Minako Mori

Fulminant sepsis caused by Bacillus cereus in patients with hematologic malignancies: analysis of its prognosis and risk factors.

Bacillus cereus is a growing concern as a cause of life-threatening infections in patients with hematologic malignancies. However, the risk factors for patients with unfavorable outcomes have not been fully elucidated. At our institution, we observed the growth of B. cereus in blood culture in 68 patients with (23) or without (45) hematologic malignancies treated from September 2002 to November 2009. We defined a case as having sepsis when more than two blood culture sets were positive for B. cereus or only a single set was positive in the absence of other microorganisms in patients who had definite infectious lesions. We determined 12 of 23 patients with hematologic malignancies as having sepsis, as well as 10 of 45 patients without hematologic malignancies (p = 0.012). Of the 12 patients with hematologic malignancies, four patients with acute leukemia died of B. cereus sepsis within a few days. In our cohort, risk factor analysis demonstrated that a neutrophil count of 0/mm3, central venous (CV) catheter insertion, and the presence of central nervous system (CNS) symptoms were significantly associated with a fatal prognosis (p = 0.010, 0.010, and 0.010, respectively). Analysis of data from our cohort in conjunction with those from 46 previously reported patients with B. cereus sepsis identified similar risk factors, that is, acute leukemia, extremely low neutrophil count, and CNS symptoms (p = 0.044, 0.004, and 0.002, respectively). These results indicate that appropriate prophylaxis and early therapeutic intervention against possible B. cereus sepsis are crucially important in the treatment of hematologic malignancies.

Successful allogeneic bone marrow transplantation for myelodysplastic syndrome complicated by severe pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the abnormal accumulation of alveolar surfactant protein in alveolar spaces. We report herein a rare case of myelodysplastic syndrome (MDS-RAEB) complicated by severe PAP, and successful allogeneic bone marrow transplantation (BMT) for both disorders. An unrelated BMT was planned for a 48-year-old male with advanced MDS-RAEB. Just before the initiation of the conditioning regimen for unrelated BMT in March 2007, he developed dyspnea. A diagnosis of PAP was made based on findings of chest X-ray, CT scanning, and the fluid obtained by bronchoalveolar lavage. To improve his dyspnea and improve BMT safety, whole lung lavage (WLL) was performed twice, with the partial improvement of PAP. Unrelated allogeneic BMT was performed in September 2007. We had to perform a third WLL because of the worsening of PAP on day 26 after BMT. Despite many infectious complications after BMT, GVHD was relatively mild. PAP had almost disappeared 6 months after BMT. He was well with favorable hematopoiesis 20 months after the BMT without any specific treatment. There has been no report of an MDS patient with PAP in whom 3 WLL procedures were performed before and after allogeneic BMT.

Hepatosplenic αβ T cell lymphoma

A 32-year-old male with chronic hepatitis B was admitted to a hospital with cellulitis in the right leg in September 2006. Pancytopenia, hepatosplenomegaly, and systemic superficial lymph node swelling were noted, and he was referred to our hospital. He developed fever and liver dysfunction in June 2007 and underwent a splenectomy. His pancytopenia subsequently improved. A pathologic diagnosis of hepatosplenic αβ T cell lymphoma was made by examining spleen tissue and biopsy specimens of the liver and mesenteric lymph node. He had stage IVB disease because neoplastic T cells were noted in the bone marrow. The response of the lymphoma to conventional chemotherapy including the CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) and DeVIC (dexamethasone, etoposide, ifoshamide, carboplatin) regimens was poor and transient. A partial remission was obtained with an ESHAP (etoposide, cisplatin, cytarabine, methylprednisolone) regimen. Therefore, we planned a bone marrow transplantation (BMT) from an HLA-haploidentical sibling donor. He was moved to the Department of Hematology, Hyogo Medical College, to receive this BMT as part of a clinical trial. During the conditioning procedure for the transplantation, however, he died of septicemia. Since hepatosplenic αβ T cell lymphoma is very rare with only 23 reported cases to date, herein we report this case and discuss the therapeutic strategy.

Successful living donor liver transplantation for severe hepatic GVHD histologically resembling autoimmune hepatitis after bone marrow transplantation from the same sibling donor

A 30‐year‐old woman developed severe liver dysfunction 1 year after bone marrow transplantation (BMT) from an HLA‐identical sibling donor for B lymphoblastic leukemia (B‐ALL) during the tapering of cyclosporin A. The histologic picture resembled autoimmune hepatitis (AIH), although neither autoantibody nor hypergammaglobulinemia was detected. She entered hepatic coma, and underwent living donor liver transplantation from the same donor on day 421 after BMT. She is well 18 months after the procedure, showing normal liver function and hematopoiesis. AIH‐like hepatic graft‐versus‐host disease (GVHD) has not been documented. This patient is the second case of living donor liver transplantation for hepatic GVHD from the same donor.

Refractory de novo myeloid sarcoma: a case report and therapeutic strategy based on bone marrow minimal residual disease

Myeloid sarcoma (MS), which usually develops concurrently with acute myeloid leukemia (AML), is an extramedullary tumor that consists of immature myeloid cells. Clinically, the incidence of MS in AML is 3–5% [1, 2], and the association of MS is linked to a poor prognosis [3]. De novo MS is characterized by leukemic tumor formation without the involvement of bone marrow and peripheral blood. Patients receiving radiotherapy or incorrect chemotherapy develop AML at a median time of 7 and 12 months, respectively, and show an extremely poor prognosis after leukemic transformation [4]. Thus, systemic chemotherapy effective against AML, which lowers the rate of leukemic transformation from 71 to 41%, is essential for the treatment of de novo MS [5]. A 17-year-old male was referred to our hospital in April 2007, because of small tumors in the left neck and supraclavicular fossa. A CT scan showed several separated tumors in the neck and mediastinum, one being 4 9 2 cm in the superior mediastinum and the others around 1.5 cm. The histologic picture of a biopsied left supraclavicular lymph node demonstrated that the normal architecture had been destroyed and completely replaced by middle-sized immature myeloid cells (Fig. 1), which expressed T-cell markers including CD2 and CD7 in addition to CD13, CD33, CD38, CD43, cytoplasmic myeloperoxidase, and HLA-DR on flow cytometry. Chromosomal analysis of the specimen revealed an abnormal karyotype of 46,XY,i(17)(q10) in 5 of 7 dividing cells. Blood and marrow cells did not contain abnormal cells as evaluated by flow cytometry and G-banding. A diagnosis of de novo MS was made. After 2 courses of intensive chemotherapy effective against AML, a complete remission (CR) of MS was achieved as evaluated by CT scan. Two months after the initial therapy, however, we detected a small population of myeloblasts (0.05% of all nucleated cells), which aberrantly expressed CD2 and CD7 in the bone marrow on flow cytometry, regardless of the disappearance of MS tumors. Thus, we regarded CD2/CD13 myeloblasts as MRD in the bone marrow. Subsequently, 3 courses of consolidation therapy including high-dose cytarabine were performed; however, MRD in the bone marrow persisted (0.05– 0.20%). Although we planned allogeneic HSCT, overt AML rapidly developed during the recovery phase after the third consolidation chemotherapy. The leukemia was highly refractory to any treatment including the regimens for acute lymphoblastic leukemia after December 2007. Chromosomal analysis of the bone marrow cells showed an abnormal karyotype of 46,XY,t(1;11)(p10;q10),add(4) (q21),i(17)(q10) in 8 of 20 dividing cells in addition to that D. Inoue (&) Y. Nagai T. Kimura S. Shimoji M. Mori K. Togami S. Tabata M. Kurata A. Matsushita K. Nagai T. Takahashi Department of Hematology and Clinical Immunology, Kobe City Medical Center General Hospital, 4-6 Minatojima nakamachi, Chuo-ku, Kobe 650-0046, Japan e-mail: daichi@kcgh.gr.jp

Multiple granulocytic sarcomas in essential thrombocythemia

A 59-year-old woman was diagnosed with essential thrombocythemia in 1988 and had been treated with hydroxyurea, mitobronitol, busulfan, and ranimustine, in that order. Hepatosplenomegaly, low-grade fever, and body weight loss manifested, and a few blasts were noted in the peripheral blood studied in March 2002. A biopsied specimen of the bone marrow showed myelofibrosis but not a leukemia in August 2004. An abnormal karyotype with der(1;13) appeared for the first time. She was treated with low-dose prednisolone. In January 2005, she experienced left hip joint pain, and magnetic resonance scanning showed a tumoral lesion in the femoral head. Histological diagnosis of the biopsied mass revealed that it was a granulocytic sarcoma, and radiotherapy was performed. In April 2005, bone scintigraphy showed multiple lesions. She became febrile and red blood cell transfusion-dependent with hepatosplenomegaly and a small number of circulating blasts. Intravenous cytarabine (low dose) and etoposide relieved the fever and hepatosplenomegaly; however, she developed a pathologic fracture of the right humerus.An additional karyotypic abnormality (7q22 deletion) was noted. She subsequently died of infection. Granulocytic sarcoma is very rare in essential thrombocythemia, and this patient may be the first reported case of essential thrombocythemia that developed multiple lesions and a pathologic fracture without transformation to overt leukemia.

Successful treatment of extranodal natural killer/T-cell lymphoma, nasal type, complicated by severe hemophagocytic syndrome, with dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide chemotherapy followed by autologous stem cell transplant

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), is mostly endemic to East Asia, and is associated with Epstein–Barr virus (EBV) infection [1]. For localized nasal disease, concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment [2]. With respect to extranasal and disseminated disease, systemic chemotherapy has become the main treatment. However, patients with stage IV, relapsed, or refractory disease have an extremely poor prognosis, with a median survival of a few months [3,4]. Here, we report our successful experience of a case of ENKL complicated by severe lymphoma-associated hemophagocytic syndrome (LAHS). We treated the patient with SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) chemotherapy in combination with radiotherapy, and then performed high-dose chemotherapy with autologous peripheral blood stem cell transplant (auto-PBSCT). A 43-year-old Japanese male was emergently transferred to our hospital in June 2007 because of a month-long high-grade fever, weight loss, hepatosplenomegaly, marked pancytopenia, and elevated levels of liver enzymes. Hematologic examination showed a white blood cell count of 0.36 10/L, a hemoglobin concentration of 8.8 g/dL, and a platelet count of 436 10/L. Serum chemistry showed abnormal results as follows: aspartate aminotransferase (AST) 180 IU/L, alanine aminotransferase (ALT) 119 IU/L, lactate dehydrogenase (LDH) 1086 IU/L (normally 120–250 IU/L), creatine phosphokinase (CPK) 558 IU/L (normally 60–250 IU/ L), alkaline phosphatase (ALP) 1263 IU/L (normally 100–340 IU/L), total bilirubin 3.3 mg/dL, C-reactive protein (CRP) 5.5 mg/dL (normally less than 0.5 mg/dL), triglyceride 290 mg/dL (normally 40– 140 mg/dL), ferritin 26 610 ng/mL (normally 20– 250 ng/mL), and soluble interleukin (IL)2 receptor 27 900 U/mL (normally 220–530 U/mL). A bone marrow aspirate demonstrated the infiltration of abnormal cells with azurophilic granules in pale abundant cytoplasm, constituting as many as 8.4% of all nucleated cells (Figure 1), which were found to be positive for CD2, cytoplasmic CD3, and CD56, but negative for CD3, 4, 5, 7, 8, and 16 by flow cytometric analysis. Furthermore, the number of monocytes and macrophages increased to 12.4% and

Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.