Tomoo Osumi

Differences in voriconazole trough plasma concentrations per oral dosages between children younger and older than 3 years of age

The relationship between trough plasma concentrations and daily doses of voriconazole was retrospectively analyzed in ≤18‐year‐old children because optimal oral voriconazole dosages for children, especially <2 years of age, is unknown. We demonstrated that the relationship changed around the age of 3 years, and that children <3 years of age required higher optimal daily doses with greater variations compared with those for older children, resulting in complicated optimal dose adjustments. Therefore, plasma concentration monitoring and individual dose adjustments are recommended for optimal and less toxic voriconazole treatments, especially for <3‐year‐old children, although additional studies are needed to validate this approach. Pediatr Blood Cancer 2010;54:1050–1052

A novel recurrent EP300–ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia

A novel recurrent EP300–ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia

Poor responses to tyrosine kinase inhibitors in a child with precursor B‐cell acute lymphoblastic leukemia with SNX2‐ABL1 chimeric transcript

In addition to BCR, various rare fusion partners for the ABL1 gene have been reported in leukemia. We have identified the fusion gene SNX2‐ABL1 in a pediatric case of acute lymphoblastic leukemia (ALL), which has only once previously been reported in an adult patient. Cytogenetic analysis detected this fusion gene arising from a t(5;9)(q22;q34) translocation. ALL cells carrying a SNX2‐ABL1 fusion exhibited a BCR‐ABL1+ ALL‐like gene expression profile. The patient poorly responded to dasatinib but partially responded to imatinib. Treatment using tyrosine kinase inhibitors requires further investigation to optimize the genotype‐based treatment stratification for patients with SNX2‐ABL1 fusion.

Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: Increased expression of a CD44 variant isoform after chemotherapy

BackgroundLi-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene p53. Loss of p53 results in increased expression of CD44, a cancer stem cell (CSC) marker, which is involved in the scavenging of reactive oxygen species (ROS). Here, we report a change in the expression of a CD44 variant isoform (CD44v8-10) in an 8-year-old female LFS patient with osteosarcoma and atypical liver cancer after chemotherapy.Case presentationThe patient visited a clinic with a chief complaint of chronic pain in a bruise on her right knee. Magnetic resonance imaging (MRI) raised the possibility of a bone malignancy. Biochemical testing also revealed significantly elevated levels of AFP, which strongly suggested the existence of a primary malignancy in the liver. MRI imaging showed the simultaneous development of osteosarcoma and liver cancer, both of which were confirmed upon biopsy. Combined therapy with surgical resection after chemotherapy was successful in this patient. Regardless of the absence of a familial history of hereditary cancer, a germline mutation in p53 was identified (a missense mutation defined as c.722 C>T, p.Ser241Phe). To better understand the cancer progression and response to treatment, immunohistochemical (IHC) analysis of biopsy specimens obtained before and after chemotherapy was performed using a specific antibody against CD44v8-10.ConclusionThis case demonstrates the ectopic up-regulation of CD44v8-10 in a biopsy sample obtained after cytotoxic chemotherapy, which confers high levels of oxidative stress on cancer cells. Because the alternative splicing of CD44 is tightly regulated epigenetically, it is possible that micro-environmental stress resulting from chemotherapy caused the ectopic induction of CD44v8-10 in vivo.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384. Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1

We introduced SNX2-ABL1, a novel ABL1-related chimeric transcript lacks SH3 and SH2 domains, into murine Ba/F3 cells and compared their function with that of BCR-ABL1. After the expression of SNX2-ABL1 proteins, Ba/F3 cells acquired an ability to proliferate in an IL-3-independent manner. Upon treatment with both imatinib and dasatinib, BCR-ABL1-expressing Ba/F3 cells underwent rapid apoptosis, whereas SNX2-ABL1-expressing Ba/F3 cells showed poorer sensitivity toward these TKIs and could proliferate in the presence of a low dose of dasatinib. Therefore, other TKIs with a more selective effect against this chimeric kinase should be used for the treatment of patients with SNX2-ABL1+ ALL.

Non-Hodgkin lymphoma and pre-existing conditions: Spectrum, clinical characteristics and outcome in 213 children and adolescents

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.

Nonsense mutation in HLA‐B*40:02 in a case with acquired aplastic anaemia: a possible origin of clonal escape from autoimmune insult

The cause of idiopathic aplastic anaemia (AA) has not been clarified, but some evidence supports the role of T cell-mediated autoimmune destruction of haematopoietic stem/progenitor cells (HSPCs; Young & Maciejewski, 1997). The condition of approximately 70% of patients with idiopathic AA has been observed to improve after immunosuppressive therapy (IST; Bacigalupo et al, 2000; Kojima et al, 2000). In vitro monoclonal or oligoclonal expansion of CD8 T-cells has been noted in patients with idiopathic AA (Risitano et al, 2004). However, the target antigens of T cells have not been clearly identified. Katagiri et al (2011) reported that a considerable proportion of Japanese patients with idiopathic AA acquired copy number-neutral loss of heterozygosity of the 6p arms (6pLOH), leading to loss of one human leucocyte antigen (HLA) haplotype. Moreover, the missing haplotype was concentrated in particular alleles: HLA-A*02:01, HLAA*02:06, HLA-A*31:01 and HLA-B*40:02. Furthermore, Japanese patients with idiopathic AA typically inherited only those four HLA alleles (Katagiri et al, 2011). These findings suggest that these HLA alleles are the target antigens of T cells in the pathogenesis of idiopathic AA and 6pLOH is the mechanism by which HSPCs escape from autoreactive cytotoxic T-lymphocytes (CTL). In this study, we report a patient with idiopathic AA who carried a nonsense mutation in an HLA allele. Tracing the case history with fluctuations in her HLA typing illustrated how HSPCs escape from autoimmune insult. A 2-year-old girl was diagnosed with severe acquired AA. Neither chromosomal abnormalities nor morphological dysplasia was observed in her bone marrow cells. Serological HLA typing was performed using the Terasaki–NIH Standard method, revealing that her phenotypes (A24/-, B55/B61, DR8/DR9) completely matched those of her father. She received immunosuppressive therapy for 20 months, leading to partial remission, but she relapsed with thrombocytopenia 7 months after discontinuing IST. Although she was retreated with IST, regular blood transfusions had been required since the age of 5 years. Therefore, stem cell transplantation was scheduled at the age of 7 years. Confirmation of her HLA type by high-resolution sequencing-based typing of a peripheral blood sample, revealed a nonsense mutation (CAG to TAG) at codon 54 in exon 2 of either HLA-B*40:02 or HLA-B*55:02 (Fig 1A). In contrast, no mutation in HLA-B alleles was found in either of her parents. To resolve the discrepancy, we re-examined the serological HLA typing by the same method. Analysis of her blood sample demonstrated that the HLA-B61 antigen, corresponding to

Epstein-Barr Virus (EBV)-positive Sporadic Burkitt Lymphoma An Age-related Lymphoproliferative Disorder?

Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV+) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV+ sBL, we compared the clinicopathologic characteristics of 33 cases of EBV+ and 117 cases of EBV-negative (EBV−) sBL in Japan. EBV+ sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV+ group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV+ group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV+ sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV+ sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV+ sBL might be different from those of EBV− sBL. Our results demonstrate that EBV+ sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV− sBL.

Imatinib is effective for prevention and improvement of fibrotic fasciitis as a manifestation of chronic GVHD.

Imatinib is effective for prevention and improvement of fibrotic fasciitis as a manifestation of chronic GVHD