe physical and laboratory findings and management of the major IBMFS: Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond Blackfan anemia. We also discuss their possible implications in the clinical features of Japanese patients.

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• Diagnosis and management of pure red cell aplasia
  Makoto HIROKAWA
  2015 Volume 56 Issue 10 Pages 1922-1931
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1922
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  Pure red cell aplasia (PRCA) is a type of bone marrow failure syndrome (stem cell failure) and is characterized by severe normocytic, normochromic anemia associated with reticulocytopenia, and the absence of erythroblasts in otherwise normal bone marrow. PRCA may be congenital or acquired, and the acquired form of chronic PRCA may present as a primary hematological disease in the absence of any other diseases or secondary to thymoma, lymphoproliferative disorders, infections, and collagen vascular diseases or after exposure to various drugs or chemicals. The most common types of acquired chronic PRCA in Japan are idiopathic, thymoma-associated and lymphoid neoplasm-associated PRCA. Initial treatment of PRCA includes the cessation of potentially deleterious drugs and careful observation for one month while making efforts to identify the cause of PRCA. Idiopathic PRCA and secondary PRCA refractory to treatment of the underlying diseases are generally treated as immune-mediated disorders. Most chronic PRCA patients successfully treated with immunosuppressants require maintenance immunosuppressive therapy. Thus, identifying the cause of PRCA is crucial for the optimal management of this disorder.

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• AML treatment strategy based on cytogenetic abnormalities and somatic mutations
  Yoichi IMAI
  2015 Volume 56 Issue 10 Pages 1932-1941
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1932
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  In addition to morphological and histocytochemical analyses of acute myeloid leukemia (AML), data on cytogenetic abnormalities and somatic mutations are used for classification of AML. The risk stratification based on these examinations facilitates determining the treatment strategy for AML. Cytogenetic risk category definitions by the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), and The Medical Research Council (MRC) classify AML patients into favorable, intermediate, and adverse groups. Approximately 80% of patients in the intermediate group have a normal karyotype and the importance of molecular genetic analyses in these patients is increasing. Somatic mutations of NPM1, CEBPA, and FLT3 are known to be related to the prognosis of AML patients. The European LeukemiaNet (ELN) introduced risk stratification for AML patients based on cytogenetic abnormalities and NPM1, CEBPA, and FLT3 mutations. This risk stratification can be used to select only chemotherapy or chemotherapy with allogeneic hematopoietic stem cell transplantation as consolidation therapy for individual AML patients. Development of molecular targeted therapies against FLT3 or IDH mutations is in progress and these novel therapies are expected to contribute to improving the prognosis of AML patients.

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• The molecular basis of leukemogenesis caused by MLL gene rearrangements
  Akihiko YOKOYAMA
  2015 Volume 56 Issue 10 Pages 1942-1949
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1942
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  Chromosomal translocations at the MLL gene generate chimeric genes of MLL and its partner, thereby causing aggressive acute leukemia. The sequence of the MLL gene was revealed in the early 1990s. Several years later, murine leukemia models using genetic engineering or retroviral gene transfer techniques were established, which spurred basic research on this disease. Since then, a series of technological breakthroughs such as DNA arrays, shRNA library screening, and deep sequencing have provided us with a much deeper understanding of the molecular basis of leukemogenesis caused by MLL mutations. Based on the understanding of these molecular mechanisms, several small molecules that inhibit critical processes of leukemogenesis have been developed as molecularly-targeted drug candidates. I herein review the rapid progress in this research on the molecular mechanisms of MLL-associated leukemia.

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• The role of hematopoietic stem cell transplantation for acute myeloid leukemia
  Koji KATO
  2015 Volume 56 Issue 10 Pages 1950-1959
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1950
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  Hematopoietic stem cell transplantation (HSCT) plays an important role in treating younger patients with acute myeloid leukemia (AML). Reduced-intensity conditioning regimens allow increased use of allogeneic HSCT for older patients. Current HSCT decisions in patients with AML are being made according to cytogenetic analysis results. A more comprehensive and detailed understanding of the genetic and epigenetic changes that are related to the pathogenesis of AML is required for better classification of risk and for improving approaches to therapy as they pertain to future HSCT decisions.

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• Treatment and clinicopathological features of relapsed, refractory or elderly AML
  Yoshikazu ITO
  2015 Volume 56 Issue 10 Pages 1960-1968
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1960
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  Currently, more than half of patients with acute myeloid leukemia (AML) are elderly. The prognosis is usually poor in these patients. Even among young people, there are still some cases with refractory or relapsed disease. Prognostic factors are categorized into leukemic, stage, and host factors. In elderly patients, the importance of host factors is increased relative to other factors. Cognitive and physical conditions should also be evaluated. Fitness for chemotherapy followed by hematopoietic cell transplantation is then determined. High-dose cytarabine or a purine nucleoside analogue combined chemotherapy is an option for treating relapsed or refractory cases. Gemtuzumab ozogamicin (GO) is not effective for single use. Results of clinical trials for GO combined chemotherapy were split. Doses and schedules still need to be discussed. Low dose chemotherapy has no survival benefit for elderly people. DNA hypomethylating agents have limited effects but do not achieve a cure. Novel drugs are under development. FLT3 inhibitors and/or IDH inhibitors are expected to exert beneficial effects. No therapy superior to conventional chemotherapy has yet been developed.

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• Genetics of hereditary hematological malignancies
  Masatoshi TAKAGI
  2015 Volume 56 Issue 10 Pages 1969-1977
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1969
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  Familial predisposition to hematological malignancies has been recognized. Some of these malignancies are part of a well-characterized familial cancer predisposition syndrome, while others are independent of cancer predisposition, and demonstrate unique familial leukemia/lymphoma syndromes. Primary immunodeficiency is also strongly associated with the development of lymphoid malignancy. Primary immunodeficiency and leukemia/lymphoma are based on the same concept, which involves differentiation blockage. Bone marrow failure syndrome is also known to be associated with susceptibility to hematological malignancy development. Bone marrow failure syndrome exhibiting myeloid differentiation is also characterized as an aspect of primary immunodeficiency. Recent progress in genome wide association studies (GWAS) identified several single nucleotide polymorphisms (SNP) associated with leukemia/lymphoma development. Some of these genes were found to be functionally related to hematological malignancies. These discoveries are contributing to elucidation of the genetic background of leukemia/lymphoma development.

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• Diagnosis of MDS: morphology, chromosome abnormalities and genetic mutations
  Tomoko HATA
  2015 Volume 56 Issue 10 Pages 1978-1984
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1978
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  Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that can transform into acute leukemia. The clinical classification of MDS which is defined by cytopenia, the rate of blasts in peripheral blood and bone marrow, dysplasia, and chromosomal abnormalities, has undergone continuous revision. To increase the accuracy of dysplastic evaluation, IWGM-MDS and the Research Committee for Idiopathic Hematopoietic Disorders, Ministry of Health, Labour and Welfare, Japan have proposed a quantitative and qualitative definition of dysplasia. Recently, refining the definition of dysgranulopoiesis was proposed by IWGM-MDS. Neutrophils with abnormal clumping of chromatin, and harboring more than 4 nuclear projections, were recognized as dysplastic features. At present, karyotypic abnormalities are detected in approximately 50% of de novo MDS and these remain the most critical prognostic factor. In the new cytogenetic scoring system, cytogenetic abnormalities were classified into five prognostic subgroups. This new classification was adopted by the revised IPSS. Approximately 80% to 90% of MDS patients have detectable mutations by whole-exon sequencing or whole genome sequencing. Many genetic mutations had biological and prognostic significance. It is important to further understand the utility of this factor in determining prognosis and in selecting among therapeutic options.

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• Current treatment strategies for myelodysplastic syndromes
  Takahiro SUZUKI
  2015 Volume 56 Issue 10 Pages 1985-1995
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1985
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  Myelodysplastic syndromes (MDS) are myeloid clonal disorders presumably induced by genetic mutations in immature hematopoietic cells. According to the international prognostic scoring system (IPSS or IPSS-R), patients are classified into two groups: lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS). A majority of LR-MDS patients manifest refractory cytopenias due to inefficient hematopoiesis, and patients in this group are principally treated with agents stimulating hematopoiesis or differentiation. On the other hand, patients with HR-MDS are at much higher risk of developing leukemia, and thus require prompt hematopoietic stem cell transplantation or chemotherapy. In this section, I will discuss current treatment strategies for MDS in Japan, including future perspectives.

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• Myeloproliferative neoplasms: pathophysiology and therapeutic strategy
  Yoko KUBUKI, Tomonori HIDAKA, Kazuya SHIMODA
  2015 Volume 56 Issue 10 Pages 1996-2004
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.1996
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  Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells (HSCs) with genetic abnormalities in combination with mutations in JAK2, MPL or CALR, which induce autosomal JAK-STAT pathway activation, and mutations in epigenetic regulator genes such as TET2 or DNMT3A. The prognosis of patients with polycythemia vera (PV) or essential thrombocythemia (ET) is relatively good, and the therapeutic goal in cases with PV or ET is to prevent thrombohemorrhagic complications. PV or ET patients at least 60 years of age or with a history of thrombosis are in a high-risk category, and are managed with low dose aspirin and cytoreductive therapy. Phlebotomy to maintain Ht <0.45 is also used to manage PV patients. The median survival for Japanese primary myelofibrosis (MF) patients is 3.9 years. Several factors including age >65 years, Hb <10 g/dl, the presence of constitutional symptoms, and the presence of blasts in blood were identified as being associated with shorter survival in MF patients. Those patients in the high-risk category are candidates for allogenic HSC transplantation (allo-HSCT), which is potentially curative but is also associated with higher therapy-related mortality. High-risk MF patients without indications for allo-HSCT are treated with JAK inhibitors, which can markedly ameliorate constitutional symptoms and splenomegaly, and might thereby lead to a degree of improvement in survival.

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• State-of-the-art management of CML in 2015 and future prospects
  Shinya KIMURA
  2015 Volume 56 Issue 10 Pages 2005-2014
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2005
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  The ABL tyrosine kinase inhibitor (TKI) imatinib mesylate has dramatically changed the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. There are several mechanisms underlying imatinib resistance. Notably, point mutations within the ABL kinase domain are the most critical cause of imatinib resistance. It has recently been recognized that adherence to ABL TKIs is very important for resistance. Four second-generation ATP competitive ABL TKIs, i.e., dasatinib, nilotinib, bosutinib and bafetinib, have been developed. The three TKIs other than bafetinib have been approved for CML in Japan. Although bosutinib has not been approved as a first line therapy, dasatinib and nilotinib demonstrated higher efficacy than imatinib for previously untreated CML in the chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harboring T315I. CML treatment is progressing rapidly and further advancements are highly anticipated. Moreover, it was recently reported that some portion of CML patients who achieved a sustained complete molecular response have been able to stop taking TKI agents.

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• Epigenetic therapy for hematologic malignancies
  Yukio KOBAYASHI
  2015 Volume 56 Issue 10 Pages 2015-2023
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2015
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  Cumulative evidence suggests that at least some hematologic malignancies are derived from alterations of epigenetic machinery. Next generation sequencing has revealed recurrent mutations of genes related to DNA methylation and histone modification in myelodysplastic syndromes (MDS), acute myeloid leukemia, malignant lymphoma, and multiple myeloma. Both these pathways are targetable and specific inhibitors of their related proteins are currently in development. Among these novel therapies, hypomethylating agents have been approved for MDS, and recently, histone deacetylase inhibitors became available for T-cell lymphoma and multiple myeloma. Agents currently undergoing clinical trials include inhibitors of IDH2 targeting DNA methylation, and EZH2, Dot1L, and BRD4 inhibitors designed to target either writers or readers of post-translational modifications (PTMs) of histones. In a phase I setting, where the maximum tolerated dose has not been reached, efficacy was reported with these agents. Furthermore, Dot1bL and IDH2 inhibitors have been shown to induce differentiation of leukemic blasts in patients with MLL gene rearrangements and IDH2 mutations, respectively, thus providing functional evidence supporting the use of inhibitors of epigenetic mechanisms as a means of differentiation therapy for hematologic malignancies.

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• The molecular pathology of classical Hodgkin lymphoma
  Naoko ASANO
  2015 Volume 56 Issue 10 Pages 2024-2031
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2024
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  In 1832, Dr. Thomas Hodgkin reported the first cases with this malignancy, which came to be named Hodgkin's disease. The cells that are a hallmark of this disease, Hodgkin and Reed-Sternberg (HRS) cells, account for only 1% of those in tumor tissues, with the majority of cells in Hodgkin lymphoma being of various inflammatory types. Advances in molecular techniques have contributed to molecular biological analysis of HRS cells. Intriguingly, HRS cells are derived from germinal center B-cells, but have lost their B-cell gene-expression and co-express non-B-cell genes. Multiple signaling pathways, including the NFκB and JAK/STAT pathways, show deregulated activity in HRS cells, suggesting an important role for these pathways in the pathogenesis of Hodgkin lymphoma. This article describes the molecular pathological characteristics of HRS cells: 1) the cellular origin of HRS cells, 2) deregulated gene expression in HRS cells, 3) genetic alterations and 4) epigenetic alterations in HRS cells, 5) the lost B-cell phenotype of HRS cells, 6) the role of EBV in Hodgkin lymphoma pathogenesis, and 7) micro-environmental interactions between HRS and reactive cells.

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• Acute lymphoblastic leukemia in adolescents and young adults
  Fumihiko HAYAKAWA
  2015 Volume 56 Issue 10 Pages 2032-2038
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2032
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  Treatments for acute lymphoblastic leukemia (ALL) have been developed, independently, by both pediatric and adult study groups. Adolescents and young adults (AYA) represent a minority of patients enrolled in either pediatric or adult clinical studies and have not been the focus of trials. However, it has become evident that intensified pediatric chemotherapy regimens might be associated with better outcomes for not only AYA but also adult patients. During the last decade, the survival of AYA ALL patients has been greatly improved with the use of pediatric or pediatric-inspired protocols. The 5-year overall survival rate is now expected to exceed 70% when AYA ALL is treated employing pediatric-type protocols. In this new context, the risk factors and the application of stem cell transplantation need to be reassessed.

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• Low grade lymphoma: research progress and questions about treatment
  Kenichi ISHIZAWA
  2015 Volume 56 Issue 10 Pages 2039-2046
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2039
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  Treatment options for follicular lymphoma (FL) are considered when patients have limited stage, low tumor burden advanced stage, and high tumor burden advanced stage disease. Although patients with limited stage FL are managed with radiotherapy (24-36 Gy), watchful waiting (WW), rituximab monotherapy, and rituximab combined with chemotherapy need to be evaluated. In patients with low tumor burdens, WW is regarded as the standard management. The usefulness of rituximab monotherapy was also recently suggested. Rituximab combined with chemotherapy improved overall survival (OS) in patients with high tumor burdens and the optimal reference regimen might be R-CHOP or rituximab combined with bendamustine. As to efficacy, improved relapse-free survival, with rituximab maintenance, has been shown. In patients with primary macroglobulinemia, fludarabine improved both progression-free survival and OS as compared with chlorambucil. As to extra-nodal marginal-zone B cell lymphoma, the addition of rituximab to chlorambucil improves both the response rate and event-free survival. Large clinical trials of lenalidomide, idelalisib, and ibrutinib are now ongoing.

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• Diffuse large B-cell lymphoma: therapeutic development based on clinical and biological heterogeneity
  Kana MIYAZAKI
  2015 Volume 56 Issue 10 Pages 2047-2055
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2047
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  Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, and is regarded as a heterogeneous group of lymphomas in terms of morphologic, immunologic, and cytogenetic features. The current standard therapy for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, which allows many patients to achieve disease cure. Despite recent progress in improving patient survival, 40% of DLBCL outcomes are still unsatisfactory. Gene expression profiling has been used to identify two distinct forms of DLBCL: the activated B-cell (ABC) subtype and the germinal center B-cell (GCB) subtype, which reflects normal B-cell differentiation. ABC DLBCL has been reported to show a more activated phenotype and a poorer prognosis than the GCB subtypes, with molecular diagnosis after R-CHOP therapy. Next generation sequencing identified unique oncogenic mechanisms and genetic complexity, which provided rational therapeutic targets. Recent studies suggest that patients with double-hit lymphoma, i.e., dual rearrangements of MYC and BCL2, have an extremely grim prognosis. Moreover, there are a number of biomarkers including CD5 and prognostic factors. Efforts to distinguish among these biomarkers will be crucial for devising individualized treatments in the future.

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• Recent advancements in molecular cytogenetics for hematological malignancies: identification of novel PVT1 fusion genes
  Masafumi TANIWAKI
  2015 Volume 56 Issue 10 Pages 2056-2065
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2056
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  Specific chromosomal abnormalities are of diagnostic and prognostic relevance as well as providing clues for the identification of causative genes in patients with hematological malignancies. Genomic array (GA) is a powerful tool for identifying both microdeletion and precise DNA breakpoints in the genes of interest. For example, GA was able to detect CDKN2A and CDKN2B deletions in a small region only 69kb in size at 9p21 that were frequently found in patients with double-hit lymphoma. Using GA combined with spectral karyotyping, fluorescence in situ hybridization, and RT-PCR, we have identified a novel PVT1 rearrangement at 8q24 which were partnered with NBEA and WWOX in multiple myeloma (MM). In patients with MM, NBEA and WWOX are frequently involved in chromosomal deletion at 13q14 and 16q23, respectively. In acute myeloid leukemia, novel fusion RNAs, PVT1-NSMCE2 and CCDC26-NSMCE2, were identified in association with marker chromosomes and double minute chromosomes derived from chromosome 8 showing 8q24 amplicons. Chromothripsis is a possible cytogenetic mechanism of generating PVT1-NSMCE2 and CCDC26-NSMCE2. As PVT1 and CCDC26 are long intergenic non-coding RNAs (lincRNAs), our study suggests that the fusion genes involving lincRNAs potentially play as-yet-unknown oncogenic functional roles. Advancements in molecular cytogenetic techniques along with next generation sequencing will facilitate the understanding of tumorigenesis in hematological malignancies.

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• Novel agents in multiple myeloma treatment
  Shigeki ITO
  2015 Volume 56 Issue 10 Pages 2066-2073
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2066
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  The introduction of bortezomib and IMiDs has improved outcomes of patients with multiple myeloma (MM). Moreover, second-generation IMiDs (pomalidomide) have recently been approved in Japan. Due to the incurability of this disease, newer drugs with different mechanisms of action designed to prolong survival and achieve cure are urgently needed. There are novel agents which appear to be promising, such as monoclonal antibodies (elotuzumab, daratumumab), second-generation proteasome inhibitors (carfilzomib), deacethylase inhibitors (panobinostat), and the kinesin protein inhibitor (Arry-520). In the MM-003 trial, there was a significant advantage in the pomalidomide plus dexamethasone arm over high-dose dexamethasone in terms of ORR, PFS, and OS in MM patients who had failed both lenalidomide and bortezomib treatment. In addition, the ASPIRE trial showed carfilzomib in combination with lenalidomide plus dexamethasone to provide a survival advantage over lenalidomide plus dexamethasone for relapsed/refractory MM. These encouraging results indicate that the use of newer agents, alone or in combinations, may overcome double-refractory disease. Other agents such as kinase inhibitors or signaling pathway inhibitors are now under investigation. The use of cocktails of different agents with different mechanisms of action in an earlier stage of the disease may help to obtain durable remissions or even disease cure.

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• Waldenström's macroglobulinemia
  Reiko WATANABE
  2015 Volume 56 Issue 10 Pages 2074-2085
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2074
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  Waldenström macroglobulinemia (WM) is a rare and incurable B-cell neoplasm characterized by lymphoplasmacytic bone marrow infiltration and the production of serum monoclonal immunoglobulin M. Therapeutic strategies for WM should be based on individual patient and disease characteristics, including age, suitability as a candidate for autologous stem cell transplantation, hyperviscosity, and comorbidities. Rituximab forms the backbone of most regimens owing to its high efficacy and tolerability. Improved response rates to bendamustine, bortezomib, or carfilzomib in combination with rituximab and dexamethasone have been reported. For older patients, a recent phase III trial showed that oral fludarabine was more effective than chlorambucil. A Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has also been reported as a promising agent. Through recent whole-genome sequencing in WM, MYD88^L265P and CXCR4^WHIM have been identified as somatic mutations. Approximately 90% of WM patients carry MYD88^L265P, which activates IRAK and BTK, which in turn activate NFκB. MYD88^L265P has been found to play a role in WM cell proliferation and survival. The other mutation, CXCR4^WHIM, has been implicated in tumor progression and drug resistance to ibrutinib. This novel genomic landscape may alter the diagnosis, prognosis, and treatment of WM.

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• Consensus report on the management of immune thrombocytopenia in pregnancy
  Yoshitaka MIYAKAWA
  2015 Volume 56 Issue 10 Pages 2086-2091
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2086
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  Primary immune thrombocytopenia (ITP) is a benign hematological disorder characterized by platelet counts under 100×10⁹/l. We updated the consensus report for the management of ITP in pregnancy after a 20-year lag. For this update, not only hematologists, but also obstetricians, pediatricians, and anesthesiologists joined our committee. We recommend that physicians maintain platelet counts above 20×10⁶/l in the first and second trimesters. We also agree that counts should be at least 50×10⁹/l and 80×10⁹/l for vaginal and C-section deliveries, respectively. There might be no obvious reasons to forbid lactation in ITP patients receiving treatment with corticosteroids. In this educational session, I will discuss the differential diagnosis of thrombocytopenia and the management of ITP in pregnant women and their neonates based on international and updated domestic guidelines.

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• Diagnosis and management of thrombotic microangiopathies
  Masanori MATSUMOTO
  2015 Volume 56 Issue 10 Pages 2092-2099
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2092
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  Thrombotic microangiopathies (TMAs) are microvascular occlusive disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, and systemic or intrarenal aggregation of platelets. TMA includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). It is now well known that TTP is caused by deficiency of ADAMTS13 activity due to mutations in the ADAMTS13 gene (Upshaw-Schulman syndrome, USS) or by acquired autoantibodies against ADAMTS13. On the other hand, more than 90% of HUS cases are associated with Shiga toxin-producing E. coli infection. The remaining 10% of patients have what is called atypical HUS (aHUS). Most aHUS cases are caused by uncontrolled complement activation due to genetic mutations in the alternative pathway, such as complement factor H, complement factor I, membrane cofactor protein (CD46), and C3. TMAs also develop in association with various underlying diseases and conditions (so-called secondary TMA) including connective tissue disorders, transplantation (hematopoietic stem cell, liver, kidney), malignancy, pregnancy, and certain drugs. Plasma exchange is the first-line therapy for most patients with TMAs. Early plasma exchange improves TMA outcomes. Monoclonal therapies, rituximab in TTP and eculizumab in aHUS, are now frequently being used as second-line treatment options.

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• Current progress and future direction of hemophilia treatment
  Tadashi MATSUSHITA
  2015 Volume 56 Issue 10 Pages 2100-2109
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2100
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  Hemophilia is a rare bleeding disorder, for which treatments are still being developing and several new agents are providing better quality of life for patents. National evidence- and/or practice-based guidelines have been published by JSTH. Recommendations offered for the hemostatic management of hemophilia have assisted healthcare providers in initiating general hemophilia care. This article first reviews the two national guidelines for patients with/without inhibitor treatments. Then, future perspectives on progress in current treatment as well as the newer agents are summarized. Treatment options anticipated to be available in the near future are proposed for all caregivers in Japan.

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• Diagnosis and treatment of acquired factor XIII/13 deficiencies: for all doctors treating the MHLW's designated intractable diseases
  Akitada ICHINOSE
  2015 Volume 56 Issue 10 Pages 2110-2122
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2110
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  Coagulation factor XIII (FXIII/13) comprises a hetero-tetramer formed by two catalytic A subunits and two carrier B subunits. Inherited/congenital FXIII/13 deficiency is a rare hemorrhagic disease, leading to severe bleeding and recurrent miscarriages. By contrast, acquired FXIII/13 deficiency is common, and is characterized by a secondary decrease in FXIII/13 resulting from its hypo-synthesis and/or hyper-consumption due to primary diseases. Autoimmune hemorrhaphilia—a severe bleeding disorder that occurs mainly in the elderly—results from the generation of anti-FXIII/13 antibodies (AH13). Although this disease is still rare, the number of patients diagnosed with AH13 has recently increased. To improve understanding of this disease, we conducted a nation-wide survey on AH13. We found approximately 50% of cases to be idiopathic. In the remaining half, autoimmune diseases and malignancies were the most common underlying disorders. Intramuscular and subcutaneous bleeding were the most frequently reported symptoms. AH13 patients with intracranial, intra-peritoneal, or retroperitoneal bleeding (s) were prone to hemorrhagic death. Therefore, physicians/hematologists must raise awareness of AH13 as a life-threatening disease. Most patients were treated with FXIII/13 concentrates to arrest bleeding and with prednisolone and cyclophosphamide to eradicate anti-FXIII/13 autoantibodies. AH13 became a ‘designated intractable disease of Japan,’ and ‘Board Certified Hematologists’ can now be qualified as designated doctors.

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• Novel oral anticoagulants (NOAC)
  Masahiro IEKO
  2015 Volume 56 Issue 10 Pages 2123-2133
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2123
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  Novel oral anticoagulants (NOACs), a direct thrombin inhibitor (TDI), and direct factor Xa inhibitors (Xa-INHs) have mainly been used for prevention of stroke associated with atrial fibrillation in place of warfarin. DTI obstructs tenase by inhibiting thrombin generated in the initial phase and feedback to the amplification phase of cell-based coagulation reactions. Xa-INHs inhibit factor Xa activity in the prothrombinase complex of the propagation phase. Since the half-life of NOACs is in the approximate range of 8-14 hours, there are peak and trough periods in the blood concentrations of these agents. During the trough period, a small amount of thrombin is generated and plays a physiological role. The antithrombotic effect of NOACs is exerted during the peak period in combination with the effects of physiological coagulation inhibitors (PCIs) such as antithrombin in the trough period. Endothelial cells are the site for action of PCIs, such that it is important that they remain in a good state for effective anticoagulation by NOACs within the lesions. In a meta-analysis of NOACs vs. warfarin treatment, the former significantly reduced stroke or systemic embolic events by 19% as compared with warfarin, due mainly to a reduction in hemorrhagic stroke, while NOAC administration also significantly reduced intracranial hemorrhage by 52%.

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• Basic understanding of the HLA system in allogeneic hematopoietic cell transplantation
  Tatsuo ICHINOHE
  2015 Volume 56 Issue 10 Pages 2134-2143
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2134
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  Human immune responses are principally characterized by the human leukocyte antigen (HLA) system, a diverse set of cell surface molecules encoded by the major histocompatibility complex gene cluster on the short arm of chromosome 6. Among various members of the HLA family, the best characterized are the classic highly polymorphic class I and class II molecules that are responsible for antigen presentation to T cells and regulation of NK cell functions. In allogeneic hematopoietic cell transplantation, sophisticated approaches to donor-recipient allele-level matching at 3 class I (HLA-A/B/C) and 3 class II (HLA-DRB1/DQB1/DPB1) loci have been proven to lower the risk of immunologic complications such as graft failure and graft-versus-host disease, and possibly to confer effective graft-versus-malignancy effects. Future areas of research include clarifying the role of relatively non-polymorphic non-classical HLA molecules (HLA-E/F/G, HLA-DM/DO) and polymorphic/non-polymorphic class I-related molecules (MICA, MICB, HFE, MR1, CD1, FcRn) in the immune regulation that follows hematopoietic cell transplantation.

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• Prophylaxis of acute graft-versus-host disease
  Makoto MURATA
  2015 Volume 56 Issue 10 Pages 2144-2152
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2144
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  Graft-versus-host disease (GVHD) is an important complication in allogeneic hematopoietic stem cell transplantation. The standard regimen for GVHD prophylaxis in bone marrow transplantation and peripheral blood stem cell transplantation from human leukocyte antigen-matched donors is a combination of a calcineurin inhibitor, such as cyclosporin or tacrolimus, and short-term methotrexate. This regimen is well researched and has been nearly optimized in terms of infusion methods and the target blood concentration. The use of mycophenolate mofetil instead of methotrexate has the advantage of a lower incidence and severity of oropharyngeal mucositis. The addition of anti-thymocyte globulin significantly decreases the incidences of severe acute GVHD and extensive chronic GVHD, but does not lead to a significant improvement in overall survival. The GVHD prophylaxis regimens in cord blood transplantation and HLA-haploidentical donor transplantation have not been standardized. The efficacy of other immunosuppressive drugs, regulatory T lymphocytes, and mesenchymal stem cells are currently under investigation. Establishment of new evidence for GVHD prophylaxis from Japan is expected.

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• Hematopoietic stem cell transplantation for acquired aplastic anemia
  Hirohito YAMAZAKI
  2015 Volume 56 Issue 10 Pages 2153-2159
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2153
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  Allogeneic hematopoietic stem cell transplantation (allo-SCT) is one of the options for curative treatment of aplastic anemia. However, physicians often hesitate in selecting this option due to the lack of ample evidence regarding the optimal conditioning regimen and long-term outcomes of allo-SCT from alternative donors. Allo-SCT is the first choice of treatment in patients under 40 years of age with stage 3-5 aplastic anemia who possess HLA-matched sibling donors. Allo-SCT from alternative donors such as unrelated individuals or employing umbilical cord blood should be considered for patients with disease refractory to immunosuppressive therapy. High dose cyclophosphamide (CY) which was formerly used as the standard conditioning regimen is currently being replaced by a reduced dose CY regimen combined with fludarabine to avoid cardiotoxicity. Peripheral blood stem cell transplantation must be avoided due to the higher incidence of chronic GVHD than with bone marrow transplantation. Among transplants from alternative donors, HLA-haploidentical SCT from related donors using post-transplant CY is now attracting considerable attention due to its low transplant-related mortality and low incidence of chronic GVHD.

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• Human herpesvirus-6 associated with hematopoietic stem cell transplantation
  Masao OGATA
  2015 Volume 56 Issue 10 Pages 2160-2169
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2160
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  Reactivation of human herpesvirus (HHV)-6B is a relatively common occurrence after allogeneic stem cell transplantation (SCT), and it is associated with the development of various post-transplant complications. HHV-6 encephalitis appears to be a significant, life-threatening complication caused by HHV-6B reactivation. HHV-6 encephalitis typically develops 2-6 weeks after SCT, and the symptoms are characterized by memory loss, seizures, and consciousness loss. Magnetic resonance imaging typically shows limbic encephalitis. Recent large-scale studies and a prospective study showed a similar incidence of HHV-6 encephalitis development, with 7.9-9.9% in cord blood transplant recipients and 0.5-1.2% in bone marrow or peripheral blood stem cell transplant recipients. Epidemiological studies suggest that post-transplant immune reactions such as GVHD, pre-engraftment immune reaction, or engraftment syndrome play important roles in the development of HHV-6 encephalitis. The mortality rate remains high, and even among survivors, many patients are left with serious neurological impairments, such as memory disturbance and seizures. Elucidation of the pathophysiology and establishment of appropriate prophylactic measures are necessary to overcome this serious complication. Besides encephalitis, associations between HHV-6 and various post-transplant complications have been reported, including pneumonitis, gastroenterocolitis, hepatitis, bone marrow suppression, and GVHD. Further investigations are needed to determine the role of HHV-6 in these complications.

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• Safer and more appropriate blood transfusion therapy
  Makoto HANDA
  2015 Volume 56 Issue 10 Pages 2170-2179
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2170
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  The risks associated with transfusion with blood components have been greatly reduced due to the implementation of innovative strategies for donor selection and testing, as well as safety measures such as universal prestorage leukocyte reduction. However, a variety of residual or unsolved risks, such as severe acute reaction of transfusion-related acute lung injury, transfusion-associated circulatory overload and transfusion-transmitted infections, remain. Patients with hematological disorders are at high risk, since they receive therapeutic interventions frequently requiring transfusion. Thereby, balancing risk and benefit for patients, hematologists should prescribe blood components through evidence-based decision-making, minimize unnecessary transfusions and then conduct safe and error-free transfusion with a standard procedure involving the transfusion process at the bedside.

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• Current status and future development of CAR-T gene therapy
  Keiya OZAWA
  2015 Volume 56 Issue 10 Pages 2180-2185
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2180
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  Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of a target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3ζ receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and malignant lymphoma.

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• Cancer immunotherapy by immuno-checkpoint blockade
  Yutaka KAWAKAMI
  2015 Volume 56 Issue 10 Pages 2186-2194
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2186
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  As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

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• Basics and clinical application of human mesenchymal stromal/stem cells
  Yasuo MIURA
  2015 Volume 56 Issue 10 Pages 2195-2204
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2195
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  Human mesenchymal stromal/stem cells (MSCs) show a variety of biological characteristics. The clinical trials database provided by the National Institutes of Health, USA, contains about 400 clinical trials of MSCs for a wide range of therapeutic applications internationally (http://www.clinicaltrials.gov, key words “mesenchymal stem cells”, as of April, 2015). Encouraging results from these clinical trials include evidence of efficacy against graft versus host disease (GVHD) in hematopoietic stem cell transplantation. Treatment for and/or prevention of engraftment failure and insufficient hematopoietic recovery have also been explored. Herein, we will address the basic principles of MSCs and the current status of clinical studies using MSCs. Future prospects for MSC-based therapy will also be discussed.

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• Roles of the gut mucosal immune system in symbiosis and immunity
  Yoshiyuki GOTO, Yosuke KURASHIMA, Hiroshi KIYONO
  2015 Volume 56 Issue 10 Pages 2205-2212
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2205
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  The intestine is a unique organ which is continuously exposed to various antigens such as food-derived antigens, as well as both commensal and pathogenic bacteria, under physiological conditions. Intestinal epithelial cells constitute both a physical and an immunological barrier system against this vast array of antigens. The α1,2-fucose-conjugated carbohydrate chains expressed on intestinal epithelial cells are physiologically and immunologically important and are regulated by type III innate lymphoid cells (ILC3). IL-22-producing ILC3 induce anti-microbial molecules such as RegIIIγ, contributing to the formation of a safeguard system for homeostasis of commensal flora in the intestinal lumen, containment of Alcaligenes in Peyer's patches, and establishment of a defensive platform against infection by pathogenic bacteria. The other intestinal innate immune cell type, the mast cell, is also a critical player. Mast cells are activated by ATP produced in host cells and commensal flora, predisposing to the development of inflammatory bowel diseases. Furthermore, mucosal mast cells regulate the differentiation of follicular helper T cells through ATP signals and contribute to subsequent IgA affinity maturation and regulating the homeostasis of commensal microflora.

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• Generation of functional organs from pluripotent stem cells
  Tatsuyuki MIYAMOTO, Hiromitsu NAKAUCHI
  2015 Volume 56 Issue 10 Pages 2213-2219
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2213
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  Hematopoietic stem cells (HSCs) have played a major role in stem cell biology, providing many conceptual ideas and models. Among them is the concept of the “niche”, a special bone-marrow microenvironment that by exchanging cues regulates stem-cell fate. The HSC niche also plays an important role in HSC transplantation. Successful engraftment of donor HSCs depends on myeloablative pretreatment to empty the niche. The concept of the stem-cell niche has now been extended to the generation of organs. We postulated that an empty “organ niche” exists in a developing animal when development of an organ is genetically disabled. This organ niche should be developmentally compensated by blastocyst complementation using wild-type primary stem cells (PSCs). We proved the principle of organogenesis from xenogeneic PSCs in an embryo unable to form a specific organ, demonstrating the generation of functionally normal rat pancreas by injecting rat PSCs into pancreatogenesis-disabled mouse embryos. This principle has held in pigs. When pancreatogenesis-disabled pig embryos underwent complementation with blastomeres from wild-type pig embryos to produce chimeric pigs, the chimeras had normal pancreata and survived to adulthood. Demonstration of the generation of a functional organ from PSCs in pigs is a very important step toward generation of human cells, tissues, and organs from individual patients' own PSCs in large animals.

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• Progress in the diagnosis and treatment of childhood AML
  Souichi ADACHI
  2015 Volume 56 Issue 10 Pages 2220-2229
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2220
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  There are about 180 cases of childhood acute myeloid leukemia (AML) in Japan annually. For differential diagnosis and risk stratification of AML treatment, different diagnostic methods such as morphology, immunophenotyping, chimeric gene, chromosome and gene analysis are essential. According to the guidelines of JSPHO (Japanese Society of Pediatric Hematology/Oncology), different treatments for APL, ML-DS, and de novo AML have been carried out according to the JPLSG (Japan Pediatric Leukemia and Lymphoma Study Group) protocols. Although the prognosis in childhood AML is as good as that in I-BFM (Europe) and COG or St. Jude (USA), new drugs are needed to achieve further improvement. The developments of treatments aimed at decreasing late complications and prognostic analysis focusing on new genes employing the next-generation sequencer are also needed.

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• Neutrophil disorders: diagnosis and hematopoietic stem cell transplantation
  Masao KOBAYASHI
  2015 Volume 56 Issue 10 Pages 2230-2239
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2230
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  Neutrophil disorders are classified into abnormal neutrophil function and granulopoiesis. The identification of genetic defects causing neutropenia and neutrophil dysfunction has revealed the mechanisms controlling myeloid differentiation and their functions. The International Union of Immunological Societies of Primary Immunodeficiencies represents the most current catalog of approximately 30 neutrophil disorders. In this report, we show the progress made in studies of the pathophysiology and treatment of these disorders, focusing on chronic granulomatous disease (CGD) and severe congenital neutropenia (SCN). Hematopoietic stem cell transplantation (HSCT) is the only available curative therapy for CGD and SCN. However, the use of HSCT as treatment for both diseases is limited by transplant-related mortality (TRM) because of active infections and intractable inflammatory complications. Recently, reduced-intensity conditioning regimens have been introduced to minimize the TRM and the late adverse effects of HSCT for both diseases. The results of HSCT using the RIC regimen for 40 patients with CGD and SCN in Hiroshima University Hospital are summarized herein. Determining the optimal line of treatment will require further accumulation to cases to refine HSCT for both diseases.

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• RASopathies and hematologic abnormalities
  Yoko AOKI
  2015 Volume 56 Issue 10 Pages 2240-2247
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2240
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  Whole exome sequencing with a next generation sequencer is increasingly being used for identifying new genes and for diagnosing genetic disorders. Numerous causative genes have been identified in Mendelian disorders as well as cancers and multifactorial disorders. Among inborn errors of development, recent advances have been noted in the identification of genes for ciliopathy, diseases with aberrant chromatin remodeling and RASopathies. We have studied molecular mechanisms, epidemiological features and mouse modeling for RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. I will present the expanding disease entity in RASopathies/mosaic RASopathies, the mechanism of cancer predisposition, mouse modeling and therapeutic approaches for RASopathies.

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• Heterogeneity of HLH pathophysiology and treatment strategies
  Takahiro YASUMI, Hirofumi SHIBATA, Saeko SHIMODERA, Toshio HEIKE
  2015 Volume 56 Issue 10 Pages 2248-2257
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2248
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  Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by immune dysregulation and hyperinflammation and is histologically characterized by the presence of benign hemophagocytic macrophages. HLH is classified as primary or secondary depending on the underlying etiology and includes conditions with various pathophysiological features. The pathogenic mechanisms underlying the different HLH subtypes remain incompletely understood and therapeutic regimens for HLH are devised on empirical bases. Herein, recent advances in the understanding of HLH pathogenesis and potential strategies for subtype-specific HLH treatment are reviewed.

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• Statistical analysis using freely-available “EZR (Easy R)” software
  Yoshinobu KANDA
  2015 Volume 56 Issue 10 Pages 2258-2266
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2258
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  Clinicians must often perform statistical analyses for purposes such evaluating preexisting evidence and designing or executing clinical studies. R is a free software environment for statistical computing. R supports many statistical analysis functions, but does not incorporate a statistical graphical user interface (GUI). The R commander provides an easy-to-use basic-statistics GUI for R. However, the statistical function of the R commander is limited, especially in the field of biostatistics. Therefore, the author added several important statistical functions to the R commander and named it “EZR (Easy R)”, which is now being distributed on the following website: http://www.jichi.ac.jp/saitama-sct/. EZR allows the application of statistical functions that are frequently used in clinical studies, such as survival analyses, including competing risk analyses and the use of time-dependent covariates and so on, by point-and-click access. In addition, by saving the script automatically created by EZR, users can learn R script writing, maintain the traceability of the analysis, and assure that the statistical process is overseen by a supervisor.

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• Appropriate use of granulocyte-colony stimulating factor in treating hematologic malignancies
  Noriko USUI
  2015 Volume 56 Issue 10 Pages 2267-2276
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2267
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  Granulocyte colony stimulating factor (G-CSF) plays important roles in treating hematologic malignancies including hematopoietic stem cell transplantation (HCT) and intensive chemotherapy. In the situation of peripheral blood cell transplantation (PBSCT), G-CSF mobilizes hematopoietic stem cells and progenitor cells into peripheral blood and thereby accelerates recovery from neutropenia and thus prevents serious infections after transplantation. In the setting of chemotherapy administration for leukemia and lymphoma, G-CSF can be given to prevent febrile neutropenia (FN) in order to maintain drug intensity and thus improve therapeutic outcomes. Based upon the guidelines abroad and in our country, G-CSF should be used as primary or secondary prophylaxis according to the risk of developing FN during chemotherapy. Patients with acute leukemia who received extremely high-risk chemotherapy benefitted from prophylactic treatment with G-CSF, especially those with acute lymphoblastic leukemia. In treating lymphomas for patients given a regimen with a high risk for FN (>20%), administration of G-CSF as primary prophylaxis is recommended. In addition, administration of primary prophylactic G-CSF is also recommended for patients given a regimen with an intermediate risk for FN (10-20%), if they have risk factors for worsening FN or infection.

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• Research ethics and conflicts of interest
  Taira MAEKAWA
  2015 Volume 56 Issue 10 Pages 2277-2284
  Published: 2015
  Released on J-STAGE: October 10, 2015
  
  DOIhttps://doi.org/10.11406/rinketsu.56.2277
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  Translating research results to clinical settings requires that both researchers and clinicians work together with pharmaceutical companies. At the same time, however, it must be recognized that pharmaceutical companies are basically profit-motivated organizations. When pharmaceutical companies develop deeper doctor-patient relationships, the benefits of individual doctors and organizations inevitably conflict with the benefits or interests of patients. To promote industry-university cooperative activities, research quality and research ethics should be of major importance and we must ensure the reliability of the scientific nature and ethics of the research for the sake of the public. In other words, “confirming the quality and reliability of research”, “ensuring transparency”, and “accountability of research activity” are all clearly warranted. For this purpose, it is mandatory that each individual involved has the ethical sophistication and professionalism expected of doctors and researchers. Each physician and researcher must bear in mind that firm insights and the highest ethical judgments regarding the problems of conflict of interest, by themselves, are the only and the final barrier preserving the fairness and transparency of medical research.

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