Satoko Oka

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.

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.

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.

Minimal-change nephrotic syndrome preceding Hodgkin lymphoma by 5 years with expression of tumor necrosis factor α in Hodgkin-Reed-Sternberg cells ☆

A 76-year-old man developed minimal-change nephrotic syndrome (NS). After treatment with prednisolone failed to induce sustained remission, cyclosporin was added. The NS improved, and prednisolone and cyclosporin doses were gradually decreased. However, he had repeated relapses of the syndrome, and at each relapse, the drug doses were increased. After 5 years, the patient developed left inguinal lymphadenopathy. The histological diagnosis was mixed cellularity classical Hodgkin lymphoma. He received 6 courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), and mixed cellularity classical Hodgkin lymphoma and NS both showed complete response. Although the association between Hodgkin lymphoma and minimal-change NS is well known, the pathogenesis is unknown. To the best of our knowledge, this is the first case report of minimal-change NS associated with Hodgkin lymphoma in which Hodgkin-Reed-Sternberg cells were immunostained for tumor necrosis factor-alpha (TNF-alpha) clearly demonstrating that Hodgkin-Reed-Sternberg produced TNF-alpha and in which the plasma level of TNF-alpha normalized after improvement of Hodgkin lymphoma by chemotherapy. The production of TNF-alpha by Hodgkin-Reed-Sternberg cells might play a key role as a potential mediator of minimal-change NS.

Hypercalcaemia induced by tumour-derived parathyroid hormone-related protein and multiple cytokines in diffuse large B cell lymphoma, not otherwise specified

oedema. The pathogenesis of ARDS is believed to involve diffuse alveolar capillary injury. Activated neutrophils are the major cellular elements that mediate acute inflammation and have been implicated in the pathogenesis of microvascular injury that occurs in ARDS. Interactions between polymorphonuclear neutrophils (PMN) and cytokines play an important role in this process. Proinflammatory cytokines such as IL-6 and TNF-a have been found to prime or activate certain PMN functions. IL-6 is a multifunctional cytokine that is produced during acute inflammatory response. It stimulates neutrophilia and thrombopoiesis and induces the synthesis of acute-phase proteins. Sustained elevations of IL-6 in the plasma and bronchoalveolar lavage of patients with ARDS have been demonstrated and negatively correlated with disease outcome and patient survival. The presence of IL-6 in the lung alone is sufficient to promote PMN infiltration and pulmonary oedema. Recent studies have demonstrated that IL-6 contributes to tissue recruitment of PMN by chemokine induction; however, little is known about the mechanisms involved in IL-6 mediated local chemokine production. IL-6 activated Stat3 may contribute to local chemokine production through transcriptional activation of chemokine genes such as those for IL-8. TNF-a is a monocyte/macrophage-derived cytokine that is known to have a broad range of activities, including tumour cytotoxicity, antiviral effects, and potent inflammatory effects. During the course of ARDS, high levels of TNF-a are present in the blood and alveolar lining fluid. TNF-a affects the functions of PMN and vessel endothelial cells, which play a major role in the pathogenesis of ARDS. TNF-a also activates endothelial phosphodiesterase 2 (PDE2), which sensitises endothelial cells to thrombin, thereby leading to endothelial hyperpermeability. Furthermore, TNF-a increases neutrophil degranulation, superoxide production, and lysozyme release, thereby causing tissue injury. To the best of our knowledge, this is the first case report of ARDS with DLBCL, NOS, showing the lymphoma cells to be immunostained for IL-6 and TNF-a. These proinflammatory cytokines produced by the lymphoma cells might play an important role in the pathogenesis of ARDS associated lung injury in some cases of DLBCL, NOS.

Primary effusion lymphoma of T-cell origin with t(7;8)(q32;q13) in an HIV-negative patient with HCV-related liver cirrhosis and hepatocellular carcinoma positive for HHV6 and HHV8

Dear Editor, A 67-year-old man with chronic hepatitis C since 1981 was found to have a few mass lesions that were detected in an abdominal echogram performed in 2006. Hepatitis C virus (HCV) viremia was confirmed by a quantitative assay of viral load of 7.8 log IU/mL in the plasma (Cobas TaqMan HCV, Roche, Branchburg, NJ). Computed tomography (CT) detected one mass in S6 and another mass in S8 in his liver. On the basis of angiographic findings and liver biopsy, he was diagnosed with HCV-associated liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Lipiodol-transcatheter arterial embolization and percutaneous ethanol injection therapy were administered for the lesions, and HCC relapse was not detected. The patient was admitted in 2008 because of an enlarging abdomen and early satiety. CT scan showed massive fluid accumulation within the peritoneal cavity but there were no new HCC lesions (Fig. 1a). A gallium-67 scintigram revealed abnormal accumulation of the isotope in the abdominal cavity. The results of serological tests for human immunodeficiency virus (HIV), Epstein–Barr virus, and human T-lymphotropic virus 1 were negative. DNA of human herpesvirus (HHV) 6 (>2.0×10 copies/10 cells) and HHV8 DNA (>2.0× 10 copies/10 cells) were detected in peripheral blood leukocytes. The smear preparations showed noncohesive large lymphoma cells with abundant cytoplasm and prominent nucleoli (Fig. 1b). Most lymphoma cells were positive for CD45RO (Clone UCHL 1, DAKO, Carpinteria, CA; Fig. 1c) and negative for CD79a and CD20. The nucleoli of lymphoma cells were positive for latent HHV6 (2002, Thermo Fisher Scientific, Wattham, MA; Fig. 1d) and HHV8 (LN53, Diagnostic BioSystems, Pleasanton, CA; Fig. 1e) infections. Southern blotting revealed a clonal rearrangement of the T cell receptor Jγ chain gene. No clonal rearrangement of the immunoglobulin heavy chain gene was found by Southern blotting. Cytogenetic analysis of GTG banding was performed, where the specimen was cultured at 37°C for 24 h in an RPMI 1640 medium containing 10% fetal calf serum and antibiotics. After adding 0.04 μg/mL colcemide for 16 h, the cell suspension was exposed to 75 mM KCL and fixed with a mixture of methanol and acetic acid (3:1). Spreads of chromosomes were made by dropping the cell suspension onto glass slides S. Nakayama-Ichiyama (*) : T. Yokote :K. Kobayashi : Y. Hirata :N. Hiraoka :K. Iwaki :A. Takayama : T. Akioka : S. Oka : T. Miyoshi : T. Hanafusa Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka 569-0801, Japan e-mail: in1304@poh.osaka-med.ac.jp

Primary cutaneous diffuse large B-cell lymphoma, leg type, with features simulating POEMS syndrome.

A 91‐year‐old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B‐cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS‐like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) were high with the lymphoma cells immunostained positively for VEGF and IL‐6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS‐like syndrome. The findings in this case suggest that the symptoms of POEMS‐like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.

Correlation between flow cytometric identification of CD33-positive cells and morphological evaluation of myeloblasts in bone marrow of patients with acute myeloblastic leukemia

Abstract Determination of the percentage of myeloblasts in bone marrow is important for the evaluation of acute myeloblastic leukemia (AML) and related disorders. Using flow cytometry with a CD45-blast gate (FCM/CD45), 226 bone marrow aspiration samples serially collected from 71 patients with de novo AML were analyzed. Bone marrow smears were evaluated independently by pathologists who did not know the corresponding flow cytometric data in advance. Patients received remission induction followed by consolidation. The CD33+ cell percentages evaluated by FCM/CD45 were strongly correlated to the myeloblast percentages determined by microscopic examination (r=0·8360, p<0·001). When only samples containing leukemic cells demonstrated by chromosomal or fluorescence in situ hybridization (FISH) analysis after induction were evaluated, positive correlations were found between CD33+ cell percentages determined by FCM/CD45 and myeloblast percentages determined by morphology (r=0·672, p<0·001). The identification of CD33+ cells by FCM/CD45 is useful for the evaluation of bone marrow myeloblasts in AML.