[Primary breast diffuse large B-cell lymphoma in an elderly man maintaining long-term complete response].

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma that mostly affects women. Here, we report a case of primary breast DLBCL that affected an older man without any autoimmune disease or drug-related female hormones. The patient was a 65-year-old man whose chief complaints were gradually-increasing lump in the right chest and swelling of the right axillary lymph nodes. He was diagnosed with malignant lymphoma through a needle biopsy on suspicion of right breast cancer with right axillary lymph node metastasis. Since the histological type could not be confirmed, right breast mass resection was performed. The patient was referred to our department for treatment because of the diagnoses of primary breast DLBCL, germinal center B-cell type (Hans classification), and clinical stage IIA. In addition to the six courses of R-CHOP therapy, intrathecal injections were used in combination to prevent CNS infiltration. He has been in complete remission for 5 years. Although rare, breast lymphoma can also occur in men; therefore, early histological diagnosis and response to CNS recurrence prevention are important.

Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma.

Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.

Varicella-zoster virus-associated fulminant hepatitis following allogeneic hematopoietic stem cell transplantation for multiple myeloma.

Disseminated visceral varicella-zoster virus (VZV) infection rarely occurs in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). To date, only a few cases of isolated VZV-induced fulminant hepatitis following allo-HSCT have been reported. We herein describe the case of a 47-year-old Japanese man with multiple myeloma who developed fulminant hepatitis 17 months after undergoing allo-HSCT. Despite receiving fresh frozen plasma and platelet transfusions, he developed a bleeding tendency (systemic purpura, petechiae and oral bleeding), slipped into a coma and eventually died. He was retrospectively diagnosed with viscerally disseminated VZV infection based on a postmortem examination and multiplex polymerase chain reaction (PCR) amplification.

Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants.

PURPOSE: The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co-administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C0h) and 2 h (C2h) after CNI administration. RESULTS: The median dose-adjusted C0h values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co-administration did not alter the dose-adjusted C0h values of tacrolimus in a patient with a CYP3A5 1/ 1 allele, it did change this value of tacrolimus in patients with CYP3A5 3 alleles. However, in patients receiving cyclosporine, no such tendency was observed. CONCLUSION: The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ.

CDR3-independent expansion of Vδ1 T lymphocytes in acquired chronic pure red cell aplasia.

Although there exist case reports describing the association of clonal expansion of γδ T cells with chronic acquired pure red cell aplasia (PRCA), there is no consensus regarding whether clonal expansion of γδ T cells are generally found in chronic PRCA. We examined the γδ T cell receptor repertoire in 19 PRCA patients and found that there was a difference in γδ T-cell repertoires between PRCA patients and healthy donors. We observed an increase in Vδ1 γδ T cells and a decrease in Vδ2 T cells in PRCA patients. CDR3δ1 size distribution patterns were skewed in 9 out of 13 PRCA patients examined, although the skewing was also observed in 7 out of 10 healthy individuals. No significant changes were present in CDR3δ1 size distribution between PRCA patients and healthy donors. Moreover, no apparent consensus amino acid motifs were identified in PRCA patients. Expansion of Vδ1 T cells and depletion of Vδ2 T cells are unique features for chronic acquired PRCA but expansion of Vδ1 T cells does not seem to be the consequence of CDR3-dependent selection. We conclude that clonal expansion of Vδ1 T cells is not a general feature for chronic acquired PRCA.

Safety and efficacy of low-dose liposomal amphotericin B as empirical antifungal therapy for patients with prolonged neutropenia.

BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

[Adult T-cell leukemia-lymphoma developed from an HTLV-1 carrier during treatment of B-cell lymphoma-associated hemophagocytic syndrome].

A 63-year-old woman was admitted to our hospital with high-grade fever, liver dysfunction, and pancytopenia. Computed tomography of the whole body revealed hepatosplenomegaly but no lymphoadenopaties. Bone marrow aspiration showed infiltrations of CD20-positive large atypical B-lymphocytes with severe hemophagocytosis. Although she was a human T-cell leukemia virus type 1 carrier, the atypical lymphocyte in bone marrow had IgH rearrangement but not TCR rearrangement. From these clinical and laboratory data, the patient was diagnosed as having B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) and treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). After 4 cycles of R-CHOP, she had achieved complete remission. However, increased numbers of CD4+CD25+ flower cells were observed in peripheral blood and HTLV-1 provirus DNA was detected after 5 cycle of R-CHOP. The patient was diagnosed as adult T-cell leukemia-lymphoma (ATL) complicated by B-LAHS. Our observations suggest that continuous immunosuppressive statement for B-cell lymphoma or the chemotherapy against B-LAHS may induce the development of ATL in an HTLV-1 carrier.

Successful treatment of necrotizing fasciitis in an upper extremity caused by Clostridium perfringens after bone marrow transplantation.

We report a 47-year-old man with acute leukemia who survived a severe case of necrotizing fasciitis caused by Clostridium perfringens involving his right upper extremity. On day 5 after stem cell transplantation, progressive local tissue necrosis led to septicemia and disseminated intravascular coagulation. Early diagnosis and prompt initiation of appropriate therapy, including surgical debridement and broad-spectrum antibiotics, were crucial. A recombinant thrombomodulin might have not only resolved the coagulation problem but also prevented multiple organ failure associated with the systemic inflammatory response.

False-positive human immunodeficiency virus antibody test and autoimmune hemolytic anemia in a patient with angioimmunoblastic T-cell lymphoma.

A 44-year-old woman was admitted with generalized lymphadenopathy, which was diagnosed as angioimmunoblastic T-cell lymphoma (AITL). The patient showed autoimmune hemolytic anemia (AIHA), polyclonal hypergammaglobulinemia and a high antinuclear antibody titer. Moreover, a human immunodeficiency virus (HIV)-1/2 screening test using the particle agglutination method was reactive. After chemotherapy for AITL, the AIHA was eliminated, and the false-positive HIV results were no longer detected. Autoimmunity associated with AITL is the likely cause of the cross-reaction with HIV and the AIHA. It is important to recognize that the cross-reaction with HIV can be a potential complication in AITL as well as AIHA.

Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.

BACKGROUND: Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration. CASE: A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. CONCLUSIONS: Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.

Fatal hemorrhagic pneumonia caused by Stenotrophomanas maltophilia in a patient with non-Hodgkin lymphoma.

Stenotrophomonas maltophilia is increasingly emerging as a multiresistant pathogen in the hospital environment. In immunosuppressed patients, this bacterium may cause severe infections associated with sepsis and multiple organ dysfunction. We report on a 57-year-old woman treated with intensive chemotherapy for non-Hodgkin lymphoma who developed severe neutropenia, hemorrhagic pneumonia, and acute respiratory failure, which led to her death within 36 h of onset of pneumonia. Postmortem examination revealed bilateral extensive intraalveolar hemorrhage associated with severe infection by the gram-negative bacterium Stenotrophomonas maltophilia. In vitro susceptibility testing showed resistance to carbapenem, cephalosporines and aminoglycosides, but sensitivity to minocycline, ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole (cotrimoxazole). Early diagnosis and adequate antibiotic treatment were difficult, as the clinical course was rapid and fulminant, and this bacterium is resistant to multiple antibiotics. To improve prognosis in such cases, it will be necessary to develop an effective prophylactic strategy for high-risk patients.

Thrombotic thrombocytopenic purpura with severe ADAMTS-13 deficiency in a patient with antiphospholipid antibodies and Charcot-Marie-Tooth disease.

A 26-year-old woman with a history of mild mental retardation, Charcot-Marie-Tooth disease (CMT) and idiopathic thrombocytopenic purpura developed severe thrombocytopenia with Coombs-negative hemolytic anemia. Magnetic resonance imaging revealed a fresh cerebral infarction in the left precentral gyrus. ADAMTS-13 deficiency caused by an inhibitor and anti-cardiolipin antibodies were detected in the blood. After treatment with prednisolone and fresh frozen plasma, ADAMTS-13 activity was normalized, the ADAMTS-13 inhibitor had disappeared and the thrombocytopenia with a bleeding tendency was improved. To our knowledge, this is the first case of thrombotic thrombocytopenic purpura caused by ADAMTS-13 deficiency associated with antiphospholipid antibodies and CMT.

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia.

Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia.

The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n = 10) and specimens of primary lymphoma (n = 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3(-)CD56(+)) cells (n = 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. Conversely, cells showing little endogenous expression of miR-21 or miR-155 were transduced by the use of lentiviral vectors, leading to their overexpression. Reducing expression of miR-21 or miR-155 led to up-regulation of phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4), or Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1). ASO-21- and ASO-155-treated cell lines all showed down-regulation of phosphorylated AKT(ser473). Moreover, transduction with either miR-21 or miR-155 led to down-regulation of PTEN and PDCD4 or SHIP1 with up-regulation of phosphorylated AKT(ser473). Collectively, these results provide important new insight into the pathogenesis of NK-cell lymphoma/leukemia and suggest targeting miR-21 and/or miR-155 may represent a useful approach to treating NK-cell lymphoma/leukemia.

[Early relapse of Burkitt's lymphoma with t(8;14) and t(14;18) after rituximab-combined CODOX-M and IVAC therapy].

A 43-year-old female was admitted with therapy-resistant pancreatitis and an abdominal tumor around the pancreatic head. Laboratory data revealed leukocytosis with a white blood cell count of 18200/microl, 25% atypical cells and an LDH of 13410 IU/l. The bone marrow was comprised of 78.4 percent lymphoblastoid cells which were positive for CD10, CD19 and CD20, and the cytogenetic study of which demonstrated the presence of t(8;14) (q24;q32) and t(14;18) (q32;q21) in the same clone. The patient was diagnosed as having Burkitt's lymphoma (BL) with t(8;14) and t(14;18). Although CODOX-M and IVAC therapy combined with rituximab achieved complete remission, she died of rapid progressive disease during whole brain irradiation before autologous peripheral blood stem cell transplantation. Even if the intensive chemotherapy with rituximab is given adequately, durable remission may not be achieved in BL with translocation of t(8;14) and t(14;18). A more effective therapy remains to be established for the treatment of this disease.

Late-onset fatal Epstein-Barr virus-associated hemophagocytic syndrome following cord blood cell transplantation for adult acute lymphoblastic leukemia.

A 43-year-old Japanese woman underwent unrelated cord blood transplantation (CBT) during remission for acute lymphoblastic leukemia with t(4; 11)(q21;q23). Tacrolimus was given for prophylaxis of graft-versus-host disease. The posttransplantation clinical course was mostly uneventful, and the leukemia remained in remission. Fourteen months after CBT, the patient developed pancytopenia and hepatic dysfunction with persistent high-grade fever. The bone marrow was hypocellular with increased numbers of macrophages and hemophagocytes. The numbers of Epstein-Barr virus (EBV) copies in peripheral blood samples were remarkably high. Although the patient showed complete donor-type hematopoiesis, the titer of viral capsid antigen immunoglobulin G was low, and the results of a test for EBV nuclear antigen were negative. There was no clinical response to the reduction of immunosuppressive therapy or to the administration of high-dose methylprednisolone, human immunoglobulin, or acyclovir. The patient died 466 days after CBT of massive gastrointestinal hemorrhage due to bone marrow and hepatic failures. This case demonstrates that fatal EBV-associated hemophagocytic syndrome (HPS) can occur more than 1 year after CBT. This report is the first of a case of late-onset EBV-associated HPS following CBT.