Takuya Nakatani

Successful treatment of congenital systemic juvenile xanthogranuloma with Langerhans cell histiocytosis-based chemotherapy.

Abstract: Juvenile xanthogranuloma (JXG), one of the most common forms of non-Langerhans cell histiocytosis (LCH), usually presents in young children as spontaneously regressing cutaneous lesions. However, the systemic type of JXG is difficult to treat in newborn infants, and fatal cases have been reported. In the patient described here, solid masses were discovered by fetal sonography during the 38th gestational week. At birth she had multiple tumors on the back, cheek, and hip as well as marked hepatosplenomegaly accompanied by respiratory failure. Laboratory results indicated pancytopenia, obstructive liver dysfunction, and coagulopathy. Brain magnetic resonance imaging revealed a tumor at the left pontine angle, and dysmorphic histiocytes were present in her spinal fluid. She was diagnosed with systemic JXG by histopathologic findings of the hip mass. The LCH-based multiagent chemotherapy including cytarabine, vincristine, methotrexate, and prednisolone ameliorated the symptoms rapidly. She was treated for 12 months and is currently doing well as a normally developing 2-year-old.

Successful management of severe L-asparaginase–associated pancreatitis by continuous regional arterial infusion of protease inhibitor and antibiotic

L‐asparaginase is a key drug in the treatment of childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, L‐asparaginase can cause a fatal complication of pancreatitis, and an effective treatment for L‐asparaginase–associated pancreatitis (AAP) has not been developed to date. The authors investigated whether rapidly treating children with AAP by continuous regional arterial infusion (CRAI) of protease inhibitor and antibiotic would quickly resolve AAP.

Complicated pathophysiology behind rituximab-induced persistent hypogammaglobulinemia.

The anti-CD20 monoclonal antibody rituximab has made a avorable impact on the prognosis of B-cell non-Hodgkin lymhoma (B-NHL), as a first-line therapy for adult cases and a econd-line therapy for pediatric cases. Additionally, rituximab has mproved the outcome of autoimmune diseases such as systemic upus erythematosus (SLE) and idiopathic thrombocytopenic purura. Complications of retuximab therapy are usually well tolerated nd manageable. Although hypogammaglobulinemia occurring fter retuximab therapy is an axiom, this hypogammaglobulinemia s usually transient and thus often unrecognized in both maligancy and autoimmune settings, with the increase of infection risk ppearing to be marginal [1]. However, it is also known that a inority of patients develop severe hypogammaglobulinemia that ersists for several years even after the completion of rituximab herapy (rituximab-induced persistent hypogammaglobulinemia RPHg]). RPHg is relatively common in malignancy patients who eceived rituximab as part of their regimen for hematopoietic stem ell transplantation (SCT) or as maintenance after SCT [2] but is ess common in patients who received rituximab for treatment of utoimmune diseases [3]. Curiously, hypogammaglobulinemia can rise even after the recovery of peripheral CD19+ B-cell numbers. imilarities in the B-cell phenotype of RPHg to that of common ariable immune deficiency (CVID), including the lack of expresion of IgG2, IgG3, and IgG4 and a profound decrease in CD27+IgD+ witched memory B cells, have been reported [4], raising the posibility that RPHg and CVID pathophysiology may partially overlap. nlike in patients with CVID, however, severe and/or recurrent nfections seem to be uncommon in patients with RPHg [3]; hether patients with RPHg have other clinical manifestations of VID, such as susceptibility to autoimmune diseases or neoplasms, s unknown. Here we report on an adolescent patient who developed RPHg ollowing treatment for B-NHL and suffered unusual complications ith sustained massive lymphadenopathy and recurrent episode f a severe form of histiocytic necrotizing lymphadenitis (Kikuchiujimoto disease [KFD]). Comprehensive analysis of the patient’s -cell phenotype was performed to evaluate possible linkages to VID pathophysiology.

Frequency and clinical features of the JAK2 V617F mutation in pediatric patients with sporadic essential thrombocythemia

Pediatric essential thrombocythemia (ET) is a rare and heterogenous disease entity. While several recent studies have focused on the role of the JAK2 V617F mutation in pediatric ET, the frequency of pediatric ET cases with this mutation and the associated clinical features remain unclear.

Hemophagocytic lymphohistiocytosis during maintenance treatment of precursor B-cell acute lymphoblastic leukemia.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but occasionally life-threatening disorder. HLH is characterized by hypercytokinemia induced by activated T-cells and macrophages, resulting in hemophagocytosis in bone marrow and other reticuloendothelial systems. Prompt diagnosis and the implementation of appropriate therapy are mandatory; otherwise this uncontrolled hypersecretion of inflammatory cytokines leads to the hyperactivation of macrophages, hypercoagulability and bone marrow suppression, resulting in multiple-organ failure [1]. The development of HLH is thought to be quite rare in patients with acute lymphoblastic leukemia (ALL) [2]. In a Japanese nationwide survey, among 567 patients diagnosed with HLH over the last 5 years it was clarified that only 3 patients with ALL (0.5%) and 9 patients with AML (1.5%) developed HLH [3]. Herein, we report a case of HLH associated with an infection that was caused by an unidentified pathogen during the maintenance phase of precursor B-cell ALL; this patient was successfully treated with immunochemotherapy including etoposide. A 2-year-old boy was admitted to our hospital with a complaint of fever. He had previously been healthy, and there was no family history of particular note. Bone marrow aspiration showed proliferation of lymphoid cells which

Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient

Investigation of genetic alterations associated with relapse in acute lymphoblastic leukemia (ALL) may help to identify druggable targets for specific therapies. Early T-cell precursor ALL (ETP-ALL) is a subtype of T-ALL with poor prognosis. Although the genetic landscape of ETP-ALL has been determined, genetic alterations related to the relapse of ETP-ALL have not been fully investigated. Here, we report the first patient with relapsed pediatric ETP-ALL to exhibit a homozygous JAK3 activating mutation, V674A, caused by acquired uniparental disomy (UPD). Single nucleotide polymorphism array analysis revealed acquired UPD (aUPD) at the 19p13.3-p12 locus only in leukemic cells at relapse. Sanger sequence of the JAK3 gene, which was located at 19p13.1 and frequently mutated in ETP-ALL, was performed in paired leukemic samples to determine homozygous JAK3 V674A mutation only in relapsed leukemic cells. In contrast, leukemic cells at initial diagnosis harbored hemizygous JAK3 V674A mutation. Further, whole-exome sequencing revealed mutations in 18 genes only in relapsed samples, although none of these was recurrent in T-ALL. These findings suggest that aUPD at 19p13.1 is partly associated with relapse in this patient. Pharmacological inhibition of JAK3 may be therapeutic in such cases.

Dyskeratosis Congenita Complicated by Hepatic Fibrosis With Hepatic Vein Thrombosis

We describe the case of 2 male siblings with dyskeratosis congenita (DC). Extensive genetic analysis failed to identify a causative genetic abnormality. The elder brother developed hepatic fibrosis accompanied with hepatic vein thrombosis at the age of 9 years. Recent studies have found that patients with DC sometimes develop hepatic complications, including cirrhosis. However, little is known about hepatic complications in patients with DC who lack these mutations. Further genetic studies are required to understand the relationship between DC and hepatic complications. In addition, although danazol can sometimes be effective for treating bone marrow failure, hepatotoxicity can be a major complication. Therefore, when danazol is administered to patients with DC, careful monitoring for hepatic complications is important.

Sorafenib Therapy for Pediatric Acute Myeloid Leukemia with FMS-like Tyrosine Kinase 3-internal Tandem Duplication Mutations: 2 Case Reports.

Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2. This patient received post-SCT sorafenib and remains in complete remission. The combination of pre-SCT and post-SCT sorafenib may thus be effective for pediatric refractory FLT3-ITD-positive AML.

Human leukocyte antigen-DR negative de novo acute myeloid leukemia with Philadelphia chromosome.

It is well known that human leukocyte antigen (HLA)-DR is present in the majority of acute myeloid leukemia (AML) [1, 2]. However, acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) usually lacks the HLA-DR expression as well as CD34 expression [2, 3]. Recently, such HLA-DR/CD34 phenotype has also been described in a subset of AML with cuplike nuclear invaginations (AML-cuplike) [4]. Cytogenetically or molecular genetically, AML-cuplike is characterized with normal karyotype and high frequency of FMS-like tyrosine kinase 3 (FLT3) gene internal tandem duplication (ITD) as well as nucleophosmin (NPM1) gene mutation [4, 5]. In this paper, we reported an extremely rare case of HLA-DR/CD34 AML, which was not categorized into either APL or AMLcuplike and showed Philadelphia chromosome (Ph) at diagnosis. A 64-year-old male was admitted to the hospital because of cellulitis of left leg in April 2008. He showed neither hepatosplenomegaly nor generalized lymph node swellings. There was no bleeding tendency. Laboratory findings were as follows: white blood cells 17.7 9 10/L, with 25% blasts and 20% basophils; hemoglobin, 14.0 g/dL; platelets, 129 9 10/L. Serum lactate dehydrogenase level and D-dimer was elevated to 386 IU/L and 50.2 lg/mL, respectively. Neutrophil alkaline phosphatase (NAP) score was within the normal range. Bone marrow showed hypercellularity with 39% blasts, 7% myelocytes, 4% metamyelocytes, 13% mature neutrophils, 1% eosinophils, 25% basophils, 8% erythroblasts and 3% lymphocytes. Morphologically, blasts were medium to large, and had round or sometimes slightly indented nuclei with dispersed chromatin. Fine azurophilic granules were sometimes found in their scant basophilic cytoplasm, but typical Auer-bodies were not detected (Fig. 1). They were cytochemically positive to myeloperoxidase (MPO) staining. Therefore, he was morphologically diagnosed as having AML-M2 according to the French–American–British (FAB) classification. There were no characteristic cuplike nuclear invaginations suggesting a diagnosis of AML-cuplike on either Wright–Giemsa or MPO staining [6]. Flow cytometric immunophenotyping using the CD45 gating method showed that leukemic blasts were CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD13, CD15, CD19, CD20, CD33, CD34, CD41, CD90, CD117 and HLA-DR, suggesting HLA-DR AML (Fig. 2). More than 85% of these cells also lacked the CD56 expression. Chromosomal analysis of bone marrow using the conventional G-banding method showed t(9;22)(q34;q11) in 14 of the 20 metaphases analyzed in addition to normal variance of inv(9)(p12q13) (Fig. 3). Fluorescence in situ hybridization (FISH) also showed BCR/ABL fusion signal in 92% of T. Inaba (&) N. Fujita Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan e-mail: inaba178@koto.kpu-m.ac.jp