Rie Kuroda

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

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.

Effective Prophylaxis Against Various Adverse Events from Mitochondrial Cytochrome b Gene Mutation Triggered by Transplant-Related Chemotherapy and Immunosuppressants.

To the Editor: Chemotherapy and hematopoietic stem cell transplantation (HSCT) are the major components of treatment for hematological malignancy, but often cause critical side effects or may reveal an occult genetic deficiency. Early recognition and supportive therapy for genetic abnormality would allow successful HSCT as in the case described here. A 10-year-old male with early T-cell precursor leukemia (ETP T-ALL) developed headache, hypertension, loss of consciousness, and seizures during chemotherapy according to the Children’s Cancer and Leukemia Study Group (CCLSG) ALL2004 protocol. [1] Magnetic resonance imaging demonstrated typical findings for posterior reversible encephalopathy syndrome (PRES), as well as restricted diffusion areas on his right occipital lobe, which is atypical for PRES.Moreover the patient hadmarked hyperglycemia (316mg/dl) and lactic acidosis (70mg/dl). Although he recovered completely, hyperlactacidemia recurred whenever the patient received subsequent chemotherapy. Therefore, we suspected that he had some sort of mitochondrial disease. Whole mitochondrial genome sequencing from peripheral blood leukocytes identified a heteroplasmic 15500G>A mutation in the cytochrome b gene, resulting in the replacement of an aspartic acid with an asparagine (D252N). As D252N has not been described in the human mitochondrial genome database (MITOMAP) (http://www.mitomap.org/MITOMAP) to date, web-based algorithmic programs were applied to predict the effect of amino acid substitution on mutated protein function. All four utilized programs [PolyPhen-2 (http://genetics.bwh.harvard. edu/pph2/), PMut (http://mmb2.pcb.ub.es:8080/PMut/), SIFT (http://sift.jcvi.org), and Mutation Taster (http://www.mutationtaster.org)] suggested that this substitution was a pathological mutation. Thepatient underwent allogeneicHSCTduring his first remission because ETP T-ALL had been recognized as very poor-prognostic leukemia[2] and because his early steroid response was poor. Coenzyme Q10 was administered for prevention of complications from the cytochrome b abnormality thatmight be triggered byHSCT. Although several supplements have been tried, only Coenzyme Q10 and its analogs have been shown to produce clinical improvement in some patientswith certain types ofmitochondrial disorders, probably due to restoration of mitochondrial respiratory chain function.[3] He exhibited noneurological symptoms duringHSCT, and remains alive in complete remission. Cytochrome b is one of the subunits of mitochondrial complex III, and a variety of clinical presentations derived from its mutations have been reported, such as Leber hereditary optic neuropathy, encephalopathy, cardiomyopathy, myopathy, and hyperlactacidemia.[4] Recently the heteroplasmic 15059G>A mutation in the mitochondrial cytochrome b gene was found to be associated with a higher risk of essential hypertension in patients with type 2 diabetes.[5] Taken together, the heteroplasmic mutation in the cytochrome b gene could have predisposed the patient to PRES-like encephalopathy. Mitochondrial disorders should be considered when patients present with atypical symptoms during chemotherapy, especially PRES-like encephalopathy or hyperlactacidemia. When interpreting the role of newly-identified genetic mutations, functional assays should ideally be performed for each gene mutation, although this might be difficult in the clinical setting. The use of web-based programs for mutated proteins might be the most practical way to avoid problems from genetic deficiencies in such situations.

Right homonymous hemianopsia following allogenic haematopoietic stem cell transplantation

A 16-yr-old boy with a history of allogenic haematopoietic stem cell transplantation (HSCT) from an unrelated donor for acute T lymphoblastic leukaemia at age 12 presented with acute-onset painless bilateral loss of right field vision. Visual fields showed a right homonymous hemianoptic defect with no macular sparing. Magnetic resonance imaging (MRI) of the left optic tract revealed hyperintense signals (Fig. 1A and B). No leukaemic relapse was identified in the central nervous system (CNS) or bone marrow. Cerebrospinal myelin basic protein levels were elevated with no oligoclonal bands. Serological autoantibodies were negative. Intravenous methylprednisolone treatment showed significant improvement on MRI. Four weeks later, acute blurring of vision recurred and MRI revealed exacerbation extending from the chiasm to bilateral optic tracts (Fig. 1C and D). Repeated intravenous methylprednisolone and immune globulin brought rapid recovery of visual acuity and MRI findings. Following oral dexamethasone and cyclosporine A treatment, no recurrence was observed on MRI in follow-up at 8 months. Homonymous hemianopsia occurs frequently in stroke and traumatic brain injuries. In this case, although the underlying mechanisms remain unclear, a post-HSCT autoimmunity mechanism similar to multiple sclerosis or CNS graft-versus-host disease was suspected.