Tatsuo Oyake

Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents.

Objective. Clostridium difficile is a major cause of diarrhea in hospitalized patients. Although pseudomembranes are crucial evidence for diagnosis of C. difficile-associated diarrhea (CDAD), some cases do not show any pseudomembranes. The aim of this study was to verify the hypothesis that pseudomembranes are not generated in immunosuppressed patients because of the absence of immunoreactions. Material and methods. We investigated the endoscopic findings of patients with ulcerative colitis (UC) or who had received hematopoietic stem cell transplantation, and who presented with C. difficile toxin A and had undergone colonoscopy between April 2002 and July 2007 at our institutes. Results. In 4 patients the diagnosis was UC and C. difficile infection, and in another 4 patients the diagnosis was CDAD after hematopoietic stem cell transplantation. None of these cases showed pseudomembranes. Shallow ulcers were found in all four cases with UC. Only non-specific findings were obtained for the CDAD patients after hematopoietic stem cell transplantation. Conclusions. Pseudomembranes, the typical evidence for CDAD, were not detected in any patients using immunosuppressive agents. Additional bacterial examination is therefore essential when UC becomes exacerbated and when patients present with diarrhea after hematopoietic stem cell transplantation, even in the absence of pseudomembranes.

Clinical and biological significance of CD56 antigen expression in acute promyelocytic leukemia.

The biological significance of CD56 antigen expression in patients with acute promyelocytic leukemia (APL) has been under investigation. We investigated the clinical and biologic features of CD56+APL. In our series, CD56 antigen was positive in 4 of 28 (14%) APL patients. No differences were found regarding age, gender, performance status (PS), initial leukocyte and platelet counts, lactate dehydrogenase (LDH) and fibrinogen (Fbg) levels according to CD56 expression. CD34 antigen was co-expressed in 3 of the 4 patients with CD56+ APL, in contrast to 2 of the 24 patients with CD56- APL (P = .01). Extramedullary relapse occurred in 3 of the 4 patients with CD56+ APL, in contrast to none of the 24 patients with CD56- APL (P = .001). Median remission duration was 4 months in CD56+ APL and was not reached in CD56- APL. The CD56+ population had a shorter remission duration (P < .0001) and disease-free survival (P < .0001). In contrast, no difference was found in overall survival. These results suggested that CD56 expression was associated with the leukemogenetic mutation at the primitive hematopoietic progenitor cell level and extramedullary relapse in APL patients treated with ATRA and chemotherapy.

Deguelin suppresses cell proliferation via the inhibition of survivin expression and STAT3 phosphorylation in HTLV-1-transformed T cells

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of aggressive ATL patients remains poor because of its resistance to conventional chemotherapy. We examined the effect of deguelin, a naturally occurring rotenoid, on HTLV-1-transformed T-cell lines, KUT-1 and MT-2 cells. We found that deguelin suppressed cell proliferation and induced cell death in these cells. Immunoblot analysis showed the inhibition of survivin expression and signal transducers, and activators of transcription (STAT) 3 phosphorylation of both cells. We also observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) in deguelin-treated cells, indicating that deguelin induces caspase-dependent apoptosis in these cells. Furthermore, proteasome inhibitor MG132 prevented the down-regulation of survivin expression and STAT3 dephosphorylation by deguelin, suggesting that the action mechanism of deguelin involves the degradation of survivin and phosphorylated STAT3 through the ubiquitin/proteasome pathway. Our data indicate that deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV-1-transformed cells. Deguelin merits further investigation as a potential chemotherapeutic agent for ATL.

Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial.

In cases of hematological malignancy, patients with persistent fever and neutropenia receive antifungal empirical therapy to prevent and treat invasive fungal infections. The clinical efficacy and safety of micafungin and voriconazole were compared.

Successful Treatment with Cyclosporine and High-Dose Gamma Immunoglobulin for Persistent Parvovirus b19 Infection in a Patient with Refractory Autoimmune Hemolytic Anemia

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA).The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection.The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/εL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments.The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients

We conducted a phase‐II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic‐phase chronic myeloid leukaemia (CML‐CP) in Japan (IMIDAS PART 2 study).

Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n  =  24) or rhTM (n  =  41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

High-Dose Immunoglobulin

Approximately 70% of the ITP patients responded to high dose of intravenous immunoglobulin. The 2011 ASH guidelines recommend an initial dose of 1 g/kg as a one-time dose. This dosage may be repeated if necessary. The EU recommendations described that adult ITP patients at high risk of bleeding or prior to surgery to correct the platelet count should be indicated for the administration of intravenous immunoglobulin. Adverse events with intravenous immunoglobulin are common, but generally acceptable. High doses of immunoglobulin are thought to be involved in the Fc receptor blockade of macrophages in the reticuloendothelial system. Several other mechanisms were elucidated.

Successful Use of Cyclophosphamide as an Add-On Therapy for Multiple Myeloma Patients with Acquired Resistance to Bortezomib or Lenalidomide

Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma.