Hiroshi Arima

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.

Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: a multicenter retrospective study in Japan.

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2nd- or 3rd-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48–12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37–17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.

Gender Identification by Calls and Body Size of the Streaked Shearwater Examined by CHD Genes

Abstract Like most seabirds Streaked Shearwaters Calonectris leucomelas have sexually monomorphic plumage. Researchers have conveniently identified gender in the field by means of two types of calls, associated with dimorphism in body size. By molecular sexing analysis using the chromo-helicase-DNA-binding (CHD) genes, we determined the gender of Streaked Shearwaters in relation to call types and body size. We recorded the type of calls, measured body dimensions and collected non-invasive samples (buccal cells or feathers) of Streaked Shearwaters at two breeding islands. As obvious amplification to identify gender by polymerase chain reaction (PCR) could not be obtained at high rates using a known universal primer pair, we developed two new primer pairs to identify gender in this species; this enabled us to identify the gender of all of the samples. Without exception all males gave high-pitched calls, whereas all females gave low-pitched calls. Molecular evidence also confirmed morphometric differences between males and females. We, therefore, conclude that Streaked Shearwaters exhibit sexual dimorphism in body size and call type. Males are significantly larger than females, and males give high calls whereas females give low calls.

Impact of occult bone marrow involvement on the outcome of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone therapy for diffuse large B-cell lymphoma

Abstract We assessed the prognostic impact of occult bone marrow involvement, determined by flow cytometry and/or polymerase chain reaction, in a population of 117 consecutive patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Twenty-four (20.5%) had morphologically diagnosed and 16 (13.7%) had occult marrow involvement, and 77 (65.8%) had no marrow involvement. Although the pretreatment characteristics of the negative or occult marrow involvement group were similar, severe hematological toxicity after R-CHOP was more frequent in the occult marrow involvement group. Progression-free survival (PFS; p = 0.015) and overall survival (OS; p = 0.035) for the occult marrow involvement group were significantly shorter than those for the negative group, and were comparable to those of the morphologic marrow involvement group, independent of the International Prognostic Index score for PFS. Occult bone marrow involvement predicts severe hematological toxicity and negatively impacts on the PFS and OS of R-CHOP therapy.

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

Expression of Tim‐1 in primary CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is a distinct subtype of extranodal lymphoma with aggressive clinical course and poor outcome. As increased IL‐10/IL‐6 ratio is recognized in the cerebrospinal fluid (CSF) of PCNSL patients, we hypothesized that PCNSL might originate from a population of B cells with high IL‐10‐producing capacity, an equivalent of “regulatory B cells” in mice. We intended in this study to clarify whether Tim‐1, a molecule known as a marker for regulatory B cells in mice, is expressed in PCNSL. By immunohistochemical analysis, Tim‐1 was shown to be positive in as high as 54.2% of PCNSL (26 of 58 samples), while it was positive in 19.1% of systemic diffuse large B‐cell lymphoma (DLBCL) samples (17 of 89 samples; P < 0.001). Tim‐1 expression positively correlated with IL‐10 expression in PCNSL (Cramers V = 0.55, P < 0.001), and forced expression of Tim‐1 in a PCNSL cell line resulted in increased IL‐10 secretion, suggesting that Tim‐1 is functionally linked with IL‐10 production in PCNSL. Moreover, soluble Tim‐1 was detectable in the CSF of PCNSL patients, and was suggested to parallel disease activity. In summary, PCNSL is characterized by frequent Tim‐1 expression, and its soluble form in CSF may become a useful biomarker for PCNSL.

Prognostic impact of activation-induced cytidine deaminase expression for patients with diffuse large B-cell lymphoma

Abstract Activation-induced cytidine deaminase (AID) plays important roles in the development of diffuse large B-cell lymphoma (DLBCL); however, its prognostic value remains controversial. Here, we evaluated AID expression in 71 DLBCL patients treated with R-CHOP by immunohistochemistry and investigated its prognostic significance. AID expression was detected in 40.8% of DLBCL samples and associated with IRF4 expression. Notably, AID expression correlated with shorter progression-free survival and overall survival for patients with high (3–5) international prognostic index (IPI) score. Moreover, it was a strong predictor of poor overall response to salvage therapy after relapse or disease progression, which may suggest its role in promoting the evolution of tumors into highly refractory disease at relapse. Our findings indicate that AID expression effectively discriminates between IPI-high score patients with different survival outcomes, and suggest that initial disease control would be particularly important for the treatment of IPI-high score patients with AID-positive DLBCL.

B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

The Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by Aicda gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8+ T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD8+ T cells specific for inoculated tumor cells, suggesting impaired antitumor T-cell activity. Gene-expression microarray revealed that altered T-cell responses were due to increased IL-33 production by Notch1-activated B cells. Knockout of IL33 or blockade of IL-33 by a receptor-blocking antibody abrogated the Treg and Th2 cell-dominant T-cell response triggered by B cells. Gene-expression data derived from human diffuse large B-cell lymphoma (DLBCL) samples showed that an activated Notch-signaling signature correlates positively with IL33 expression and Treg cell-rich gene-expression signatures. These findings indicate that B cells harboring dysregulated Notch signaling alter T-cell responses via IL-33, and suggest that aberrant activation of Notch signaling plays a role in fostering immune privilege in mature B-cell neoplasms.