Takashi Kanazawa

Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984–1999

We report the long-term results of Tokyo Childrens Cancer Study Groups studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)±s.e. was 67.2±2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0±1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m2 had no advantage over prednisolone 60 mg/m2 in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8–22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.

TLS/FUS-ERG fusion gene in acute lymphoblastic leukemia with t(16;21)(p11;q22) and monitoring of minimal residual disease

This study reports a 1-year-old boy with precursor B cell acute lymphoblastic leukemia (ALL) carrying t(16;21)(p11;q22). Reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequence analysis showed TLS/FUS-ERG chimeric mRNA with a novel junctional pattern of exon 7 of TLS/FUS and exon 6 of ERG. He did not respond to ALL-oriented therapy. Complete remission (CR) was achieved by chemotherapy oriented for acute myeloid leukemia. Allogenic bone marrow transplantation was done and he has been in CR for 24 months. TLS/FUS-ERG chimeric mRNA was not detected after CR. This is the first report of an ALL patient with a TLS/FUS-ERG fusion transcript.

Increased serum monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-8 concentrations in hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is characterized by hypercytokinemia caused by macrophage and T cell activation. We analyzed the serum concentrations of monocyte chemoattractant protein (MCP)‐1, macrophage inflammatory protein (MIP)‐1β, and interleukin (IL)‐8 to investigate the roles of these chemokines in the pathophysiology of HLH.

Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia.

Wiskott–Aldrich syndrome (WAS) is a rare X‐linked immunodeficiency caused by defects of the WAS protein (WASP) gene. Patients with WAS typically demonstrate micro‐thrombocytopenia.

Successful induction of immune tolerance by continuous infusion of recombinant factor VIII in a haemophilia A patient with high-inhibitor titres

Summary.  The successful and persistent abolition of the inhibitor is of significant clinical benefit, as it allows for the restoration of the usual treatment with clotting factor concentrate. We describe a successful induction of immune tolerance by continuous infusion of recombinant factor VIII (rFVIII) in a 5‐year‐old boy with severe haemophilia A and high‐responding inhibitor. He had previously been subjected to immune tolerance induction (ITI) with rFVIII at 100 units (U) kg−1 three times weekly. One year after the beginning of therapy tolerance was not achieved and a high titer of inhibitor was detected (15 Bethesda Units). The patient had a sudden onset of severe neck pain. The diagnosis of spinal epidural haematoma was revealed by magnetic resonance imaging, and emergency laminectomy with evacuation of the haematoma was required. The patient received sequential therapy for surgery first as bolus rFVIII injection of 500 U kg−1 in order to overwhelm the inhibitor and then as continuous infusion at 6 to 12 U kg−1 hour−1 to avoid bleeding episodes in the postoperative period. After the 3 weeks of continuous infusion, the inhibitor became undetectable. Thereafter, prophylactic treatment with rFVIII was started three times weekly, and the inhibitor has remained undetectable for 6 months. The, present case suggests that continuous infusion of rFVIII may be an effective therapy to induce immune tolerance.

CBL mutations in infant acute lymphoblastic leukaemia

Infant acute lymphoblastic leukaemia (ALL) is relatively rare, occurring in approximately 2Æ5–5% of cases of childhood ALL (Biondi et al, 2000). Infant ALLs are much more likely to present with high leucocyte counts, hepatosplenomegaly and overt central nervous system (CNS) diseases (Taki et al, 1996). T cell phenotype is much less common in infants, while myeloid antigen co-expression and the absence of CD10 expression are more frequent in infants than in older children with ALL. When molecular techniques [such as fluorescence in situ hybridization (FISH) or Southern blot analysis] are used in addition to karyotype, MLL gene rearrangements (MLL-R) are found in 70–80% of infant ALL compared with only 2–4% of older children with ALL (Taki et al, 1996; Biondi et al, 2000). Thus, infant ALL appears to be biologically distinct from the disease in older children (more than 1 year old). In this regard, recent reports of somatic mutations of the CBL proto-oncogene in myeloid neoplasms are intriguing, because these CBL mutations were shown to result in aberrant tyrosine kinase signalling, which also leads to activation of RAS signalling pathways. So far, we and others have reported that CBL mutations occur in a variety of myeloid neoplasms, including de novo acute myeloid leukaemia (AML) (Caligiuri et al, 2007), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm, especially in chronic myelomonocytic leukaemia (CMML) (Sanada et al, 2009), and juvenile myelomonocytic leukaemia (JMML) (Shiba et al, 2010). The importance of CBL mutations regarding leukaemogenesis is substantially increased. Recently, we found CBL mutation in therapy-related AML with MLL-R (Shiba et al, 2011). Interestingly, the MLL-CBL fusion gene has been reported in a de novo AML case (Fu et al, 2003), and this prompted us to search for possible CBL mutations in infant ALL with MLL-R. Because CBL mutations thus far reported were almost all clustered within exons 8–9 that encode Linker/RING finger domains (Caligiuri et al, 2007; Sanada et al, 2009; Shiba et al, 2010), we confined our mutation analysis to these exons, in which polymerase chain reaction-amplified exons 8–9 were subjected to direct sequencing using an ABI PRISM 310 Genetic Analyser (Applied Biosystems, Branchburg, NJ, USA). The study adhered to the principles of the Helsinki Declaration, and was conducted under the regulations enacted by the Ethics Board of Gunma Children’s Medical Centre. CBL gene analysis was performed in 41 infant ALL patients in which MLL-R was found in 33 patients (80Æ5%), including 15 patients with t(4;11)(q21;q23), 4 with t(9;11)(p22;q23) and 5 with t(11;19)(q23;p13.3). Median age at diagnosis was 4Æ7 months (range, 0–12 months). We also performed CBL gene mutation analysis in 28 B cell precursor (BCP)-ALL patients (age range, 1–14 years). Heterozygous mutations of the CBL gene were identified in 2 (4Æ9%) of 41 infant ALL patients, but not in older children with BCP-ALL. These were located in exon 8 (Fig 1). One patient was a 3-month-old female with t(4;11)(q21;q23) and the other patient was a 6-month-old male with t(11;19)(q23;p13.3). They were registered and treated on two Japanese infant leukaemia protocols, MLL96 and MLL98 respectively (Isoyama et al, 2002; Kosaka et al, 2004). Although strong association between CBL mutations and 11q-acquired uniparental disomy (aUPD) has been reported (Sanada et al, 2009), we did not perform the single nucleotide polymorphism array analysis due to lack of DNA. MLL-R are more frequent in younger infants; up to 90% of infant ALL less than 6 months old at diagnosis have detectable MLL-R compared with 30–50% of infant ALL aged 6–12 months (Taki et al, 1996). MLL-R ALL has a characteristic gene expression profile that significantly differs from that of non-MLL-R BCP-ALL and of AML, confirming that MLL-R ALL is a biologically unique leukaemia subtype.

CBL mutation in childhood therapy-related leukemia

Therapy-related leukemia and myelodysplastic syndrome (t-Leuk/MDS) are mainly caused by topoisomerase II inhibitors that cause acute myeloid leukemia (AML) with an 11q23 translocation or by alkylating agents that induce MDS/AML with an AML1 mutation and monosomy 7.1, 2 Two types of t-Leuk/MDS can be distinguished, one of which has a long latency (5–7 years) and is seen following alkylating agents, frequently with an preleukemic phase.1 The other has a short latency period (1–3 years), no preleukemic phase, and is strongly associated with the administration of topoisomerase II inhibitors and chromosomal abnormalities involving 11q23 translocation/MLL rearrangement (MLL-R).2 Repair of etoposide (VP-16)-stabilized DNA topoisomerase II covalent complexes may initiate MLL-R observed in patients.3

Mesial temporal sclerosis associated with methotrexate-induced leukoencephalopathy.

Mesial temporal sclerosis is a common form of symptomatic, localization-related epilepsy in children and adolescents, but its occurrence with acute lymphoblastic leukemia is rare. We present clinical records and neuroimaging results of a 13-year-old patient with acute lymphoblastic leukemia who developed recurrent partial seizures after an episode of leukoencephalopathy thought to be caused by methotrexate. Neuroradiologic images revealed hippocampal abnormalities consistent with the findings of mesial temporal sclerosis. Mesial temporal sclerosis was not previously reported in acute lymphoblastic leukemia patients with methotrexate-induced leukoencephalopathy. However, our case suggests that the pathogenesis of mesial temporal sclerosis may be associated with methotrexate-induced neurotoxicity.

NOTCH1 mutation in a female with myeloid/NK cell precursor acute leukemia

A 6‐year‐old Japanese female was diagnosed as having myeloid/NK cell precursor acute leukemia (MNKL) using immunocytochemical analysis. The patient was treated by cord blood transplantation from an HLA 1‐locus mismatched unrelated donor after chemotherapy comprising cytosine arabinoside, idarubicin, etoposide, and L‐asparaginase. We detected a nonsense mutation, C7412A, resulting in S2471X, where X is a terminal codon, in the PEST domain of NOTCH1 in this patient. The presence of the NOTCH1 activating mutation in MNKL might suggest a possible role in the leukemogenesis of MNKL. Pediatr Blood Cancer. 2010;55:1406–1409.

Bilateral ovarian teratomas successfully treated by ovary-conserving technique

Correspondence: Hayato Yamauchi, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3 – 39 – 22 Showa-machi, Maebashi, Gunma 371 – 8511, Japan. Received 1 June 2004; accepted 9 February 2005. Benign or malignant teratomas are the most common ovarian neoplasms in adolescents. There have been some discussions about treatment strategies for these tumors, especially bilateral ovarian teratomas. 1 Moreover, surgical therapy of the ovarian teratoma has also been controversial, and the method ranges from an ovary-conserving operation to ovariosalpingectomy. 2 – 7