The incidence of second primary malignancies (SPMs) in Japanese patients with myeloma or myeloma-related diseases was studied by using the Kansai Myeloma Forum (KMF) database registered from November 2012 to March 2015. We studied 1,571 cases. Hematologic malignancies were documented in 10 patients, and solid tumors in 36 during this period. The cumulative 5-year incidence was estimated to be 1.0% for hematological malignancies and 3.7% for solid tumors. In the patients with smoldering myeloma or MGUS without treatment, solid tumors but not hematologic malignancies developed, though the cumulative incidence of each malignancy did not differ significantly from that in patients receiving treatment. Although statistical analysis showed that treatment with melphalan, bortezomib, lenalidomide, or thalidomide had no effect on the occurrence of hematological malignancies, lenalidomide administration was more frequent in the patients with solid tumors. To evaluate the SPMs in myeloma or myeloma-related diseases more accurately, accumulation of a larger number of patients and longer observation are needed.

Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T cells. We aimed to ascertain the relationships between soluble CD25 (sIL-2R) and CD30 (sCD30) levels and nodal or extra-nodal involvement of ATL. Our study subjects were ATL patients whose sIL-2R and sCD30 levels were measured before initial therapy (n=32). Their sCD30 levels correlated significantly with the number of ATL cells in peripheral blood (PB) (ρ=0.456; P=0.009), while sIL-2R levels correlated significantly with the number of nodal lesions (ρ=0.660; P=0.001). We then also assessed the relationships of pulmonary lesions with the number of ATL cells in PB, lactate dehydrogenase levels, sIL-2R levels, and sCD30 levels in 24 patients whose pleural effusions and hilar lymphadenopathy were investigated before initial therapy. The results suggested that a high number of ATL cells in PB may be associated with pulmonary lesions. It is known that metalloproteinases shed and cleave cytokine receptors such as CD25 and CD30 from the cell surface as well as E-cadherin and extracellular matrix. It seems that serum levels of sIL-2R and sCD30 indicate the activation of metalloproteinases associated with ATL involvement in vivo.

A 74-year-old man visited our hospital with complaints of anorexia, weight loss, and impaired activities of daily living. He presented mild consciousness disturbance at the first visit, but specific causes were identified. The IgD level was>2,000 mg/dl and bone marrow biopsy was performed after aspiration failed due to excessive density. He was diagnosed with IgD/λ multiple myeloma (MM). He lapsed into a coma with an extremely high ammonia level of 484 μg/dl on day 8 after admission. His diagnosis was established as hyperammonemic encephalopathy (HE). He was treated with dexamethasone (Dex) pulse therapy and continuous hemodiafiltration. Minor improvement of hyperammonemia was achieved. Combination therapy with bortezomib and Dex was commenced. His ammonia level rapidly decreased and his mental state improved. HE accompanied by MM is rare and further studies are needed to clarify outcomes in response to treatment using the novel agent Bor. Although HE is potentially fatal, we found Bor to be rapidly effective against HE.

Pediatric anaplastic large cell lymphoma (ALCL) is a chemosensitive malignancy, but about 30% of patients experience relapse. In most of these patients, a second complete remission is obtainable with salvage chemotherapy, though relapse free survival rates are as low as 30-60%. Herein, we report a 6-year-old boy with relapsed anaplastic lymphoma kinase (ALK) positive ALCL successfully treated with vinblastine monotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reduced intensity conditioning (RIC) regimen, from his father. One HLA locus from the father was mismatched. The boy had neither severe graft-versus-host disease nor transplantation related complications. He is currently well and has remained disease free for 10 months, to date, since transplantation. Allo-HSCT with a RIC regimen may be a promising treatment strategy for relapsed ALK positive ALCL based on obtaining graft-versus lymphoma effects as well as reducing transplantation-related mortality.

A 34-year-old man, working at a park in Tokyo, Japan, was repeatedly bitten by mosquitoes while cutting grass. He was hospitalized with sudden fever, fatigue, and weakness. He was eventually diagnosed with dengue virus infection, detected using reverse transcription polymerase chain reaction for the genome and by the presence of nonstructural protein 1 in his peripheral blood. Symptomatic treatments such as acetaminophen for the fever were not effective. Moreover, peripheral blood examination showed drastically decreased white blood cells and platelets, as well as marked elevations of ferritin and soluble interleukin 2 receptor. Furthermore, bone marrow examination revealed increased macrophages with hemophagocytosis. Dengue infection with hemophagocytic lymphohistiocytosis (HLH) was ultimately diagnosed. Half-dose steroid pulse therapy for three days dramatically reduced his temperature, thereby ameliorating physical symptoms and restoring normal peripheral blood data. He was discharged 12 days after admission. Dengue infection with HLH is rare and this is the first report, to our knowledge, of domestic dengue infection with HLH in Japan. Early steroid therapy may be effective in such cases.

An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was <1% and the ADAMTS13 inhibitor titer was 3.2 BU/ml. He received plasma exchange and steroid administration until remission was achieved. Seven months later, he suffered from paralysis of the right hand, hemolytic anemia, and thrombocytopenia. We confirmed TTP recurrence based on ADAMTS13 activity <1% and an ADAMTS13 inhibitor titer of 19.4 BU/ml. Four infusions of rituximab were administered in addition to plasma exchange and steroid pulse therapy. Platelet count recovery was observed within 5 days. No severe side effects related to rituximab occurred. Although rituximab has not been approved for TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor.

We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative.

An 83-year-old woman was admitted to our hospital with a severe headache and purpura. She had previously been diagnosed with idiopathic thrombocytopenia purpura (ITP) and achieved complete remission with steroid therapy. Steroid therapy had been completed one week prior to the current admission. The recurrence of severe thrombocytopenia (<1.0×10⁴ platelets/μl) was detected and a CT scan revealed pituitary hemorrhage without pituitary adenoma. She received steroid therapy combined with intravenous immunoglobulin, which resulted in the amelioration of ITP and improvements in the pituitary hemorrhage. Intracranial hemorrhage, which is the most serious bleeding manifestation in ITP, is relatively uncommon. Pituitary apoplexy in ITP is extremely rare.

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased risk of malignancies. Diagnosis is often difficult due to the wide variety of clinical expressions. The representative diseases are Diamond Blackfan anemia (DBA), Fanconi anemia (FA), congenital sideroblastic anemia (CSA), congenital dyserhthropoietic anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Next-generation sequencing technologies have facilitated the discovery of germline mutations that cause IBMFS. Recently, Japanese groups have identified novel causative genes for DBA, FA and congenital thrombocytopenia by applying whole exome-sequencing. In this review, we will highlight recent studies on DBA, FA and CSA in Japan, which have employed next-generation sequencing technologies to elucidate the genetic etiology of IBMFS.

Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations.

Somatically acquired genomic alterations have been recognized as key hallmarks inducing acute lymphoblastic leukemia (ALL), though recent knowledge acquired from genome-wide association study (GWAS) has revealed that inherited genetic variations (germline) are associated with ALL susceptibility as well as disease onset. The proportion of ALL cases attributable to an inherited genetic predisposition has been recognized as being much higher in clinical practice than previously thought since familial cases with hematopoietic transcriptional factors (PAX5 and ETV6) were reported. Considering the characteristics related to inherited variants, issues associated with these variants persist from childhood throughout the patient's entire life, and specific approaches to both familial ALL cases and carriers with inherited variants are thus urgently needed. This review focuses on familial ALL caused by the two aforementioned transcriptional factors (PAX5 and ETV6).

The pharmacokinetics and pharmacodynamics of therapeutic drugs can greatly vary among individuals. For example, it is sometimes necessary to alter the treatment of childhood acute lymphoblastic leukemia from the standard protocol. Genetic variation is one important factor, which can exert a wide range of effects on sensitivities and responses to therapeutic agents. Thiopurine S-methyl transferase (TPMT) is a useful test for predicting 6-mercaptopurine (6-MP) sensitivity in Caucasians. However, it is not effective for predicting the 6-MP therapeutic responses of Japanese patients because the frequency of TPMT deficiency is lower in the Japanese population (approximately 1% versus approximately 10% in Caucasians). Recently, NUDT15 polymorphisms have been reported to be predictive factors contributing to responsiveness to thiopurine therapy in Asians. The associations between genetic variants and therapeutic responses have been reported in Western countries. However, questions remain about whether results studying other races are applicable to Japanese due to differences in genetic variant frequencies among races. To provide personalized therapy based on genetic factors, we need to ascertain the relationships between genetic variants and therapeutic responses in Japanese childhood acute lymphoblastic leukemia cases.

Acute leukemia, especially acute lymphoblastic leukemia, is the most common tumor in childhood. Survival in pediatric acute leukemia cases has improved significantly, but once a relapse occurs, the long-term survival rates decrease markedly. Recently, SNP array and next-generation sequencing have revealed the relapse mechanism of pediatric leukemia and genetic alterations which drive leukemia recurrence.

The acquisition of fundamental information by the use of recent technologies, including omics-based molecular analyses and total RNA sequencing, has opened the door to further advances in physiological studies on new animal models. Currently, we are endeavoring to develop a comparative hematology protocol in order to build a discovery platform. All vertebrates, with the exception of a few species, have universally peripheral erythrocytes and hemoglobin, suggesting erythropoiesis to be an evolutionary index.

Two key questions remain unanswered in the erythropoiesis field: Why and how do erythroblasts enucleate in mammalian species? Recent studies have unveiled the roles of various molecules, cytoskeletal proteins, motor proteins, vesicle transport, signaling pathways, lipid rafts and actomyosin ring contraction in the enucleation process. However, few reports provide insights into the fitness benefit for mammalian species of having anucleate erythrocytes. Herein, we discuss the biological significance of enucleation of human erythroblasts based on our recent results and on evolutionary considerations related to the biology of hemoglobin and the comparative biochemistry of erythrocyte membrane cytoskeletal proteins, such as protein 4.1R. We specifically focus on the Mesozoic era, a geological period during which dinosaurs and the ancestors of mammalian species coexisted. Approximately 200 million years ago, at the beginning of this era, the earth's atmosphere was hypoxic. Interestingly, animals adopted different respiration systems to adapt to this hypoxic environment. Recent studies using state-of-the-art technologies have shown that dinosaurs might have had nucleated erythrocytes. After dinosaurs became extinct about 65.5 million years ago, their respiration system was maintained by birds. We propose a new adaptive theory that establishes a correlation between evolution towards nucleated or anucleate erythrocytes depending on organism respiration systems during the Mesozoic era.

Erythropoiesis has classically been described as occurring in two waves: first primitive and then definitive erythropoiesis. In the mouse embryo, definitive erythropoiesis begins in the yolk sac and then shifts to the liver, spleen, and bone marrow. The fetal liver serves as the primary organ for erythroid cell expansion and maturation at mid-gestation and its mechanisms have been well investigated with special attention to niche cells expressing cytokines such as SCF, TPO and IGF2. Previously, our group reported that DLK1⁺ hepatoblasts support fetal liver hematopoiesis, particularly erythropoiesis, through EPO, SCF and matrix secretion. Loss of DLK1⁺ hepatoblasts in Map2k4^-/- mouse embryos resulted in decreased numbers of hematopoietic cells in the fetal liver. When sorted DLK1⁺ hepatoblasts were further analyzed by microarray, several genes encoding proteinases and peptidases were highly expressed in DLK1⁺ hepatoblasts. Based on the hypothesis that high molecular weight proteins are digested into small peptides that may regulate hematopoiesis, we screened out peptides, and identified KS-13 (PCT/JP2010/067011). Both KS-13 and modified KS-13, known as SL-13R, proliferate and increase the number of hematopoietic stem/progenitors from human cord blood cells in vitro. We hereby present our findings on the extrinsic regulation of embryonic erythropoiesis with special attention to niche cells, identification of niche-derived peptides, and implications for future hematotherapy.

Erythropoiesis requires large amounts of iron for hemoglobin synthesis, which is mainly provided by macrophages and the intestines in a transferrin (Tf)-bound form. Bone marrow erythroblasts incorporate Tf through endocytosis, which is mediated by transferrin receptor 1 (TFR1). Recently, human TFR1, aside from its role as a Tf receptor, was also found to be a receptor for the H-subunit of ferritin (FTH). In humans, hematopoietic erythroid precursor cells express high levels of TFR1 and specifically take up the FTH homopolymer (H-ferritin). H-ferritin inhibits the formation of burst forming unit-erythroid colonies in vitro. TFR2, which is also a Tf receptor, is predominantly expressed in hepatocytes and erythroid precursor cells. In the liver, TFR2 forms a complex with HFE, a hereditary hemochromatosis-associated protein, and acts as an iron sensor. In mice, hepatocyte-specific knockout of the TFR2 gene has been shown to cause systemic iron-overload with decreased expression of hepcidin, the central regulator of iron homeostasis. In erythroid cells, TFR2 forms a complex with the erythropoietin receptor and facilitates its trafficking to the cell membrane. Moreover, hematopoietic cell-specific knockout of the TFR2 gene causes microcytic erythrocytosis in mice. This review focuses on the molecular evolution and functions of these TFRs and their ligands.