Kodai Kuriyama

Acute Leukemia Showing t(8;22)(p11;q11), Myelodysplasia, CD13/CD33/CD19 Expression and Immunoglobulin Heavy Chain Gene Rearrangement

t(8;22)(p11;q11) is a rare but recurrent chromosome translocation that has been reported in 11 cases of myeloproliferative neoplasm or B-acute lymphoblastic leukemia. This translocation results in an in-frame fusion of FGFR1 on 8p11 and BCR on 22q11, and causes constitutive activation of the tyrosine kinase of the BCR/FGFR1 chimera protein. Here, we report the twelfth case of hematological tumor bearing t(8;22)(p11;q11). The bone marrow showed hypoplastic and tri-lineage dysplasia with 24.4% abnormal cells. The abnormal cells were not defined as myeloid or lymphoid morphologically, lacking a myeloperoxidase reaction. Flow cytometric analysis of the bone marrow cells revealed that the abnormal cells expressed CD13, CD33, CD34, and CD19, and that a fraction of the abnormal cells was positive for CD10. Southern blot analysis of the bone marrow cells showed rearrangement of the immunoglobulin heavy chain gene, a genetic hallmark of B-cell differentiation. Previously reported cases with t(8;22)(p11;q11) suggested an association between myeloid and B-lymphoid tumors, whereas other chromosome translocations involving FGFR1 on 8p11 showed a link between myeloid and T-lymphoid tumors. Our observation supports that t(8;22)(p11;q11) might define a dual myeloid and B-lymphoid disorder.

Real-time monitoring of antimicrobial use density to reduce antimicrobial resistance through the promotion of antimicrobial heterogeneity in a haematology/oncology unit

BACKGROUND In haematology/oncology units, the frequent and heavy use of broad-spectrum antimicrobials can lead to outbreaks of antimicrobial resistance. Increasing antimicrobial heterogeneity might be a useful strategy for preventing such resistance. METHODS A real-time antimicrobial use density (AUD) monitoring system (RAMS) was developed to precisely assess antimicrobial heterogeneity. This study was prospectively conducted over a 39 month period and involved 970 patients. Patient-specific antimicrobial therapy with five carbapenems (meropenem, biapenem, panipenem/betamipron, imipenem/cilastatin and doripenem) and four non-carbapenems (piperacillin/tazobactam, ceftazidime, cefozopran and cefepime) was prescribed in the first 12 months. A first-line antimicrobial was selected from among nine antimicrobials according to a predetermined schedule for the next 15 months. AUD-based antimicrobial selection was implemented using the RAMS during the last 12 months. We compared our findings for the RAMS period with those for the other periods to determine the effects of RAMS-based AUD monitoring on antimicrobial resistance. RESULTS The mean absolute difference between the AUD values of carbapenems and non-carbapenems (AUD deviation) was 6.0% in the RAMS period (range 0.5%-15.8%) and antimicrobial heterogeneity (AUD deviation <10%) was achieved in 10 out of 12 months (83.3%). Furthermore, during the RAMS period, AUD deviation was significantly smaller and the frequency of outbreaks of antimicrobial-resistant strains other than Stenotrophomonas maltophilia was significantly decreased (from 7.9% to 3.5%; P < 0.01) compared with the other periods. CONCLUSIONS The longer period of stable antimicrobial heterogeneity achieved by the RAMS strengthened its preventive effects against antimicrobial resistance. Optimal antimicrobial heterogeneity based on real-time AUD monitoring could reduce the frequency of outbreaks of antimicrobial resistance.

Refractory Ascites with Liver Fibrosis Developed in Late Phase Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Patients.

We report cases of three patients of refractory ascites without other fluid retention that occurred around five months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). All three patients expired and postmortem examinations revealed unexpected liver fibrosis lacking histological evidences of graft-versus-host-disease (GVHD). The three patients showed normal hepatic function and size before transplantation. During their clinical courses, serum biochemistry test showed no elevation of hepatic enzymes and bilirubin; however, imaging studies demonstrated hepatic atrophy at the onset of ascites. One of the liver specimens showed bile obstruction, which could be seen in hepatic damage by GVHD. Although ascites resulting from venoocclusive disease in early phase allo-HSCT is well documented, ascites associated with hepatic fibrosis in late phase allo-HCST has not been reported. Further clinico-pathological studies on similar patients should be required to ascertain refractory ascites associated with liver fibrosis after allo-HSCT.

B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia

B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

Enforced expression of MIR142, a target of chromosome translocation in human B-cell tumors, results in B-cell depletion

MicroRNA142 (MIR142) is a target of chromosome translocations and mutations in human B-cell lymphomas. We analyzed an aggressive B-cell lymphoma carrying t(8;17)(q24;q22) and t(6;14)(p21;q32), and sought to explore the role(s) of MIR142 in lymphomagenesis. t(8;17)(q24;q22) involved MYC on 8q24 and pri-MIR142 on 17q22. MYC was activated by a promoter substitution by t(8;17)(q24;q22). t(8;17)(q24;q22) was an additional event after t(6;14) (p21;q32), which caused the over-expression of CCND3. Southern blot analyses revealed that the MIR142 locus was deleted from the affected allele, whereas Northern analyses showed over-expression of MIR142 in tumor cells. Although previous studies reported an over-expression of mutations in MIR142 in B-cell lymphomas, limited information is available on the functions of MIR142 in lymphomagenesis. Therefore, we generated bone marrow transplantation (BMT) and transgenic (Eμ/mir142) mice, which showed enforced expression in hematopoietic progenitor cells and B cells, respectively. BMT mice showed decreased numbers of all lineage-positive cells, particularly B cells, in peripheral blood. Eμ/mir142 mice showed decreased numbers of IgM-positive splenocytes, and exhibited altered B-cell phenotypic changes induced by lipopolysaccharide. Our results suggest that over-expression of MIR142 alters B-cell differentiation, implying multi-step lymphomagenesis together with MYC activation and CCND3 over-expression.

Long-term complete remission of early hematological relapse after discontinuation of immunosuppressants following allogeneic transplantation for Sezary syndrome

Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma and is chemo-resistant. Allogeneic hematopoietic stem cell transplantation is a promising therapy for SS; however, relapse is common. Therapeutic options after relapse have not been established. We managed an SS patient with hematological relapse within one month after transplantation. After discontinuation of immunosuppressants, she achieved complete remission and remained relapse-free. The chimeric analyses of Tcells showed that the full recipient type became complete donor chimera after immunological symptoms. This clinical course suggested that discontinuation of immunosuppressants may result in a graftversus- tumor effect, leading to the eradication of lymphoma cells.

An Epstein-Barr virus susceptible immature T-cell line, WILL4, established from a patient with T-lymphoblastic lymphoma bearing CD21 and a clonal EBV genome

We managed a patient with an Epstein-Barr virus-associated T-cell lymphoblastic lymphoma. Mediastinal tumor cells at initial admission were positive for CD4, CD8, and TdT. Interestingly, a lymph node at necropsy was compatible for a CD4-positive peripheral T-cell lymphoma without CD8 and TdT expression, suggesting a different phenotype from the mediastinal tumor. Tumor cells in pleural effusion continued to proliferate in in vitro and were designated as WILL4. WILL4 cells were positive for CD3, CD4, CD8, CD21, T-cell receptor (TcR) αβ, and TdT, indicating a similar phenotype to thymocytes. Southern blot analyses showed that the pleural tumor and WILL4 cells shared a TcR gene rearrangement, and that both contained a clonal EBV genome in an episomal form. RT-PCR showed that EBNA1 and LMP1 were expressed in the fresh tumor and WILL4 cells. Southern blot analyses revealed that WILL4 cells were susceptible to EBV infection in vitro using B95-8 supernatant. Anti-CD21 antibody inhibited in vitro infection of EBV, suggesting that CD21 plays a role in EBV infection into WILL4 cells. In vitro infection of EBV did not affect latent gene expression in WILL4 cells. WILL4 is a useful tool for analyzing the roles of EBV in onocogenesis in immature T-lymphoid malignancies.

An Optimal Approach for Fluoroquinolone Garenoxacin Prophylaxis in Patients with Hematological Malignancies and Chemotherapy-induced Neutropenia

Antibiotic prophylaxis such as that with fluoroquinolone reportedly reduces infectious episodes in patients receiving chemotherapy regimens with the risk of febrile neutropenia. However, optimum patient characteristics, the timing of initiation, and antibiotics for prophylactic treatments have yet to be identified. We herein conducted a single-arm monocenter clinical study to elucidate the therapeutic profiles of fluoroquinolone garenoxacin prophylaxis for patients with hematological malignancies (HMs). Fever was not present for the duration of chemotherapyinduced neutropenia in 29 (43.9%) out of 66 patients. A shorter duration of prophylaxis until chemotherapy-induced neutropenia had a more potent effect on delaying febrile episodes, even in patients with fever. Excessive neutropenia (minimum zero neutrophils/l) negatively affected prophylactic effects. Garenoxacin accounted for 4.5% of the minor adverse events observed such as mild renal damage and skin reactions. Therefore, the study suggests that the initiation of garenoxacin prophylaxis from the introduction of neutropenia could be an effectual strategy for preventing chemotherapy-induced febrile episodes in HM patients with moderate neutropenia.

Successful intrathecal chemotherapy combined with radiotherapy followed by pomalidomide and low-dose dexamethasone maintenance therapy for a primary plasma cell leukemia patient

Primary plasma cell leukemia (PPCL) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease. Central nervous system (CNS) involvement with PPCL has an extremely poor prognosis. We describe a 46-year-old man with PPCL treated with a combination of lenalidomide, bortezomib, and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation (allo-SCT). Despite achieving a very good partial response, the patient suffered from an isolated CNS relapse 12 months after allo-SCT. He was immediately started on concurrent intrathecal chemotherapy (IT) and cranial irradiation (RT). Subsequently, pomalidomide and low-dose dexamethasone (Pd) were given as maintenance therapy. He has been without CNS recurrence for more than 18 months. Our case suggests that concurrent IT and RT followed by Pd maintenance therapy may be an effective option to control CNS relapse of PPCL after allo-SCT.

Successful Immunosuppressive Therapy for Severe Infectious Mononucleosis in a Patient with Clonal Proliferation of EBV-infected CD8-positive Cells.

A 30-year-old woman was diagnosed with severe infectious mononucleosis (IM). The Epstein-Barr virus (EBV) had infected both CD19- and CD8-positive cells, and clonal proliferation of EBV-infected cells and T-cells was detected. Although we suspected malignant lymphoma, her condition improved following immunosuppressive therapy. A similar case was recently reported; therefore, this case is the second case of IM with EBV-infected CD8-positive cells and clonal proliferation of EBV-infected cells. Our results demonstrate that the clonal proliferation of EBV-infected cells is not always an indication for chemotherapy in the primary infection phase and that monitoring the EBV viral load is useful for therapeutic decision-making.