Hideaki Maeba

A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity.

To test the hypothesis that analyses of drug targets for polymorphism will help to establish gene-based information for the treatment of cancer patients, we investigated the functional single-nucleotide polymorphisms in the human cytidine deaminase (HDCA) gene. The cDNAs from 52 leukaemia/lymphoma samples and 169 control blood samples were direct-sequenced and analysed for the polymorphisms. Three different polymorphisms (A79C, G208A and T435C) were identified in the coding region of the HDCA gene and displayed allelic frequencies of 20.1%, 4.3% and 70.1%, respectively. No association with susceptibility to disease was observed. A novel polymorphism, G208A produced an alanine to threonine substitution (A70T) within the conserved catalytic domain. By introduction of the polymorphic HCDA genes into the yeast CDA-null mutants, the HCDA-70T showed 40% and 32% activity of prototype for cytidine and ara-C substrates, respectively (P < 0.01). The ara-C IC50 value of the yeast transformants carrying HCDA-70T was 757 +/- 33 micromol and was significantly lower (P < 0.01) than that of prototype (941 +/- 58 micromol). This study demonstrated a population characterized with 208A genotype for, which potentially leads one more sensitive to ara-C treatment than prototype. Accumulation of polymorphisms in the genes responsible for drug metabolism and determination of polymorphism-induced biological variations could provide the additional therapeutic strategies in risk-stratified protocols for the treatment of childhood malignancies.

Reactive Peripheral Blood Plasmacytosis in a Patient with Acute Hepatitis A

Reactive plasmacytosis is a transient expansion of plasma cell progenitors and precursors. This rare condition has been reported to occur mainly in infections and tumors. We describe a case of acute hepatitis A presenting with marked peripheral blood plasmacytosis. Plasma cells made up 27.5% of the mononuclear cells and had the immunophenotype CD10-CD19+CD20-CD21-CD23-CD34-CD38++HLA-DR+. Although the level of interleukin 6 was not increased, the presence of activated T-cells with an inverted CD4/CD8 ratio and high levels of soluble interleukin 2 receptor and neopterin indicated a marked immune response to acute hepatitis A. The patient’s plasma cells had almost disappeared from the blood by hospital day 16. This report may represent the first described case of reactive peripheral blood plasmacytosis in acute hepatitis A.

Massive hyper-reactive hematopoietic nests in bilateral iliac bones in a patient with mild aplastic anemia

To the Editor: We encountered a patient with aplastic anemia (AA) whose bone marrow (BM) specimens showed hypercellular marrow with slight dysplastic signs, because relatively massive hematopoietic nests were retained in limited areas, especially in BM biopsy sites. In this situation, it seemed to be hard to think of AA in a differential diagnosis. A 14-year-old male was found to have mild pancytopenia. His complete blood count showed a red blood cell count of 3.24 10/L, hemoglobin level of 11.0 g/dL, MCV of 96.9 fL, and a reticulocyte count of 38 10/L. White blood cell count was found to be 2.85 10/L with a differential count of 36% neutrophils, 58% lymphocytes, 1% eosinophils, 1%

Pathognomonic serum cytokine profiles identify life-threatening langerhans cell histiocytosis.

Keywords: Langerhans cell histiocytosis; cytokine profile; IL18; sTNFR ; haemophagocytic syndrome

Intermittent X-linked thrombocytopenia with a novel WAS gene mutation

X‐linked thrombocytopenia (XLT) is caused by mutations in the WAS gene and characterized by thrombocytopenia with minimal or no immunodeficiency. Patients with XLT usually exhibit persistent thrombocytopenia, and intermittent thrombocytopenia has been described only in two families. Here, we report a patient with intermittent XLT carrying a novel missense mutation (Ala56Thr). He showed residual expression of Wiskott–Aldrich syndrome protein in the lymphocytes and platelets. There appeared to be an association between normal platelet numbers and a post infectious state. Our findings further support the importance of analysis of Wiskott–Aldrich syndrome protein in male patients who exhibit fluctuating courses of thrombocytopenia. Pediatr Blood Cancer 2014;61:746–748.

Salvage allogeneic stem cell transplantation in patients with pediatric myelodysplastic syndrome and myeloproliferative neoplasms

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable approach for myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN); however, the event‐free survival rate of patients with pediatric MDS and MPN is still only approximately 60%. Although salvage HSCT is the only curative approach for patients with the failure of previous HSCT, its safety and efficacy have yet to be determined.

Hearing impairment accompanied with low-tone tinnitus during all trans retinoic acid containing chemotherapy

To the Editor: All trans retinoic acid (ATRA), a derivative of vitamin A, is a major component of treatment for acute promyelocytic leukemia (APL), but often causes side effects such as ATRA syndrome and intracranial hypertension (ICH). We describe the first case of APL with hearing impairment accompanied with low-tone tinnitus, probably as a side effect of ATRA. A 12-year-old nonobese female patient with APL achieved complete remission (CR) by induction chemotherapy including ATRA. Subsequently, she received multidrug chemotherapy (ATRA 45mg/m2 daily PO, days 4–10, cytarabine IV, days 1–3, mitoxantrone IV, day 1, triple intrathecal therapy [methotrexate, cytrabine, hydrocortisone], day 1) and chemoprophylaxis (fluconazole and trimethoprimsulfamethoxazole). Cerebrospinal fluid opening pressure was elevated (27 cm H2O) but biochemical and cytological findings were normal. She presented with headache and nausea from day 9 and was treated with dexamethasone (DEX). Her symptoms improved immediately and DEX was ceased on day 14. On day 20, she complained of low-tone tinnitus in the right ear with a slight headache and nausea, without vertigo and nystagmus. Pure tone audiometry revealed low-frequency sensorineural hearing loss in the right ear. DEX was restarted and her tinnitus gradually resolved. Pure tone audiometry normalized on day 30. She maintained CR and had no relapse of hearing symptoms by prophylactic use of DEX in the following consolidation phase including ATRA. Although the pathogenesis of ATRA-associated ICH remains uncertain, ATRA and its metabolites are thought to influence intracranial pressure through perturbation of the blood–brain barrier and the structures involved in the production and drainage of cerebrospinal fluid.1 The incidence of ATRA-induced ICH is less than 1% in adults, while it is as high as 10% in children.2 Age-related changes in responses to ATRA stimulation or reduction of RARA receptor expression have been posited to explain this difference.1 Therefore, globally ATRA in childhood APL treatment has been shifted to lower dose (25mg/m2).3–5 ATRA-relatedhearing impairment associatedwith ICHhasnotbeen reportedbefore.However, this clinical phenomenon is perhapsnot surprising because idiopathic ICH causes low-tone tinnitus in response to the spread of ICH via perilymph fluid in the cochlear canal that connects the intracranial cavity to the inner ear, leading to an imbalance of internal and external lymph.6 Though it is not clear how long ICH persists after cessation of ATRA treatment, in a previously reported case of vitamin A-induced ICH, papilledema was slow to improve after vitamin A cessation even though severe symptoms such as headache improved rapidly.7 This suggests that mild-to-moderate ICH without symptoms could linger for some time after vitamin A cessation. Similarly, in our case mild ATRA-associated ICH might have persisted and caused tinnitus later. Hearing symptoms caused by ICH are generally reversible. However, neurological outcomes can sometimes be worse if therapy is not started promptly.8,9 As children seldom complain of tinnitus spontaneously,10 careful observation of pediatric APL patients is warranted to avoid irreversible neurological damagedue toprolongedmild ICH.

Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript

Yasuhiro Ikawa , Ryosei Nishimura, Hideaki Maeba, Toshihiro Fujiki , Rie Kuroda, Kazuhiro Noguchi, Masaki Fukuda, Shintaro Mase, Raita Araki, Yusuke Mitani, Tomohiko Sato, Kiminori Terui, Etsurou Ito, Issay Kitabayashi and Akihiro Yachie Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori Prefecture, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan

Improvement of refractory acyclovir-resistant herpes simplex virus type 1 infection by continuous acyclovir administration

Resistant herpes simplex virus type 1 (HSV-1) infection is sometimes fatal for immunocompromised patients. Here, we report 10-year-old girl receiving hematopoietic stem cell transplantation developed refractory HSV-1 infection, which was persisted to intermittent acyclovir (ACV) or foscarnet (FOS) administrations but was improved by continuous ACV administration. The isolates from the lesion were identified with low susceptibilities to ACV and FOS by plaque reduction assay due to DNA pol gene mutation. Continuous ACV administration overcomes the efficacy of intermittent administration and could be the best option to treat severe HSV-1 infectious patients.

A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter helps diagnose immune thrombocytopenia (ITP)

Various disorders cause severe thrombocytopenia, which can lead to critical hemorrhage. Procedures that rapidly support the diagnosis and risk factors for serious bleeding were explored, with a focus on immune thrombocytopenia (ITP). Twenty-five patients with thrombocytopenia, including 13 with newly diagnosed ITP, 3 with chronic ITP, 6 with aplastic anemia (AA), and 3 with other thrombocytopenia (one acute myeloid leukemia, one acute lymphoblastic leukemia, and one hemophagocytic lymphohistiocytosis), were reviewed. In addition to platelet-related parameters obtained by an automated hematology analyzer, flow cytometric analysis of platelets was performed. A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter, which is specific to ITP, but not other types of thrombocytopenia, was found. CD62P-positive platelets were increased in newly diagnosed ITP cases compared to control (P < 0.0001), AA (P = 0.0032). Moreover, detection of dramatic changes in these parameters on sequential monitoring may suggest internal hemorrhage, even absent skin or visible mucosal bleeding. The bleeding score for visible mucosae had a negative correlation with platelet count and a positive correlation with immature platelet fraction (%), forward scatter, and CD62P. This characteristic flow cytometric pattern makes it possible to distinguish ITP from other thrombocytopenic disorders.