Erina Sakamoto

Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2

We have recently demonstrated that granulocyte‐colony stimulating factor (G‐CSF) delays human neutrophil apoptosis via up‐regulation of cellular inhibitor of apoptosis 2 (cIAP2), which is dependent on activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the distinct receptors, exert the antiapoptotic effect on human neutrophils through the similar mechanism. IFN‐α (type I IFN) and IFN‐γ (type II IFN), like G‐CSF, delayed human neutrophil apoptosis through the protein synthesis‐dependent mechanism. Stimulation of neutrophils with IFN‐α or IFN‐γ resulted in tyrosine phosphorylation of STAT1 and STAT3 but not phosphorylation of STAT5, Akt, extracellular signal‐regulated kinase, and p38 mitogen‐activated protein kinase. IFN‐α and IFN‐γ induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl‐1, and A1. IFN‐α‐ and IFN‐γ‐induced up‐regulation of cIAP2 mRNA and protein, phosphorylation of STAT3, and antiapoptotic effect were inhibited significantly by pretreatment of cells with AG490, a specific inhibitor of JAK2. These findings suggest that cIAP2 expression is up‐regulated by IFN‐α and IFN‐γ through, at least in part, activation of the JAK2‐STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN‐α‐ and IFN‐γ‐mediated antiapoptotic effect on human neutrophils.

Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma

BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

Enhanced neutrophil motility by granulocyte colony‐stimulating factor: the role of extracellular signal‐regulated kinase and phosphatidylinositol 3‐kinase

The effect of granulocyte colony‐stimulating factor (G‐CSF) on human neutrophil motility was studied using videomicroscopy. Stimulation of neutrophils with G‐CSF resulted in enhanced motility with morphological change and increased adherence. Enhanced neutrophil motility was detected within 3–5 min after G‐CSF stimulation, reached a maximum at 10 min, and was sustained for approximately 35 min. The maximum migration rate was 84·4 ± 2·9 μm/5 min. A study using the Boyden chamber method revealed that G‐CSF‐stimulated neutrophils exhibited random migration but not chemotaxis. Enhanced neutrophil motility and morphological change were inhibited by MEK [mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) kinase] inhibitors (PD98059 and U0126), and a phosphatidylinositol 3‐kinase (PI3K) inhibitor (wortmannin), but not by a p38 MAPK inhibitor (SB203580). These findings are consistent with the fact that G‐CSF selectively activates MEK/ERK and PI3K, but not p38, in neutrophils. MEK/ERK activation was associated with G‐CSF‐induced redistribution of F‐actin and phosphorylated myosin light chain. Enhanced neutrophil motility was observed even in the presence of neutralizing anti‐CD18 antibody, which prevented cell adherence. These findings indicate that G‐CSF induces human neutrophil migration via activation of MEK/ERK and PI3K.

Prognostic value of serum surfactant protein D level prior to transplant for the development of bronchiolitis obliterans syndrome and idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) and idiopathic pneumonia syndrome (IPS) cause high mortality and impaired survival after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Early recognition of patients at high risk of developing BOS/IPS may lead to improving the outcome of allo-HSCT. We retrospectively analyzed serum surfactant protein A, D (SP-A, -D) and Kerbs von Lungren 6 Ag (KL-6) levels before allo-HSCT in 56 patients who survived more than 90 days after allo-HSCT and compared values of these serum markers and other transplant factors in BOS/IPS patients with those in non-BOS/IPS patients. Five patients developed BOS and two developed IPS at a median interval of 303 and 117 days (range, 100–452 and 95–153) from transplantation. As a result of univariate analysis, pretransplant serum SP-D levels but not SP-A, KL-6 in BOS/IPS patients were significantly lower than those in non-BOS/IPS patients (P=0.03). In multivariate analysis, the patients with lower pretransplant serum SP-D level had a trend toward frequent development of BOS/IPS (P=0.08). Constitutive serum SP-D level before allo-HSCT may be a useful, noninvasive predictor for the development of BOS/IPS.

The prophylactic effect of itraconazole capsules and fluconazole capsules for systemic fungal infections in patients with acute myeloid leukemia and myelodysplastic syndromes: A Japanese multicenter randomized, controlled study

We performed a randomized, controlled study comparing the prophylactic effects of capsule forms of fluconazole (n = 110) and itraconazole (n = 108) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) during and after chemotherapy.There were 4 cases with possible systemic fungal infection in the itraconazole group, and there were 8 possible and 3 probable cases in the fluconazole group. Adverse events did not significantly differ in the 2 groups. In patients with MDS or in the remission-induction phase of chemotherapy, the numbers of cases with probable or possible infections were lower in the itraconazole group than in the fluconazole group, whereas no difference was seen in patients with AML or in the consolidation phase of therapy. In patients with neutrophil counts of <0.1 * 109/L lasting for more than 4 weeks, the frequency of infection in the fluconazole group (5 of 9 patients) was significantly higher than in the itraconazole group (0 of 7 patients; P = .03). Our results suggest that both drugs were well tolerated in patients with AML or MDS who received chemotherapy and that the efficacy of itraconazole for prophylaxis against systemic fungal disease is not inferior to that of fluconazole.

Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan

Recently, empirical antifungal therapy with intravenous itraconazole (ITCZ) for neutropenic patients with antibiotics-resistant fever has been approved by Japanese Ministry of Health, Labour and Welfare on the bases of previous multicenter trials of foreign countries. In this study, we conducted a single-arm, multicenter, prospective study in order to evaluate the efficacy of empirical ITCZ injection on Japanese patients. Sixty-eight patients with hematological diseases who underwent anticancer chemotherapy or stem cell transplantation were enrolled. In this study, we found that the overall clinical response rate to ITCZ injection was 67.6% and success rate of achieving composite endpoints including survival, defervescence during neutropenia, no breakthrough fungal infections, and no premature discontinuation of drug was 50.0%. Mild adverse reactions were observed in 6 patients (8.8%). Further analysis revealed that possible/probable deep fungal infection according to the 2002 and 2008 criteria defined by EORTC/MSG were found in 19.1 and 7.5% of the patients, respectively. Interestingly, response rate to ITCZ injection of possible/probable cases according to the 2002 and 2008 criteria was 61.5% (8/13) and 100% (5/5), respectively. These results not only proved the good efficacy and safety of empirical ITCZ injection for Japanese patients, but also indicated a utility of the drug on future “presumptive” approach.

Analysis of elderly patients with diffuse large B-cell lymphoma: aggressive therapy is a reasonable approach for ‘unfit’ patients classified by comprehensive geriatric assessment

The treatment strategy for diffuse large B‐cell lymphoma (DLBCL) in elderly patients is problematic. Although several researchers have reported the effectiveness of comprehensive geriatric assessment (CGA) and the futility of curative treatment in ‘unfit’ patients with DLBCL, these propositions are not firmly established.

Two cases of ampulla (takotsubo-shaped) cardiomyopathy associated with hemophagocytic lymphohistiocytosis.

There have been many reports of patients with ampulla cardiomyopathy described as takotsubo-shaped cardiomyopathy in the cardiovascular field. This unique cardiomyopathy is characterized by transient apical ballooning and hypokinesis of the left ventricle. We describe 2 cases of ampulla cardiomyopathy associated with hemophagocytic lymphohistiocytosis (HLH). In both of the patients, ventricular dysfunction suddenly occurred during the active phase of HLH. In each case, the findings on ECG, echocardiogram and left ventriculogram were compatible with ampulla cardiomyopathy. To our knowledge, this communication is the first to report cases of ampulla cardiomyopathy associated with HLH. Our cases suggest that HLH hypercytokinemia may have a role in causing ampulla cardiomyopathy.

Extramedullary plasmacytoma of the dura mimicking meningioma

In December 2005, a 59-year-old man presented at ourNeurosurgery Department with a 2-month history ofamnesia and gait disturbance. A solid mass lesion wasdetected in the right temporal region on magnetic reso-nance imaging (MRI), presumed to be a meningioma(Fig. 1). He underwent surgery via a right temporal frontalcraniotomy and partial resection of the mass. Biopsy of themass demonstrated a densely cellular tumor composed ofplasma cells, positive for IgG and kappa light chain(Fig. 2), and negative for lambda chain, CD56 and cyclinD1. These findings were consistent with intracranialplasmacytoma.No additional sites of plasmacytoma were identified oneither computed tomography or bone scintigraphy, and bonemarrow plasmacytosis was absent (1.8% plasma cells,morphologically normal), and bone marrow cells showed anormal karyotype. Serum immunoglobulin levels werealmost normal (IgG 1,374 mg/dL, IgA 443 mg/dL, IgM54 mg/dL, IgE 81 IU/mL, IgD 7.6 mg/dL), and postopera-tive serum protein immunoelectrophoresis showed a smallM-component only (IgG-j). Urine Bence-Jones protein wasnot detected. Other organopathies, such as nephropathy,hypercalcemia and bone region, were absent. Thus, a diag-nosis of extramedullary plasmacytoma was made accordingto the classification of the International Myeloma WorkingGroup (IMWG) [1]. He underwent external beam radio-therapy to the brain at a dosage of 50 Gy, which resulted inthe disappearance of the remaining tumor region.In January 2007, he developed hoarseness and thoracicpain. Since CT scans demonstrated new masses at other sites(rib and vertebral bones), he was diagnosed with diseaseprogression. Laboratory findings showed an increased totalserum protein of 8.6 g/dL, IgG 3,629 mg/dL, and serumprotein immunoelectrophoresis revealed an evidentM-component of IgG-j. Bone marrow examination showedno evidence of plasmacytosis (2.4% plasma cells, withoutatypia) and chromosomal analysis revealed a normalkaryotype. Thereafter, he received several courses of che-motherapy with vincristine, doxorubicin and dexametha-sone. Despite treatment, regrowth of the mass was observed.He refused further therapy and was discharged from ourhospital.Patients with a solitary dural plasmacytoma have beenreported with a female predominance of 84% and a meanage of 50.2 years. Clinically, combination therapy includ-ing surgical resection followed by at least 50 Gy radio-therapy is recommended, and long-term survival has beenobserved. On the other hand, patients with myelomatousmeningeal involvement have shown an extremely poorprognosis despite intensified treatment, including intrathe-cal and/or systemic chemotherapy and cranial radiotherapy[2]. Our patient showed a recurrence almost 1 year after theinitial diagnosis. We consider that postoperative radio-therapy was delayed by about 2 months because of inten-sive care, which might have caused the early recurrence.

BK virus-associated nephropathy in an HIV-positive patient with gingival plasmablastic lymphoma

BK virus (BKV) nephropathy is common after renal transplantation, but less well characterized in patients with human immunodeficiency virus (HIV). Here, we report a rare case of BKV nephropathy in a patient with acquired immunodeficiency syndrome (AIDS)-related plasmablastic lymphoma (PBL). A 32-year-old man was admitted to our hospital with a complaint of gingival swelling in the right lower jaw of 3-month duration in February 2006. He had been diagnosed with an AIDS-related cytomegalovirus (CMV) enteropathy, in January 2006, when his CD4-positive lymphocyte count was 40/lL and HIV RNA viral load was 84000 copies/mL. He had no prior history of homosexuality or drug abuse. Treatment with ganciclovir and highly active antiretroviral therapy (HAART) was begun 1 month before admission to our hospital. On examination, there was a small left anterior cervical adenopathy, but no other lymph node was palpable. Intraorally, a painful outgrowth from the gingiva was present in the right mandibular molar area (Fig. 1). Laboratory values available on admission included a white blood cell count of 2130/lL (76% polymorphonuclear leukocytes, 18% lymphocytes, 5% eosinophils), a hemoglobin concentration of 8.6 g/dL, and platelet count of 367000/lL. Lactate dehydrogenase was 428 IU/L, blood urea nitrogen was 8.8 mg/dL and serum creatinine was 0.78 mg/dL. Urine dipstick indicated neither proteinuria nor glycosuria, and specific gravity was 1.010. The CD4 count was 3/lL, and HIV viral load was 4400 copies/mL. Biopsy sample from the right mandible region showed monomorphic dense proliferation of lymphoid cells with large, central or eccentrically placed nuclei, prominent nucleoli and abundant mitotic figures (Fig. 2). Immunohistochemical stains revealed that the large atypical lymphocytes were positive for CD79a, kappa light chain and CD38, and weakly positive for CD20 and Epstein–Barr virus (EBV) latent membrane protein (LMP). Results were negative for CD3, CD10, lambda light chain and CD138. The proliferation rate, as assessed by Ki-67/MIB-1 staining, was over 90%. EBV was identified by in situ hybridization, but no evidence of human herpes virus-8 (HHV-8) was detected. A diagnosis of PBL was made based on the diagnostic criteria of WHO. Computed tomography (CT) scans of the neck revealed an infiltrative mass in the right mandible with swelling of the soft tissue, and a lymph node (23 9 15 mm) in the left neck. Additional imaging of the chest, abdomen, and pelvis, and bone marrow aspiration were negative for lymphoma. Clinically, he had stage 2 disease. Chemotherapy was begun with cyclophosphamide, doxorubicin, vincristine and prednisolone. After three cycles of chemotherapy, he underwent external beam radiotherapy to the neck at a dosage of 30 Gy, which resulted in the disappearance of the remaining tumor lesion; however, he developed severe cytopenia and kidney dysfunction that serum creatinine progressed from 0.9 to 5.5 mg/dL over a 3-month period. Antiretroviral drugs and ganciclovir were suspected as the etiology, but a trial to M. Manabe (&) Y. Yoshii S. Mukai E. Sakamoto H. Kanashima H. Teshima Department of Hematology, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-Ku, Osaka 534-0021, Japan e-mail: m1153564@med.osaka-cu.ac.jp