Wataru Kishimoto

First case report of sepsis caused by Mycobacterium wolinskyi in chronic myelogenous leukemia.

Infections caused by Mycobacterium wolinskyi have rarely been reported, and essentially all were cellulitis and/or osteomyelitis related with traumatic event or surgical wound. Here, we present the 1st case of septic complication due to this organism in a patient with chronic myelogenous leukemia of the 1st but late chronic phase.

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.

Multiple Myeloma Presenting with Autoimmune Autonomic Ganglionopathy

Autoimmune autonomic ganglionopathy is an autonomic disorder that occurs as a symptom of paraneoplastic neurological syndrome. To date, there have been no reports on multiple myeloma with autoimmune autonomic ganglionopathy. A 37-year-old Japanese woman suffered from orthostatic hypotension was diagnosed with multiple myeloma (IgG kappa type), and a serological examination revealed the presence of anti-ganglionic nicotinic acetylcholine receptor (anti-gAChR) antibodies. She was treated for multiple myeloma, as a result, the autonomic disturbance improved and her anti-gAChR antibody titer decreased to undetectable levels, despite the fact that she only achieved a partial remission of multiple myeloma. Treatment for multiple myeloma may improve autoimmune autonomic ganglionopathy.

Dose-Modified Ifosfamide, Epirubicin, and Etoposide is a Safe and Effective Salvage Therapy with High Peripheral Blood Stem Cell Mobilization Capacity for Poorly Mobilized Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma Patients

A dose modified ifosfamide, epirubicin, and etoposide (IVE) regimen was prospectively assessed for its efficacy in mobilizing peripheral blood stem cells for autologous transplantation. Two patients with Hodgkins lymphoma and two with non-Hodgkins lymphoma who were undergoing stem cell therapy were studied. All patients had a history of multiple treatments with insufficient stem cell mobilization. The dose modified IVE regimen consisted of ifosfamide 3 g/m(2) intravenously (IV) administered on days 1-2 in combination with epirubicin 50 mg/m(2) IV on day 1 and etoposide 200 mg/m(2) (100 mg/m(2) in two patients with complete remission) IV on days 1-3. The ifosfamide dosage was reduced to two-thirds of the original protocol. A substantial high yield of CD34(+) cells was achieved when patients were treated with a dose-modified IVE regimen, compared with that during the previous regimen (two with the ifosfamide, carboplatin, and etoposide [ICE] regimen, one with high-dose cyclophosphamide and one with the original IVE regimen). Two patients who had refractory and residual disease received a 200 mg/m(2) dose of etoposide, which resulted in tumor reduction (one patient with complete remission and one with further reduction in tumor size). After the IVE regimen, all four patients had a sufficient yield of CD34(+) cells in total, which was available for stem cell transplantation. Hematological and non-hematological toxicities were comparable in all regimens. This single-center prospective study demonstrated that the dose-modified IVE regimen can be used as a safe treatment with high mobilizing efficacy in heavily pretreated lymphoma patients.