Taiji Yokote

Antifungal prophylaxis with micafungin in neutropenic patients with hematological malignancies.

The aim of the study was to assess the antifungal prophylactic efficacy, safety, and tolerability of micafungin, 150 mg daily, and to evaluate the usefulness of monitoring 1,3-β-d-glucan (BG) in neutropenic patients undergoing chemotherapy for hematological malignancies. This investigation was a retrospective, non-randomized study. A group of patients who did not receive systemic antifungal prophylaxis was compared to another group of patients who received micafungin 150 mg daily. All patients admitted with hematological malignancy and undergoing chemotherapy or stem cell transplant were included. The plasma BG level was measured once weekly. The clinical endpoint was the diagnosis of invasive fungal infection (IFI). Antifungal prophylaxis led to a significant decrease in the occurrence of IFI (from 12.3% to 1.5%, p = 0.001). Few severe adverse effects clearly attributable to micafungin were seen. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of BG values >8.9 pg/mL for diagnosis of IFI were 0.90, 0.99, 0.82, 0.99, and 0.99, respectively. Micafungin, 150 mg daily, is an effective and safe drug for antifungal prophylaxis, and monitoring of BG antigenemia is a useful tool for diagnosis of IFI in neutropenic patients with hematological malignancies.

Successful treatment with micafungin of invasive pulmonary aspergillosis in acute myeloid leukemia, with renal failure due to amphotericin B therapy.

Invasive aspergillosis is an important factor in the morbidity and mortality of patients suffering from hematologic disorders treated with chemotherapy. Treatment with amphotericin B is often limited because of toxicity, particularly nephrotoxicity. We describe a case of invasive pulmonary Aspergillus fumigatus infection in acute myeloid leukemia with renal failure due to amphotericin B therapy, which responded to treatment with a new antifungal agent, micafungin. Micafungin appears to be an effective and safe therapy for Aspergillus infections with renal failure due to amphotericin B.

TNF-α expression in tumor cells as a novel prognostic marker for diffuse large B-cell lymphoma, not otherwise specified.

Several cytokines promote malignant cell growth and are therefore believed to contribute to disease aggressiveness. The cytokine tumor necrosis factor-&agr; (TNF-&agr;) acts as a tumor-promoting factor and has been linked to all tumorigenic stages in many cancers. Here, we evaluated 62 lymphoma tissue specimens from patients having diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) by immunostaining with anti–TNF-&agr; antibody. Cytoplasmic TNF-&agr; reactivity in ≥20% of the tumor cells was considered positive. Our results demonstrated that tumor specimens from DLBCL, NOS patients could be divided into 2 types—TNF-&agr; positive (38 cases, 61%) and TNF-&agr; negative (24 cases, 39%)—and that TNF-&agr; positivity in DLBCL, NOS was correlated with poorer overall survival (OS; P=0.0005, log rank test) and progression-free survival (PFS; P=0.0330, log rank test) compared with TNF-&agr; negativity. Cox regression analysis showed that TNF-&agr; expression was a significant prognostic factor for OS (P<0.0001) and PFS (P=0.0323). Regarding OS and PFS, multivariate analysis showed that TNF-&agr; expression in tumor cells was an independent prognostic factor for the International Prognostic Index (IPI). Therefore, TNF-&agr;-positive DLBCL, NOS may constitute a unique subtype of DLBCL, NOS with an aggressive clinical course. The addition of TNF-&agr; expression to the IPI may significantly improve the predictive prognostic value. The therapeutic strategy of DLBCL, NOS patients should be based on correct prognosis; therefore, patients with poor prognoses could be more accurately detected by evaluating both TNF-&agr; expression levels and the IPI.

Vascular endothelial growth factor and interleukin 6 expression by Hodgkin/Reed-Sternberg cells

A 20-year-old Japanese man presented with a 4-month history of progressive fatigue, fever, cervical lymphadenopathy and oedema. Physical examination showed bilateral cervical, axillary, mediastinal and inguinal lymphadenopathy and gynecomastia (top left, computed tomography). The white blood cell count was 12Æ9 · 10/l, haemoglobin concentration 10Æ5 g/dl and platelet count 719 · 10/l. The serum lactate dehydrogenase and C-reactive protein levels were 602 IU/l and 156Æ3 mg/l respectively. Plasma levels of interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) were elevated to 446 pg/ml (normal <4Æ0 pg/ml) and 1710 pg/ml (normal range, 62–707 pg/ml) respectively. A right cervical lymph node biopsy showed nodular sclerosing Hodgkin’s disease (top right). Immunoperoxidase staining showed Hodgkin/ReedSternberg cells to be positive for IL-6 (bottom left) and VEGF (bottom right) antibodies. Following one course of combination chemotherapy, the clinical signs disappeared, the laboratory data normalized and the plasma levels of IL-6 and VEGF decreased to 5Æ0 pg/ml and 100 pg/ml respectively.

Expression of vascular endothelial growth factor by plasma cells in the sclerotic bone lesion of a patient with POEMS syndrome

Sirs: Bone lesions are frequently present in patients with POEMS syndrome [1, 2]. Since solitary bone lesions are often plasmacytomas, they must be aggressively treated with surgery or radiotherapy. We report a case of POEMS syndrome with a solitary bone lesion. In this patient, plasma cells in the osteosclerotic lesion were the source of vascular endothelial growth factor (VEGF). A 42–year-old man developed distal dominant polyneuropathy two months after myocardial infarction. Following the onset of neurological symptoms, he exhibited edema, bristly skin, and swelling of the liver in the abdominal CT. Platelet counts were 822,000/mm, and immunoelectrophoresis demonstrated Mprotein of IgA k. Serum IL-6 and VEGF were measured using standardized ELISA (SRL, Inc., Tokyo, Japan). Although the IL-6 level was normal (2.1 pg/ml. Normal value; <4.0 pg/ml), the serum VEGF level was significantly elevated (18,500 pg/ml). He was diagnosed with POEMS syndrome. However, bone marrow aspiration from the ileum exhibited a normal appearance, and CT of the chest and the abdomen revealed no abnormal lesions, suggesting solitary or extramedullary plasmacytoma. Following steroid pulse therapy, treatment with prednisolone reduced the serum VEGF to 860 pg/ ml with marked improvement of muscle weakness and skin lesions. Although the neuropathy remained clinically stable, he again exhibited edema and bristly skin 9 months after the pulse therapy, and the serum VEGF was increased to 5,120 pg/ml. Bone scintigraphy demonstrated a spot

Pulmonary parenchymal infiltrates in a patient with CD20‐positive multiple myeloma

Abstract:  A 53‐yr‐old woman developed a dry cough after the completion of multi‐agent chemotherapy. The biopsy specimens showed diffuse infiltrates with multiple myeloma (MM) cells. Immunohistochemistry revealed positive staining in MM cells with surface CD20, surface CD38, and cytoplasmic IgG. This report represents the first reported case of pulmonary parenchymal infiltrates in a patient with CD20‐positive MM.

Preferential expression of phosphatidylglucoside along neutrophil differentiation pathway

Phosphatidylglucoside (PtdGlc), a new type of glycolipid, was recently identified. We examined PtdGlc expression in normal blood cells and leukemic cells using an anti-PtdGlc monoclonal antibody, DIM-21. Neutrophils, monocytes, HL-60 cells and a subset of cord blood (CB) CD34+ cells, but not erythroblasts, expressed lipid antigen. PtdGlc was preferentially expressed along the neutrophil differentiation pathway of CB CD34+ cells treated with cytokines and HL-60 cells treated with retinoic acid. PtdGlc expression was not increased in HL-60 cells treated with phorbol ester. CB CD34+ cells contained a population of PtdGlc+ cells, and CB CD34+PtdGlc+ cells produced mainly granulocyte-macrophage colonies and a small number of erythroid colonies. A positive correlation between PtdGlc expression and CD15 expression in leukemic cells from patients with acute myeloblastic leukemia was shown. These results indicate that increasing PtdGlc expression is seen with neutrophil maturation.

Role of mast cells in fibrosis of classical Hodgkin lymphoma

The underlying mechanism of fibrosis in classical Hodgkin lymphoma (CHL) remains uncertain. This study aimed to investigate the association of fibrosis in the lymph nodes of patients with CHL through histological examination of the expression of cytokines associated with fibrosis and mast cell proliferation. Additionally, we sought to determine the degree of mast cell infiltration in a nodular sclerosis subtype of CHL (NSCHL) compared with that in non-NSCHL. We analyzed lymph nodes from 22 patients with CHL, of which eight were of the NSCHL and 14 of the non-NSCHL subtype, using immunohistochemical staining of forkhead box P3 (FOXP3), transforming growth factor (TGF)-β, interleukin (IL)-3, IL-13, and stem cell factor (SCF). Mast cells were positive for TGF-β and IL-13, and FOXP3-positive cells were negative for TGF-β. Only the expression of IL-13 in Hodgkin and Reed–Sternberg (HRS) cells was significantly more frequently observed in NSCHL than that in non-NSCHL (P = 0.0028) and was associated with a higher rate of fibrosis (P = 0.0097). The number of mast cells was significantly higher in NSCHL than that in non-NSCHL (P = 0.0001). A significantly positive correlation was observed between the rate of fibrosis and the number of mast cells (correlation coefficient, 0.8524; 95% CI, 0.6725–0.9372) (P <0.0001). The number of mast cells was significantly higher in the group with IL-13-positive HRS cells than that in the group with IL-13-negative HRS cells (P = 0.0157). Based on these findings, we hypothesize that IL-13 production by HRS cells may lead to fibrosis, and furthermore, promote mast cell proliferation and infiltration. This in turn might further produce the fibrotic cytokines IL-13 and TGF-β, resulting in fibrosis typical of NSCHL.

Expression of tumour necrosis factor‐α and its receptors in Hodgkin lymphoma

mus-associated post-transplant autoimmune hemolytic anemia. Pediatric Transplantation, 10, 358–361. Zhan, P., Tey, S.K., Koyama, M., Kuns, R.D., Olver, S.D., Lineburg, K.E., Lor, M., Teal, B.E., Raffelt, N.C., Raju, J., Levegue, L., Markey, K.A., Varelias, A., Clouston, A.D., Lane, S.W., MacDOnald, K.P. & Hill, G.R. (2013) Induced regulatory T cells promote tolerance when stabilized by Rapamycin and IL-2 in vivo. Journal of Immunology, 191, 5291–5303.

Co‐infection of human herpesvirus‐6 and human herpesvirus‐8 in primary cutaneous diffuse large B‐cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type is a distinct clinicopathological entity found predominantly in elderly women. Compared with primary cutaneous lymphomas of other skin sites, PCLBCL, leg type exhibits a more aggressive behaviour and worse outcome. Thus, after several years of considerable debate, PCLBCL, leg type was determined to be a subtype of diffuse large B-cell lymphoma (DLBCL), and is now recognized as a separate entity by the World Health Organization and the European Organization for Research and Treatment of Cancer consensus classification for primary cutaneous lymphomas (Swerdlow et al, 2008). A 91-year-old woman presented with a rapidly growing, proliferative, cutaneous lesion on her left lower limb. One month later, a swelling developed in her left inguinal region and subsequently on the left side of her neck, for which she was admitted to our hospital. Physical examination revealed a slightly tender, purplish red, erythematous, reticular, focally indurated plaque with irregular borders on her left lower limb. The skin lesion continued to expand and multiple nodules appeared on the surface of the plaque (Fig 1). The results of blood analysis were as follows: white blood cell count, 9Æ58 · 10/l (82Æ8% neutrophils and 10Æ4% lymphocytes); red blood cell count, 3Æ66 · 10/l; haemoglobin, 97 g/l; platelet count, 481 · 10/l; lactate dehydrogenase, 774 iu/l and C-reactive protein, 135Æ3 mg/l. Serological tests for human immunodeficiency virus (HIV) and human T-cell leukaemia virus type 1 were negative. A biopsy specimen obtained from the leg lesion showed diffuse cellular infiltration throughout the dermis and subcutaneous tissue composed predominantly of abnormally large lymphoma cells. The lymphoma cells had oval to round vesicular nuclei with prominent nucleoli (Fig 2A). Immunohistochemical analysis of the tumour cells indicated that they were positive for CD20, CD79A, BCL2, BCL6 and MUM1 and negative for CD3, CD10, CD30 and CD138. The nucleoli of lymphoma cells were positive for human herpesvirus-6 (HHV-6), detected with rat monoclonal antibody 2002 (recognizing the 60/110 kDa envelope glycoprotein of HHV-6) (Thermo Fisher Scientific, Waltham, MA, USA) (Fig 2B), and also positive for human herpesvirus-8 (HHV-8), detected with rat monoclonal antibody LN53 (recognizing the latent nuclear antigen [LNA-1] open reading frame 73 of HHV-8) (Diagnostic BioSystems, Pleasanton, CA, USA) (Fig 2C). Epstein–Barr-encoded RNA in situ hybridization was negative. Southern blot analysis showed clonal rearrangement of the IGH@ gene. Computerized tomography scans revealed lymphadenopathy of the left side of the neck and left inguinal region. Bone marrow aspiration and biopsy yielded normal results. These findings were consistent with the features of PCLBCL, leg type and non-germinal centre B-cell-like subtype (Hans et al, 2004; Swerdlow et al, 2008). Following treatment with two courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), lymphadenopathy disappeared and the patient’s skin lesions showed improvement. Recent studies have demonstrated that HHV-6 and -8 participate in the pathogenesis of a wide range of malignant lymphomas. HHV-6 is a member of the genus Roseolovirus, subfamily Betaherpesvirinae. It is a human lymphotropic virus that has often been detected in acquired immunodeficiency syndrome-related lymphomas and CD30-positive lymphomas, such as Hodgkin lymphoma and angioimmunoblastic lymphadenopathy with dysproteinemia (Luppi et al, 1993; Valente et al, 1996). A possible pathogenic role of HHV-6 in lymphoproliferative disorders has been emphasized by the ability of HHV-6 DNA to transform established NIH 3T3 cells, which in turn form rapidly growing and metastasizing tumours when injected into nude mice (Razzaque, 1990). A gene homologous to the so-called rep gene of human adeno-associated virus type 2 has been identified in the HHV-6 genome (Thomson et al, 1991). The HHV-6 expression of a gene acting as a mode of heterologous gene expression and cellular transformation is likely to have important consequences for infected host cells (Araujo et al, Fig 1. Clinical presentation of the tumour on the left lower limb on admission. Correspondence