Hideyuki Nakazawa

Torsion analysis in the early detection of anthracycline-mediated cardiomyopathy

AIMS Anthracyclines have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Early detection of subclinical left ventricular (LV) dysfunction following a low dose of anthracyclines may be a preventive strategy. The aim of this study was to determine torsion analysis using two-dimensional speckle-tracking imaging (STI), useful for detecting early anthracycline-mediated cardiotoxicity. METHODS AND RESULTS Conventional and Doppler echocardiography images were obtained from 25 patients (mean age 58 ± 11 years) before chemotherapy and 1 and 3 months after treatment. The cumulative anthracycline doses were 98 ± 59 and 170 ± 87 g/m(2) at 1 and 3 months, respectively. After standard echocardiography, LV torsion and twisting velocity profiles from apical and basal short-axis images were analysed using STI. LV dimensions and ejection fraction did not change throughout follow-up. Although isovolumic relaxation time showed prolongation 3 months after chemotherapy, other Doppler indices did not show significant changes. However, significant deteriorations in torsion (P < 0.0001 by ANOVA), twisting rate (P < 0.0001 by ANOVA), and untwisting rate (P < 0.001 by ANOVA) were found 1 month after chemotherapy. A significant negative correlation was observed between cumulative anthracycline doses and torsion (r = -0.524, P < 0.0001). CONCLUSION LV torsion analysis could be a useful non-invasive approach for early detection of subclinical anthracycline cardiotoxicity.

Significance of chemokine receptor expression in aggressive NK cell leukemia

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.

Promising approach for aggressive NK cell leukaemia with allogeneic haematopoietic cell transplantation

Objectives:  Aggressive natural killer cell leukaemia (ANKL) is a malignant disorder of mature NK cells with a poor prognosis, for which no effective therapeutic approach has been established. We investigated the role of allogeneic haematopoietic cell transplantion (allo‐HCT) in ANKL.

Neutrophilic dermatoses with acute myeloid leukemia associated with an increase of serum colony-stimulating factor

We report a case of acute myeloid leukemia with folliculitis, Sweets syndrome, and neutrophilic panniculitis after remission induction chemotherapy for acute myeloid leukemia. The level of endogenous granulocyte colony-stimulating factor was closely associated with disease activity.

Intestinal diffuse large B-cell lymphoma associated with celiac disease : A Japanese case

Intestinal non-Hodgkin’s lymphoma (NHL), especially the T-cell type, is well known to be associated with celiac disease (CD), an enteropathic disorder with a propensity for certain racial and genetic backgrounds. CD is typically characterized by gastrointestinal (GI) symptoms, anti-transglutaminase antibodies in the sera, and microscopical findings of the intestinal mucosa, which resolve with a gluten-free diet (GFD). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. We describe a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient’s lymphoma has been in a state of complete response, and his GI symptoms have improved with a GFD. This case suggests that the possibility of CD and its association with intestinal NHL should be kept in mind, even in Asian populations.

Induction of Polyploidization by Jaspamide in HL-60 Cells

Jaspamide, a natural peptide isolated from the marine sponge Hemiastrella minor, was used in the study of polyploidy in HL-60 cells. Jaspamide at 5 × 10–8 M concentration exhibited antiproliferative activity and an increased CD4 and CD14 surface expression. After 2 days of cultivation, 56.3% of the exposed cells became multinuclear compared with 2.4% in controls. Moreover, the size and the number of nuclei of the cells increased in a time-dependent manner. An increased number of metaphase chromosomes was observed by microscopical enumeration after colcemid treatment for 60 min. The analysis of the DNA content of these cells, measured by propidium iodide staining, revealed a significant increase in the cells percentage with increased DNA content. Taken together, these findings indicate that the jaspamide treatment induces polyploidization in the HL-60 cell line.

Screening Tests Using Serum Tissue Transglutaminase IgA May Facilitate the Identification of Undiagnosed Celiac Disease among Japanese Population

The prevalence of celiac disease (CD) among Japanese population has been unknown, whereas it has been increasingly recognized in the US and in the European countries. The aim of the present study is to identify possible cases with CD among Japanese population and clarify the relevance of screening for the disease. We conducted a serologic screening for the disease among 710 Japanese patients and 239 healthy volunteers at a local tertiary teaching hospital, using an anti-tissue transglutaminase IgA (TTG-IgA) test, and histological examination of the small intestines from the TTG-IgA positive subjects. There were no TTG-IgA positive sera among the healthy volunteers. Twenty of the patients (2.8%), including eight with malignant lymphoma, were tested positive for TTG-IgA. The histological examination of the eleven patients among those with positive TTG-IgA, seven showed villous atrophy and partial lymphocytes infiltration in the mucosa, which could be compatible to mucosal changes observed in CD. Five of them had non-Hodgkin lymphoma in the gastrointestinal tracts. Serologic tests using TTG-IgA might be relevant to screen for those with undiagnosed CD among Japanese population.

Spliceosome-related gene mutations in myelodysplastic syndrome can be used as stable markers for monitoring minimal residual disease during follow-up.

Various gene mutations have been reported in patients with myelodysplastic syndrome (MDS). Serial studies of mutations during follow-up are important for investigating the stability of the mutations for use as minimal residual disease (MRD) markers. Sequential quantitative analyses of 5 patients with spliceosome-related gene mutations by allele-specific quantitative polymerase chain reaction revealed that the U2AF1 S34F and SF3B1 K666N were persistently retained during the disease progression. The spliceosome-related gene mutations appear to be stable during disease progression and may be useful as potential markers for MRD monitoring in MDS patients that usually lack established specific MRD markers.

Late relapse of extranodal natural killer/T cell lymphoma, nasal type, after more than ten years

Extranodal NK/T cell lymphoma, nasal type (ENKL) is a malignant lymphoproliferative disorder of NK cells characterized by an invasive nature with vascular damage and necrosis [1–3]. The upper aerodigestive tracts, especially nasal cavities, are commonly involved (the nasal type), and in minor populations, other sites such as the skin, intestines, or soft tissues other than the aerodigestive tracts are the main invasive sites (extranasal type). ENKL is more prevalent in Asians and Central Americans, and a lower incidence among Caucasians is recognized. ENKL is also characterized by a strong association with Epstein-Barr virus (EBV). The clinical outcome of ENKL varies depending on the involved site and clinical stage, and the prognosis is considerably worse than that of other lymphomas, although the recent therapeutic progress including in concurrent chemoand radiotherapy against limited-stage nasal type ENKL and the introduction of hematopoietic cell transplantation (HCT) might improve the outcome [4–6]. Some cases of ENKL have been known to relapse after a long duration of complete response [7,8]; however, the biological mechanisms of ENKL including those of such cases are still unknown. Here, we report three Japanese cases of ENKL who relapsed after a period of longer than 10 years of complete response after the initial treatment. Case one was a 44-year-old male who had suffered from intermittent nasal discharge and was diagnosed with non-Hodgkin lymphoma, diffuse pleomorphic type, with clinical stage IIE in 1991. He had received combination chemotherapy of methotrexate (MTX), doxorubicin (ADR), cyclophosphamide (CY), vincristine (VCR), and bleomycin (MACOP-B) and local irradiation. He achieved complete response (CR) and had been well until 2007, when he noticed hoarseness and was found to have a paralaryngeal tumor. The tumor was diagnosed as ENKL with positivity for cytoplasmic CD3, CD56, TIA1, granzyme B, and EBV by immunohistochemical studies and in situ hybridization, respectively. He needed trachostomy for bronchial obstruction, and multiple skin lesions also developed. He was administered carboplatin, etopside, ifosdamide (IFO), and dexamethasone, with no improvement, so he was also given cytosine arabinoside, IFO, MTX, and L-asparaginase. He reached CR after three courses of chemotherapy. Months later, he died of exacerbation of his ENKL. Re-examination of the histological specimen of the primary lesion taken in 1991 revealed identical morphological features and the same immunophenotypes and EBV positivity as the relapsed lesions. He was clarified as having had a relapse of ENKL after 16 years. The second case was a 36-year-old female who was diagnosed with, diffuse, medium sized, NHL, which was positive for CD45RO and negative for CD20, in a right nasal tumor in 1989. She received four courses of MACOP-B and 50 Gy involved field irradiation (IFR). She had maintained a CR until

Donor lymphocyte infusion for extranodal NK/T cell lymphoma, nasal type, relapsed after allogeneic hematopoietic SCT.

Extranodal NK/T cell lymphoma, nasal type (ENKL), is a rare type of non-Hodgkins lymphoma derived from natural killer (NK) cells in most cases and is closely associated with EBV.1 Nasal ENKL of limited stage has a relatively good prognosis when treated with high-dose radiotherapy with chemotherapy; however, in refractory or relapsed cases, the prognosis is dismal.2 Allogeneic hematopoietic cell transplantation (HCT) has been performed for a limited number of cases of ENKL, which led to a cure in some.3 Graft-vs-lymphoma (GVL) effects are possible in these cases, although anti-lymphoma effects of drugs or irradiation in the conditioning regimens are not excluded.