Fumiko Tanaka

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation

Yanagimachi M, Naruto T, Tanoshima R, Kato H, Yokosuka T, Kajiwara R, Fujii H, Tanaka F, Goto H, Yagihashi T, Kosaki K, Yokota S. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor‐related neurotoxicity after hematopoietic stem cell transplantation. u2028Clin Transplant 2010: 24: 855–861.

Human parechovirus-3 infection in nine neonates and infants presenting symptoms of hemophagocytic lymphohistiocytosis

Human parechovirus-3 (HPeV-3) has been reported to cause a sepsis-like illness in neonates and young infants. We experienced the occurrence of HPeV-3 infection in nine neonates and young infants (eight boys, one girl; aged 14–52xa0days, median 31xa0days). They were admitted to our hospital with the chief complaints of fever persisting for 3–5xa0days (median 4xa0days) and lethargy. Five infants presented with abdominal distension and six had a rash (including acral reddening), as was previously reported with this viral infection. Abdominal distension with navel protrusion and acral reddening during the course were characteristic. Laboratory data were characterized by elevated values for serum AST, LDH, FDP, D-dimer, ferritin, soluble IL-2 receptor, triglyceride, choline esterase, and urinary β2-microglobulin. Two of our nine patients presented with a hemophagocytic lymphohistiocytosis (HLH)-like illness and required specific therapy. These data suggest that HPeV-3 is an important virus that can cause hypercytokinemia, which sometimes leads to HLH, and systemic inflammatory response syndrome in neonates and young infants.

Suppressed neutrophil function in children with acute lymphoblastic leukemia

Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 ± 13.2 or 70.0 ± 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 ± 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.

Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (pxa0<xa00.001, OR 6.40, 95xa0% CI 2.39–17.16) and renal dysfunction (pxa0=xa00.013, OR 3.15, 95xa0% CI 1.27–7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (pxa0=xa00.009, OR 5.54, 95xa0% CI 1.54–19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

Long-term follow-up of children with refractory immune thrombocytopenia treated with rituximab

Data on long-term outcomes of children with refractory immune thrombocytopenia (ITP) treated with rituximab are limited. We retrospectively analyzed the long-term effect of rituximab on 22 pediatric ITP patients (11 boys and 11 girls). Compete response (CR) (platelet count ≥100xa0×xa0109/L) and partial response (PR) (platelet count 30–99xa0×xa0109/L) were achieved in nine (41xa0%) and two (9xa0%) patients, respectively. Of the 11 responders, eight subsequently relapsed 2–26xa0months after initial rituximab treatment. The 5-year relapse-free rate was 14xa0% (3/22, 95xa0% confidence interval: 0–27xa0%) with a median follow-up period of 6.4xa0years. Five initial responders with subsequent relapse and one non-responder received multiple rituximab treatments of nine courses; all patients responded to the second rituximab therapy without any significant toxicity. All eight patients who relapsed after an initial response and six of 11 non-responders achieved CR or PR with subsequent treatment, including repeated courses of rituximab, splenectomy, steroids, and other immunomodulating agents. Our findings indicated that the sustained effect of rituximab on children with refractory ITP is low, but that the long-term outcome of ITP itself is not poor. Furthermore, repeated rituximab administration may be a promising therapy for those who relapse after an initial response.

The Potential and Limits of Hematopoietic Stem Cell Transplantation for the Treatment of Autosomal Dominant Hyper-IgE Syndrome

PurposeAutosomal dominant hyper-IgE syndrome (AD-HIES) is included among primary immunodeficiencies, and results from heterozygous mutations in the signal transduction and activator of transcription 3 (STAT3) gene. AD-HIES leads to impaired Th17 cell differentiation and IL-17 production, and is associated with increased susceptibility to bacteria and fungi. It was reported that several patients with AD-HIES were treated with hematopoietic stem cell transplantation (HSCT). The efficacy of HSCT in treating AD-HIES is variable. This study aims to evaluate the long-term clinical and immunological efficacy of HSCT for AD-HIES.MethodsWe have followed for more than 8xa0years two patients with AD-HIES who were treated with HSCT. Their ability of IL-17 production was evaluated by flow cytometry.ResultsBoth patients indicated the normal ability of IL-17 production and their serum IgE levels decreased after HSCT. On the other hand, they suffered from pulmonary complications of AD-HIES such as pneumatoceles and bronchiectasis even after HSCT; however, the frequency of infections was decreased.ConclusionsAlthough the dysfunction of STAT3 in non-hematological tissues such as the lungs could not be corrected by HSCT, AD-HIES patients with risk factors for pulmonary complications may benefit from immunological correction by HSCT before severe pulmonary complications occur. Future studies should investigate risk factors for pulmonary complications in AD-HIES patients.

A case of fetal leukemia with intracranial hemorrhage and early-onset jaundice

We report a case of a neonate who was diagnosed as having congenital leukemia after presenting with an intracranial hemorrhage. The chief symptom was early-onset jaundice due to the hemorrhage. The intracranial hemorrhage and post-hemorrhage hydrocephalus advanced. In addition, the leukemia worsened leading to death at 14xa0days old. The possibility of leukemia, although rare, should be considered as a cause of intracranial hemorrhage in term babies.

Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX‐treated pediatric patients affected by hematological malignancies

Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX‐related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5‐aminoimidazole‐4‐carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX‐related leukoencephalopathy in pediatric patients affected by hematological malignancies.

Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty‐four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty‐three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.

Clinical Courses of Two Pediatric Patients with Acute Megakaryoblastic Leukemia Harboring the CBFA2T3-GLIS2 Fusion Gene

Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene.