Yasuhiro Ikawa

Expansion of activated eosinophils in infants with severe atopic dermatitis

Abstract  Background : There is increasing concern in Japan over infants with atopic dermatitis (AD) who present with severe systemic complications, such as hypoproteinemia, electrolyte disturbances, and delayed growth and development. They are often associated with extremely increased numbers of circulating eosinophils. However, the clinical significance of eosinophil expansion has not been thoroughly investigated.

Dense methylation of types 1 and 2 regulatory regions of the CD10 gene promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene.

Infant acute lymphoblastic leukemia (ALL) displays distinct biologic and clinical features with a poor prognosis. The CD10-negative immunophenotype of infant ALL is a hallmark and provides a predictable signature of mixed-lineage leukemia (MLL) rearrangement. Although CD10 negativity reflects an earlier stage of B-cell development, complete IgH gene rearrangements (VDJH), found in almost half of the patients, show more mature IgH status. Discordance between immunophenotype and genotype of infant ALL suggests an aberrant process in immunophenotypic steps of differentiation or a secondary down-regulation of CD10 expression. In this study, CD10-negative infant ALL with MLL/AF4, CD10-positive infant ALL with germline MLL, CD10-positive pre-B ALL cell line, infant acute myeloid leukemia (AML; M5) with MLL/AF9 and pediatric AML (M2) with AML1/ETO were analyzed for VDJH status and methylation of CD10 gene promoters. Three of the 4 infant ALL samples showed complete rearrangements of the VDJH gene with productive joints. Bisulfite sequencing of CD10 type 1 and 2 promoters showed that more than 84% of the cytosine-phosphate-guanine (CpG) dinucleotides identified were methylated in all 3 CD10-negative infant ALL samples with MLL/AF4. The CpG dinucleotides distributed in the clusters of putative Sp1-binding sites and functionally active regulatory regions of the promoters were fully methylated. In contrast, none of the CpG dinucleotides were methylated in the CD10-positive ALL samples. Structural evidence of dense methylation in the CD10 gene promoter suggested that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism.

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.

Leopard skin appearance of cutaneous polyarteritis nodosa on 18Ffluorodeoxyglucose positron emission tomography

An 8-year-old girl was referred to us with fever, erythematous papules and painful subcutaneous nodules located over her extremities and bilateral arthritis of the ankles and knees. Laboratory findings revealed leucocytosis (13 410/mm) and elevated CRP concentration (1.4 mg/dl) and ESR (61 mm/h). MRI of the thighs revealed multiple high-signal nodular lesions throughout the subcutaneous tissue and subfascial muscle tissue of the thighs. F-Fluorodeoxyglucose PET (F-FDG-PET) revealed a unique, leopard skin appearance with multiple, disseminated hot spots throughout the muscle and subcutaneous tissue in upper and lower extremities (Fig. 1). A skin biopsy of a subcutaneous nodule revealed necrotizing vasculitis. The diagnosis of cutaneous PAN was made. She was treated with prednisolone and maintained on ciclosporin and monthly infusions of CYC. F-FDG-PET is a promising new technique to evaluate metabolic activity, with F-FDG accumulations in cells that have a high rate of glycolysis [1]. Increased uptake of F-FDG is observed in vasculitis lesions with infiltrations of inflammatory cells [2]. In this patient, F-FDG-PET revealed a unique, leopard skin appearance with multiple, disseminated hot spots throughout the muscle and subcutaneous tissue. These findings indicate that F-FDG-PET is useful for the evaluation of the extent and location of inflammation in patients with cutaneous PAN.

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

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

Monoblastic sarcoma of the kidneys in an infant leukaemia.

An 8-month-old Japanese boy was diagnosed with acute monocytic leukaemia [AMoL, M5b according to French–American–British (FAB) classifications] with t(9;11)(p22;q23). Abdominal magnetic resonance imaging demonstrated a homogeneous solid mass (25 · 36 · 25 mm) in the upper pole of the left kidney (Fig. 1A) and a cortical mass (diameter, 10 mm) in the lower portion of the right kidney. Renal masses were hypointense relative to renal cortex on both T1and T2weighted imaging, with weak homogeneous gadolinium enhancement. Histopathological examination of creamcoloured biopsy sections revealed diffuse infiltration of cells surrounding intact glomeruli in the renal parenchyma (Fig. 1B). Predominant monoblastic features were shown on imprints (Fig. 1C). Fluorescence in situ hybridisation and Southern blot analyses identified the rearrangement of mixed-lineage leukaemia (MLL) gene, confirming a diagnosis of monoblastic sarcoma of the kidney. Monoblastic sarcoma is a less-common form of myeloid sarcoma, and may precede or occur concurrently with AMoL with 11q23/MLL rearrangements. Any part of the body can be involved, but renal involvement is rare and no cases of infants have previously been reported. In cases such as the present, pathologically confirmed diagnosis is essential to establish appropriate therapeutic strategies, as the differential diagnosis could include primary renal tumours.

Immunostaining of Sulfatide-Storing Macrophages in Gallbladder of a Patient With Metachromatic Leukodystrophy

To the Editor: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency in arylsulfatase A, leading to accumulation of sulfatide, mainly in neural tissues.1 Lysosomal storage of sulfatide also occurs in visceral organs such as the gallbladder, which is known to the lethal complication as hemobilia.2 The pathological findings of hemobilia have previously been reported as hyperplastic epithelium, thickened mucosa, and infiltration of macrophages bearing metachromatic material in submucosal tissue. Several reports have demonstrated accumulation of sulfatide as a metachromatic appearance on toluidine blue staining or cytoplasmic lamellated material under electron microscopy.2,3 However, metachromasia on toluidine blue staining suggests the presence of either sulfatide or mucin. Despite the biological importance in MLD, attempts to visualize sulfatide specifically in tissue sections have not been reported so far. Here, we describe the pathologic findings of gallbladder alteration in a six-year-old boy with MLD using immunostaining with antigalactocerebrosidesulfatide (anti-GalC-SUL) antibody. A six-year-old boy, who had been diagnosed with MLD at age two years after deterioration of motor and mental performance, presented to our hospital after developing a black stool. He was pale and tachycardic (heart rate, 164 beats per minute). Blood pressure was within the normal range (88 50 mm Hg). Blood testing revealed severe anemia (hemoglobin, 4.0 g dL) and hypoproteinemia (total protein, 5.1 g dL). Abdominal ultrasonography demonstrated dilatation of intrahepatic bile ducts and diffuse thickening wall of the gallbladder. Gastrointestinal fiber revealed active bleeding through the ampulla of Vater (Figure A). The patient underwent emergency cholecystectomy to resolve active hemobilia. The gallbladder was enlarged and bleeding from the thickened gallbladder wall. Postoperatively, anemia was improved and no episodes of rebleeding were seen. On gross examination the gallbladder wall was markedly thickened, but the mucosal surface was smooth. Clear and

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.