[Non-traumatic splenic rupture during the chemotherapy and successful management by emergency splenectomy in a patient with blastic plasmacytoid dendritic cell neoplasm].

Spontaneous rupture of the spleen is a rare but important complication in hematological malignancies. Without splenectomy, the mortality rate of these patients is nearly 100%. We present a blastic plasmacytoid dendritic cell neoplasm case with this complication. Nine days after initiation of chemotherapy, the patient had increased epigastric pain and a drop in hemoglobin. CT scan showed an enlarged spleen surrounded by hemorrhage. Spontaneous rupture of the spleen was diagnosed. Although the patient had severe bone marrow suppression due to chemotherapy, emergency splenectomy was performed and the patient recovered.

[Extramedullary onset of mixed phenotype acute leukemia with MLL gene rearrangement].

Rearrangements of the mixed lineage leukemia MLL gene at chromosome 11q23 are common chromosomal abnormalities in human leukemia. MLL fused with numerous partner genes causes different leukemia phenotypes that depend on the function of partner genes. MLLT3-MLL is generated by translocation t(9;11), which primarily induces acute myeloid leukemia in humans, whereas MLLT3-MLL induces ALL or biphenotypic leukemia in mice. The microenvironment that surrounds leukemia cells plays a central role in this process. We report a patient with mixed phenotype acute leukemia with MLLT3-MLL. This patient, a 44-year-old woman, initially exhibited extramedullary leukemia with multiple tumors and subsequently developed bone marrow disease. The leukemia cells exhibited myeloid (CD13 and MPO) and B cell (CD19 and CD79a) phenotypes. Chromosomal analysis and RT-PCR assay revealed tumor cells with the MLLT3-MLL fusion gene. We treated this patient with a drug regimen for AML (Ara-C plus anthracycline), and complete remission was obtained. This report describes the fourth case of mixed phenotypic leukemia with extramedullary disease. The extramedullary circumstance may underlie the biphenotypic features of these patients.

Rituximab activates Syk and AKT in CD20-positive B cell lymphoma cells dependent on cell membrane cholesterol levels.

The introduction of rituximab, an anti-CD20 monoclonal antibody, has dramatically improved the treatment outcomes of patients with B cell lymphoma. Nevertheless, the clinical response to rituximab varies, and a subpopulation of patients does not respond well to this antibody. Although several molecular events have been shown to be involved in the mechanism of action of rituximab, recent studies have demonstrated that intracellular signaling pathways and the direct effects of rituximab on cell membrane components are responsible for the antilymphoma action of this drug. In the present study, we demonstrated that rituximab activated Syk and Akt, molecules with antiapoptotic functions, in several CD20-positive lymphoma cell lines. Notably, rituximab activated Syk and Akt in all the tested primary lymphoma samples from six patients. Our results show that the cholesterol levels in lymphoma cell membranes have a crucial role in the regulation of Syk and Akt. The depletion of cholesterol from the cell membrane completely blocked rituximab-induced Syk and Akt activation. Simvastatin, an inhibitor of cholesterol synthesis, also abrogated rituximab-mediated Syk and Akt activation. Finally, we report that rituximab inhibited the apoptosis induced by chemotherapeutic drugs, which was observed solely in Akt-activated cells. This work demonstrates for the first time that rituximab paradoxically works to suppress apoptosis under certain conditions in a manner that is dependent on the cell membrane cholesterol level. Our observations provide novel insights and suggest that the cell membrane cholesterol level represents a new biomarker for predicting patient response to rituximab. Furthermore, the modulation of lipid rafts could provide a new strategy for enhancing the antilymphoma action of rituximab.

[Multiple myeloma complicated with Takotsubo cardiomyopathy].

A 67-year-old woman with refractory multiple myeloma was admitted to our hospital for salvage therapy. She developed fever several days after chemotherapy was initiated and complained of chest pain. Since abnormal electrocardiogram was demonstrated. Emergency coronary angiography was performed, but the coronary artery did not demonstrate stenosis. Thereafter, the patient was diagnosed as having takotsubo cardiomyopathy. Hydragogue and nitric acid preparation transiently improved chest symptoms, but high fever persisted despite antibiotic and antifungal agents. She died on the 9th day after the initiation of chemotherapy. Physicians need to be aware that cardiomyopathy may develop as a severe side effect of chemotherapy.

Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan.

Abnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most important transcription factors for the adaptation of cells to hypoxia, is frequently observed in numerous types of solid tumors. Dysregulation of HIF-1 induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-associated enzymes in cancer cells, which in turn leads to the promotion of tumor growth. In the present study, we examined the pathophysiologic role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that HIF-1 may be a molecular target for myeloma therapy. We identified constitutive expression of the hypoxia-inducible factor-1 alpha (HIF-1alpha)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1alpha expression through activation of the AKT and mitogen-activated protein kinase signaling pathways. Inhibition of HIF-1 function either by echinomycin, a specific HIF-1 inhibitor, or a siRNA against HIF-1alpha resulted in enhanced sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of HIF-1 drastically reduced both basal and IGF-1-induced expression of survivin, one of the most important anti-apoptotic proteins in myeloma cells. We conclude that HIF-1 inhibition may be an attractive therapeutic strategy for multiple myeloma.