A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia.

Barasertib (AZD1152) is a highly potent and selective Aurora B kinase inhibitor. The safety, efficacy and pharmacokinetic (PK) profile of barasertib were investigated in Japanese patients with advanced acute myeloid leukemia. Barasertib (50-1200mg) was administered as a continuous 7-day intravenous infusion every 21 days.

Three cases of bortezomib-resistant multiple myeloma with extramedullary masses.

In some patients with multiple myeloma, extramedullary masses may be present at diagnosis or may develop during treatment. Recently, multiple myeloma has been treated using newer therapeutic regimens based on thalidomide and bortezomib. Using these drugs, positive responses to treatment, not found with conventional antineoplastic agents, have been reported along with an improvement in patient outcome.

Melphalan-prednisolone and vincristine-doxorubicin-dexamethasone chemotherapy followed by prednisolone/interferon maintenance therapy for multiple myeloma: Japan Clinical Oncology Group Study, JCOG0112.

A multicenter phase III study for untreated multiple myeloma was conducted to investigate a switch-induction chemotherapy with melphalan-prednisolone and vincristine-doxorubicin-dexamethasone followed by randomization on maintenance therapy for patients achieving plateau. Between November 2002 and November 2005, 34 patients were registered. The study was closed early because of poor accrual.

Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial.

Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH.

Establishment of a xenograft model of human myelodysplastic syndromes.

Background: To understand how myelodysplastic syndrome cells evolve from normal stem cells and gain competitive advantages over normal hematopoiesis, we established a murine xenograft model harboring bone marrow cells from patients with myelodysplastic syndromes or acute myeloid leukemia with myelodysplasia-related changes.

Design And Methods: Bone marrow CD34(+) cells obtained from patients were injected, with or without human mesenchymal stem cells, into the bone marrow of non-obese diabetic/severe combined immunodeficient/IL2Rγ(null) hosts. Engraftment and differentiation of cells derived from the patients were investigated by flow cytometry and immunohistochemical analysis.

Characteristics of CD5-positive splenic marginal zone lymphoma with leukemic manifestation ; clinical, flow cytometry, and histopathological findings of 11 cases.

Splenic marginal zone lymphoma (SP-MZL) is a rare low-grade B-cell neoplasm that often shows leukemic manifestation. Less than 20% of cases of SP-MZL express CD5. We analyzed 11 cases of CD5-positive SP-MZL with leukemic manifestation.

Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma.

Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model.

Introduction of human β-defensin-3 into cultured human keratinocytes and fibroblasts by infection of a recombinant adenovirus vector.

Cultured epidermal autografts and cultured skin substitute are vulnerable to infection. Human beta defensin (HBD)-3 is an antimicrobial peptide that exhibits a wide-spectrum antimicrobial activity against gram-positive/negative bacteria and fungi. This study determined whether normal human keratinocytes (NHKs) and human dermal fibroblasts (HDFs) transfected with the HBD-3 gene secrete HBD-3 peptide with an antimicrobial activity.

Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B-cell non-Hodgkin lymphomas (B-NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B-NHL or mantle-cell lymphoma (MCL). Patients received bendamustine (120 mg/m(2) ) on days 1-2 of a 21-day cycle, for up to six cycles.

Clinical efficacy and safety of biapenem for febrile neutropenia in patients with underlying hematopoietic diseases: a multi-institutional study.

A multi-institutional study was conducted to assess efficacy and safety of biapenem (BIPM), a carbapenem antibiotic, as an initial-stage therapeutic agent for febrile neutropenia (FN) in patients with hematopoietic diseases. A total of 216 patients from 25 medical institutions were enrolled in this study; of these, 204 were included in the safety analysis and 178 in the efficacy analysis. The combined (excellent and good) response rate was 67.

Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose-escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m(2) (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles.

Traumatic stress in Japanese broadcast journalists.

Job-related traumatic stress experienced by broadcast journalists in Japan was investigated. A questionnaire inquiring about the most traumatic event they faced when covering the news and the Impact of Event Scale-Revised (IES-R) were administered to 270 journalist participants working for Japanese news companies. Of these, 6% met the IES-R criterion for potential posttraumatic stress disorder (PTSD).

Persistence of derivative chromosome 22 after achieving a major molecular response in chronic myeloid leukemia with a cryptic BCR-ABL1 fusion gene.

We herein report the findings of a 47-year-old Japanese female with chronic myeloid leukemia (CML) with a cryptic BCR-ABL1 transcript on chromosome 9 and a derivative chromosome 22 unrelated to BCR-ABL1. Although she achieved and continued to demonstrate a major molecular response to imatinib treatment following interferon-alpha, there was persistence of a derivative chromosome 22. A detailed chromosome/molecular studies, including serial karyotyping analysis, finally resulted in the karyotyping at the disease onset to be 47,XX,+del(22)(q11.

Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic T-cell lymphoma.

Patients affected by autoimmune diseases (rheumatoid arthritis (RA), psoriasis, and dermatomyositis) treated with methotrexate (MTX) develop lymphoproliferative disorders (LPDs). These cases have been reported to be diffuse large B-cell lymphoma, Hodgkin lymphoma, or polymorphous post-transplant LPDs. However, angioimmunoblastic T-cell lymphoma (AITL) is extremely rare in the medical literature.

Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma.

Oral fludarabine is more convenient than intravenous fludarabine in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma (B-NHL), we conducted a multicenter phase II study. Patients with relapsed indolent B-NHL with two or fewer prior regimens and up to 16 doses of rituximab were eligible.

A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura.

This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 microg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to > or =50 x 10(9)/L) continued romiplostim weekly during the treatment-continuation phase.

Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

A phase 1/2 study was conducted to assess the safety and efficacy of dasatinib in Japanese patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) resistant or intolerant to imatinib. In phase 1, 18 patients with chronic phase (CP) CML were treated with dasatinib 50, 70, or 90 mg twice daily to evaluate safety. Dasatinib View Article and Find Full Text PDF

A case of acquired aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy.

Acquired aplastic anemia is a rare hematopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. Acquired aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy such as antithymocyte globulin or cyclosporine.

[Granulocytic sarcoma of the prostate presenting with urinary obstruction which progressed to acute myeloid leukemia].

A 71-year-old man presented with progressive dysuria. Several imaging examinations indicated possibility of prostate tumor, therefore he underwent prostate biopsy. This resulted in a diagnosis of granulocytic sarcoma of the prostate.

Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.

We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Abeta deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Abeta plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Abeta pathologies, respectively.

Delta-like 4 is indispensable in thymic environment specific for T cell development.

The thymic microenvironment is required for T cell development in vivo. However, in vitro studies have shown that when hematopoietic progenitors acquire Notch signaling via Delta-like (Dll)1 or Dll4, they differentiate into the T cell lineage in the absence of a thymic microenvironment. It is not clear, however, whether the thymus supports T cell development specifically by providing Notch signaling.

Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis.

Hematopoiesis is a dynamic and strictly regulated process orchestrated by self-renewing hematopoietic stem cells (HSCs) and the supporting microenvironment. However, the exact mechanisms by which individual human HSCs sustain hematopoietic homeostasis remain to be clarified. To understand how the long-term repopulating cell (LTRC) activity of individual human HSCs and the hematopoietic hierarchy are maintained in the bone marrow (BM) microenvironment, we traced the repopulating dynamics of individual human HSC clones using viral integration site analysis.

Expression of Delta-like 1 in the splenic non-hematopoietic cells is essential for marginal zone B cell development.

The Notch ligand Delta-like 1 (Dll1) is critical for the generation of marginal zone (MZ) B cells in the spleen. However, the precise mechanism underlying the differentiation of MZB cells is unclear. To determine whether hematopoietic cells or non-hematopoietic cells provides the Dll1-mediated signals to primitive hematopoietic cells, we transplanted lineage(-)c-kit(+)Sca-1(+) (KSL) bone marrow cells derived from wild-type (Dll1(+/+)) GFP-transgenic mice into lethally irradiated Dll1 conditional knockout (cKO) mice.

Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: does body weight matter?

Imatinib at a daily dose of 400 mg is the standard treatment for chronic myelogenous leukemia in the chronic phase. However, the feasibility of this dose for small Japanese adults has not been clarified. We prospectively investigated the toxicity and efficacy of this dose in adult Japanese patients.