Cardiac amyloid light-chain amyloidosis (AL amyloidosis) is a rare disease with a very poor prognosis, associated with plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance and multiple myeloma. Though bortezomib-containing regimens have achieved high hematologic response rates, there are still few reports describing the outcomes of Japanese patients. Six patients with severe cardiac AL amyloidosis were treated with bortezomib-containing regimens. Involved free light chain (iFLC) decreased immediately in most of these cases. However, the condition of heart failure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) worsened in the early phase of this treatment and then improved several months later. At 29 months, the median duration of follow-up (2-47months), all patients remain alive except one who died of sudden cardiac arrest. Bortezomib-containing regimens are considered to be among the effective treatments for severe cardiac AL amyloidosis.

A 10-year-old girl developed L-asparaginase (ASP)-associated pancreatitis during chemotherapy for acute lymphocytic leukemia. Her symptoms showed alleviation with continuous regional arterial infusion of protease inhibitor and systemic somatostatin analog therapy. She had intermittent and marked hypertriglyceridemia, an initial trigger for pancreatitis, probably as a side effect of ASP and steroids. However, we considered the pancreatitis to have developed mainly because of factors other than hypertriglyceridemia as lipoprotein analysis confirmed chylomicron levels to be nearly undetectable. Extremely large chylomicrons contribute directly to the onset of pancreatitis by causing blockage of small vessels. Although it is necessary to examine patients for dyslipidemia developing as a side effect of ASP, therapeutic intervention for hypertriglyceridemia is not considered to prevent the onset of ASP-associated pancreatitis.

We present a 36-year-old woman who had been taking oral dasatinib for 3 years for the treatment of chronic myelogenous leukemia (CML). Although adverse events such as thrombocytopenia and pleural effusion developed, she showed a major molecular response (MMR) 22 months after the initiation of oral dasatinib administration, and the therapy was thus continued. Approximately 34 months after oral dasatinib initiation, she developed severe exertional dyspnea and had to be urgently hospitalized. There was no apparent pleural effusion increase, and neither imaging nor blood test results suggested pneumonia or other infections. Pulmonary arterial hypertension (PAH) was suspected on the basis of transthoracic echocardiography. PAH was then confirmed by right heart catheterization. Though dasatinib was discontinued on the day of hospitalization, pulmonary hypertension and heart failure progressed, and she did not respond to catecholamines or PDE5 (phosphodiesterase type 5) inhibitors. On the 4^th hospital day, she experienced cardiopulmonary arrest and died 1 week later. Cases with PAH due to oral administration of dasatinib have been reported previously. However, cases showing the rapid progression documented in our patient are rare and we advocate that PAH be considered a potential adverse event associated with dasatinib therapy.

We describe two hemodialysis patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine. A 65-year-old woman (case 1) received azacitidine at 75 mg/m² for 7 days, and a 52-year-old man (case 2) with liver cirrhosis received a 70% dose of azacitidine. Both cases developed grade 4 cytopenia, but they achieved transfusion independence after 3 and 2 courses, and the durations of remission were 10 and 11 months, respectively. Case 1 had the complication of febrile neutropenia (FN) twice during the 1^st and 2^nd courses, but continued to receive azacitidine treatment thereafter. Case 2 developed infectious peritonitis during the sixth course, and azacitidine treatment was thus discontinued. After a 4-month treatment interruption, he became transfusion-dependent, and re-induction of azacitidine was successful. Of note, the course of case 1 was complicated by erythema nodosum on admission, which then disappeared after one course of azacitidine treatment. The mean durations of hospitalization were 17.5 and 23 days per course of azacitidine treatment, respectively. Though there are few reports of azacitidine treatment for hemodialysis patients with high-risk MDS, we advocate administering azacitidine to such patients, while paying close attention to the dose intensity of azacitidine and taking prompt action to manage infectious complications.

Recent advances in surgical corrections and supportive care for congenital heart disease have resulted in increasing numbers of adult survivors who may develop hematological malignancies. Treatments including chemotherapy for such patients may cause serious hemodynamic or cardiac complications, especially in those receiving stem cell transplantation. We present a 29-year-old woman with acute lymphoblastic leukemia and congenital heart disease. She had been diagnosed with pulmonary atresia with an intact ventricular septum at birth, and the anomaly was surgically corrected according to the Fontan technique at age 9 years. Her induction chemotherapy required modifications due to poor cardiac status with Fontan circulation. However, after surgical procedures including total cavopulmonary connection and aortic valve replacement at first complete remission, her cardiac status was significantly improved. Subsequently, she underwent cord blood stem cell transplantation at the third complete remission. She required intensive supportive care for circulatory failure as a pre-engraftment immune reaction and stage III acute graft versus host disease of the gut, but recovered from these complications. She was discharged on day 239, and remained in complete remission at 1-year post-transplantation.

A 48-year-old man was transferred to our emergency room because of sudden-onset epigastric pain and nausea. Abdominal contrast-enhanced computed tomography (CT) showed splenomegaly with splenic infarction and intra-abdominal bleeding, suggestive of splenic rupture. An emergent open splenectomy was performed. His spleen was markedly swollen and showed continuous bleeding due to a laceration. On histopathological examination, his spleen was filled with abnormal tumor cells. He was diagnosed as having mantle cell lymphoma based on the findings of immunohistochemical and cytogenetic analyses of the spleen. Mantle cell lymphoma cells were identified in the bone marrow and ileum, and he was determined to be in stageIVA by positron emission tomography (PET)-CT. He was administered rituximab combined with hyper-CVAD/MA chemotherapy (R-hyper-CVAD/MA regimen). After two courses of the R-hyper-CVAD/MA regimen, he achieved complete response, as confirmed by PET-CT. He received four courses in total of the R-hyper-CVAD/MA regimen, followed sequentially by high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). He is currently alive and free of disease. This is the 10^th report of a mantle cell lymphoma case with spontaneous splenic rupture. We herein review previous reports and emphasize the importance of awareness of hematological malignancies when encountering a case with spontaneous splenic rupture.

Peliosis hepatis (PH) is a condition involving benign tumors pathologically characterized by multiple blood-filled cavities, mostly affecting the liver and spleen. Androgenic-steroids are widely used in patients with bone marrow failure syndromes (e.g.: aplastic anemia) and these patients are at increased risk of developing PH. Although patients with PH are generally asymptomatic, PH can progress to liver failure and even fatal spontaneous intraabdominal hemorrhage. Therefore, early diagnosis is critical in order to prevent life-threatening complications of PH. We herein report a patient with PH which had been treated with danazol, who presented with liver dysfunction and multiple hepatic lesions on imaging studies at the time of diagnosis. Although the patient presented with disseminated intravascular coagulation (DIC), a bone marrow biopsy revealed no evidence of leukemic transformation. The patient was diagnosed as having danazol-induced PH, and these abnormalities spontaneously resolved after the discontinuation of danazol. PH is one of the most important complications of long-term administration of androgenic-steroids. Although the mechanisms remain unclear, the multiple blood-filled cavities characteristic of PH may be responsible for the development of DIC. Therefore, monitoring of coagulation markers might also be a key strategy for early diagnosis of PH.

Crystal-storing histiocytosis (CSH) is characterized by the accumulation of large histiocytes with intracytoplasmic crystallized immunoglobulin and is typically associated with hematological malignancies. A 69-year-old man, who had a history of left nephrectomy and chemotherapy for renal pelvic cancer six years earlier, had received a CT scan every year thereafter and a small nodule was found in the left lower lobe of his lungs two years prior to the current presentation. Because of progression of this pulmonary nodule, he underwent pulmonary lobectomy on suspicion of lung cancer. He was ultimately diagnosed as having CSH accompanied by mucosa-associated lymphoid tissue lymphoma stage IAE. In the absence of further treatment, he has been well with no recurrence of the disease for 10 months postoperatively. Because CSH could reportedly be an initial presentation of hematological malignancies, careful observation and evaluation for the presence of these blood disorders is essential.

The molecular pathogenesis of peripheral T-cell lymphoma (PTCL) has gradually been clarified in terms of genomic abnormalities. Insights into these genomic abnormalities have provided clues to understanding the pathogenesis of PTCL. Furthermore, the origins of lymphoma cells have been clarified by investigating the distribution of genomic abnormalities in tumor cells and non-tumor blood cells. Multistep tumorigenesis has been suggested to be a fundamental mechanism underlying the development of angioimmunoblastic T-cell lymphoma (AITL), a distinct subtype of PTCL: premalignant cells evolve from hematopoietic progenitors via mutations in epigenetic regulators. These cells then further differentiate into tumor cells via the addition of tumor-specific G17V RHOA mutations. Meanwhile, AITL are composed of various infiltrating cells as well as tumor cells. Most notably, AITL tissues are characterized by massive infiltration of B cells partially infected by Epstein-Barr virus, follicular dendritic cells, and high endothelial venules. Infiltration of these cell types has been thought to be a reactive process, promoted by cytokines and chemokines released from tumor cells. Considering the multistep mechanisms of AITL allows us to analyze whether these infiltrating cells are also derived from premalignant cells. Indeed, the mechanisms underlying massive infiltration of bystander cells might be more complicated than previously imagined.

Recent clinical trials for T/NK-cell lymphomas are summarized herein, focusing on ATL and extranodal NK/T-cell lymphoma (ENKL). The outcomes of patients with these malignancies were the poorest among various peripheral T-cell lymphomas (PTCLs) in the International T-Cell Lymphoma Project. JCOG has conducted several clinical trials aimed at improving these poor outcomes. For aggressive ATL, JCOG is conducting a phase II trial of VCAP-AMP-VECP followed by allogeneic SCT. For localized ENKL, concurrent chemoradiotherapy has shown promising and durable efficacy in the phase I/II study. Among various new agents for PTCLs and ATL, mogamulizumab has shown promising efficacy for relapsed ATL. A subsequent phase II study of mogamulizumab using the same dose and schedule for relapsed PTCL/CTCL also showed promising efficacy. To establish a new standard for untreated aggressive ATL, a randomized phase II study of VCAP-AMP-VECP with or without mogamulizumab was conducted. Higher % CR was obtained (52% vs 33%) in the former arm, suggesting that VCAP-AMP-VECP plus mogamulizumab is a reasonable option. Lenalidomide recently showed promising efficacy for ATL in phase I and II studies.

Adult hematopoietic stem cells (HSCs) reside in bone marrow and are maintained in a dormant state within a special microenvironment, their so-called “niche”. Detaching from the niche induces cell cycle progression, resulting in a reduction of the reconstitution capacity of HSCs. In contrast, fetal liver HSCs actively divide without losing their stem cell potentials. Thus, it has been unclear what types of cellular responses and metabolic changes occur in growing HSCs. We previously discovered that HSCs express relatively low levels of endoplasmic reticulum (ER) chaperone proteins governing protein folding, making HSCs vulnerable to an elevation of stress signals caused by accumulation of un-/misfolded proteins (ER stress) upon in vitro culture. Interestingly, fetal liver HSCs do not show ER stress elevation despite unchanged levels of chaperone proteins. Our latest studies utilizing multiple mouse models revealed that in the fetal liver bile acids as chemical chaperones play a key role supporting the protein folding which results in the suppression of ER stress induction. These findings highlight the importance of ER stress regulations in hematopoiesis.

Hematopoietic stem cells (HSCs) have unique functional properties, including self-renewal and multi-lineage differentiation potential, and are thought to be fully responsible for lifelong hematopoiesis. However, recent studies have shown that HSCs divide much more slowly than thought, and, therefore, that daily hematopoiesis is maintained not by HSCs but by hematopoietic progenitors with limited self-renewal. When hematopoietic stress such as an infection occurs, hematopoietic production is at high demand at the site of infection. To meet hematopoietic needs, HSCs are also presumably recruited to orchestrate hematopoiesis. The beneficial and detrimental effects of inflammation on HSC function and the associated hematopoietic regulation are discussed herein, by summarizing recent findings.

Tumor immunotherapy, especially tumor antigen specific T cell therapy, is currently attracting attention. However, a critical issue still awaits resolution; it is difficult to efficiently expand tumor antigen-specific T cells. To solve this problem, we are now utilizing iPS cell technology. When iPS cells are established from tumor antigen specific T cells, T cells regenerated from these iPS cells are expected to express the same TCRs as the original T cells. In line with this concept, we succeeded in regenerating tumor antigen specific cytotoxic T cells. The regenerated T cells exhibited TCR specific killing activity comparable to that of the original cells, and were able to kill leukemia cells in an antigen-specific manner. We are currently endeavoring to apply this method clinically. In the future, we intend to establish an allogeneic transfusion system, in which various tumor antigen specific T-iPS cells from a wide range of HLA haplotype homozygous donors will be lined up as a “T-iPS cell bank”, with the aim of making off-the-shelf tumor immunotherapy a reality.

Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called “immune checkpoint blockers”, such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies. Anti-cancer therapy by immune cells, i.e. cell-based immunotherapy, is expected to be more effective than antibody therapy, because immune cells can recognize, infiltrate, and act in cancer tissues more directly than antibodies. In order to achieve cell-based anti-cancer immunotherapy, it is necessary to develop manufacturing systems for mass-production of immune cells. Our group has been studying immunotherapy with myeloid cells derived from ES cells or iPS cells. These pluripotent stem cells can be readily propagated under constant culture conditions, with expansion into a large quantity. We consider these stem cells to be the most suitable cellular source for mass-production of immune cells. This review introduces our studies on anti-cancer therapy with iPS cell-derived dendritic cells and iPS cell-derived macrophages.

The aim of stem cell therapy for Parkinson's disease (PD) is to reconstruct local synapse formation and/or induce the release of dopamine and cytokines from grafted cells in the putamen. Fetal ventral-midbrain cells reportedly relieve the neurological symptoms of PD patients. However, induced pluripotent stem cells (iPSCs) are expected to provide an alternative donor cell population because of their capacity for self-renewal and pluripotency. A protocol to generate dopaminergic (DA) neurons from iPSCs has been developed, and human ESCs were proven to function in the brains of rat and monkey PD models. We have developed a method of isolating DA neuron progenitors as a donor cell population, which allows safe and efficient transplantation.

Induced pluripotent stem cells (iPSCs) are not only a valuable resource for regenerative medicine, but also a promising tool for disease modeling and drug discovery. Patient-specific iPSCs harboring disease-specific mutations are extremely useful for investigating disease mechanisms and novel treatment approaches. In the field of hematology, attempts to establish iPSCs from tumor cells such as those of leukemia or myelodysplastic syndrome (MDS) were largely unsuccessful because proper reprogramming processes were hampered by their extensive genetic alterations. In contrast, congenital disorders caused by a single genetic mutation are ideal candidates for deriving iPSCs. We have been investigating the molecular mechanisms underlying leukemia and MDS by implementing iPSC technology. Familial platelet disorder (FPD) is a rare autosomal dominant disorder characterized by thrombocytopenia and a high propensity for developing acute leukemia, which is caused by heterozygous mutation of RUNX1. We have successfully established iPSCs from three distinct FPD pedigrees and examined the responsible defect during hematopoietic development. This system will serve as a novel unprecedented platform for prospectively studying hematologic disorders using human cells.