Junichi Mimaya

Risk factors for early death in neonates with Down syndrome and transient leukaemia.

Transient leukaemia (TL) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells in the peripheral blood that resolves spontaneously. Some TL patients die at an early age due to organ failure. Seventy DS patients with TL were studied retrospectively to identify clinical and laboratory characteristics associated with early death (<6 months of age). Sixteen of 70 patients (22·9%) died early. The main causes of death were organ failure, particularly hepatic and cardiopulmonary failure. On univariate analysis, early gestational age (EGA), high white blood cell (WBC) count (≥100 × 109/l), percentage of peripheral blasts, elevated aspartate transaminase (AST), elevated direct bilirubin (DB), and low Apgar score were significantly associated with poor survival. On multivariate analysis, EGA, WBC count, and DB were independent predictors of poor outcome. A simple risk stratification system combining EGA and WBC count was devised to predict poor outcome. Term infants (EGA ≥ 37 weeks) whose WBC count was lower than 100 × 109/l had the best outcome [7·7% (3/39) died early], while preterm infants (EGA < 37 weeks) whose WBC count was higher than 100 × 109/l had the worst outcome [54·5% (6/11) died early]. This stratification system may be useful for identifying high‐risk patients who need early therapeutic interventions.

Phase I study of irinotecan in pediatric patients with malignant solid tumors.

Purpose To determine the dose-limiting toxicity, maximum tolerated dose, and potential efficacy of irinotecan in children with refractory malignant solid tumors. Patients and Methods In the present phase I clinical trial, 28 patients received irinotecan 50 to 200 mg/m2 per day by intravenous 2-hour infusion over the course of 3 days, repeated once after an interval of 25 days. Fifty-one treatment courses were administered to these patients. Results Dose-limiting toxicities were observed at the dose of 200 mg/m2 per day for 3 days. Diarrhea and hematopoietic toxicities were the dose-limiting factors, and the former required support with intravenous fluid administration. The occurrence of vomiting was variable. Decreases in clinical tumor marker levels were observed in the majority of patients who received two cycles of irinotecan 80 mg/m2 per day to 200 mg/m2 per day over the course of 3 days, and partial response was attained in four patients who received irinotecan in two cycles of 140 mg/m2 per day to 200 mg/m2 per day over the course of 3 days. Pharmacokinetic studies showed that the plasma concentration of irinotecan and its active metabolite SN-38 ranged from 93 to 2,820 ng/mL and 5.2 to 34.8 ng/mL, respectively, during 3-day infusions of irinotecan 200 mg/m2 per day. The mean clearance of irinotecan was 14.54 L/h per m2 (range 8.45–20.83 L/h per m2). Conclusion The maximum tolerated dose was determined to be a dose of irinotecan between 160 mg/m2 per day and 180 mg/m2 per day administered over the course of 3 consecutive days on an inpatient basis, repeated once after 25 days off, and our results indicate that irinotecan is a promising anticancer agent that is worthy of phase II trials in pediatric solid tumors.

Correlation of Clinical Features With the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Juvenile Myelomonocytic Leukemia

Mutations in RAS, neurofibromatosis type 1 (NF1), and PTPN11, constituents of the granulocyte-macrophage colony-stimulating factor signaling pathway, have been recognized in patients with juvenile myelomonocytic leukemia (JMML). We assessed 71 children with JMML for NRAS, KRAS, and PTPN11 mutations and evaluated their clinical significance. Of the 71 patients, three had been clinically diagnosed with neurofibromatosis type 1, and PTPN11 and NRAS/KRAS mutations were found in 32 (45%) and 13 (18%) patients, respectively. No simultaneous aberrations were found. Compared with patients with RAS mutation or without any aberrations, patients with PTPN11 mutation were significantly older at diagnosis and had higher fetal Hb levels, both of which have been recognized as poor prognostic factors. As was expected, overall survival was lower for patients with the PTPN11 mutation than for those without (25 versus 64%; p = 0.0029). In an analysis of 48 patients who received hematopoietic stem cell transplantation, PTPN11 mutations were also associated with poor prognosis for survival. Mutation in PTPN11 was the only unfavorable factor for relapse after hematopoietic stem cell transplantation (p = 0.001). All patients who died after relapse had PTPN11 mutation. These results suggest that JMML with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome.

Antithymocyte globulin and cyclosporine for treatment of 44 children with hepatitis associated aplastic anemia.

We analyzed the outcomes of 44 children with hepatitis associated aplastic anemia (HAA) who received immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA). Fourteen (31.8%) patients achieved complete response and 17 (38.6%) achieved partial response, for an overall response rate of 70.4% after 6 months. Seven non-responders received bone marrow transplantation from an HLA-matched unrelated donor and 6 out of 7 are alive. The probability of overall survival at 10 years was 88.3±4.9%, which supports the role of IST with ATG and CsA as treatment of choice for children with HAA without an HLA identical sibling donor.

SIGNET RING CELL CARCINOMA IN A POLYP OF THE COLON

Undifferentiated adenocarcinoma of the colon occurring in a 6‐year‐old boy was presented. The tumor characterized by the signet ring cell appearance developed in a polyp of the descending colon. The signet ring cell carcinoma is in general a rare morphologic form of colonic carcinoma. According to our review of the literature there have been described 16 patients under 10 years of age with colonic or rectal carcinoma, disclosing 2 cases of undifferentiated or signet ring cell carcinoma including the present case. In children, mucin producing adenocarcinoma is the most predominant type of colonic carcinoma, and 48% of the colonic carcinomas are of signet ring cell carcinoma in children under 17 years of age.

Comparison of intermittent or continuous methotrexate plus 6-mercaptopurine in regimens for standard-risk acute lymphoblastic leukemia in childhood (JCCLSG-S811)

From 1981 to 1983, 131 previously untreated patients with acute lymphoblastic leukemia (ALL) standard‐risk group were entered to the protocol JCCLSG‐S811. Of 119 eligible patients, 115 (96.6%) attained complete remission by treatment with prednisone (PRD) plus vincristine (VCR) or vindesine (VDS). After preventive central nervous system (CNS) therapy including 18 Gy cranial irradiation and three doses of intrathecal methotrexate (MTX), the patients were assigned randomly to the two maintenance chemotherapies, Regimen A and Regimen B. Regimen A (intermittent regimen) consisted of PRD (120 mg/m2/day by mouth for 5 days) plus 6‐mercaptopurine (6MP) (175 mg/m2/day by mouth for 5 days) plus VCR (2.0 mg/m2 intravenously) alternating biweekly with MTX (225 mg/m2 intravenously). Regimen B (continuous regimen) consisted of 6MP (50 mg/m2/day by mouth) plus MTX (20 mg/m2/ week by mouth) combined with pulses of PRD and VCR (the same dosages as Regimen A) every 4 weeks. As the late intensification therapy (LIT), five courses of high‐dose MTX (2000 mg/m2 per dose per week intravenously for three doses every 12 weeks) with leucovorin rescue were administered to all patients who were in continuous complete remission (CCR) for more than 2 years. Sixty and 55 patients, respectively, were registered in Regimen A and B. The CCR rates in Regimen A and B were 75.1% ± 5.8% (mean ± 1 SE) and 49.7% ± 7.3% (P < 0.01) at 4 years, and 72.1% ± 6.3% and 49.7% ± 7.3% (P < 0.05) at 5 years, respectively. In Regimen B, CNS and testicular relapses increased after 3 years of CCR. In addition, the patients in Regimen B had a much higher incidence of infections than Regimen A. The LIT did not seem to have important effects on the duration of CCR. From these data we conclude that the intermittent cyclic regimen of 6MP and MTX may be more effective as compared to the continuous administration of these drugs in the maintenance chemotherapy.

Increasing Incidence of Critical Liver Disease among Causes of Death in Japanese Hemophiliacs with HIV-1

Critical liver diseases are now major causes of death in HIV-1-infected patients after the remarkable improvement in the clinical status resulting from highly active antiretroviral therapy. We report the results of an analysis on causes of deaths related to liver diseases based on our surveillance of hemophiliacs infected with HIV-1 up until May 31, 2002. A total of 1,405 patients (hemophilia A, 1,084, and hemophilia B, 321) were registered. The cumulative number of deaths was 534 (hemophilia A, 414, and hemophilia B, 120) by May 31, 2002. Hepatic disease due to HCV infection was found in 29.8% (95% confidence interval: 20.3–40.7%) of the total cases with known causes of death after 1997, whereas this value was 14.0% (95% confidence interval: 10.8–17.7%) before 1997 (p < 0.01). We observed an increasing incidence of critical hepatic diseases among HIV-1-infected hemophiliacs, thus suggesting that treatment of HCV infection is essential for HIV-1-infected hemophiliacs.

Consensus guideline for diagnosis and treatment of childhood idiopathic thrombocytopenic purpura.

A practice guideline aimed at standardizing the treatment for childhood idiopathic thrombocytopenic purpura (ITP) is presented. This consensus guideline is based on a survey carried out via a questionnaire prepared by the ITP Committee of the Japanese Society of Pediatric Hematology and sent to society members. The survey questionnaire included questions on the diagnosis of ITP submitted for the purpose of revising the ITP diagnostic guideline prepared in 1990 by the Research Group for Intractable Hematopoietic Disorders; a revised diagnostic guideline also is presented.

Polymorphism of CCR5 affecting HIV disease progression in the Japanese population

Among several factors associated with HIV-1 disease progression, genetic polymorphism of CCR2, CCR5, and CXCR4 in HIV-1 infection has been found. Single-nucleotide polymorphisms (SNPs) in the CCR2, CCR5, and CXCR4 genes as well as a 32-base pair deletion in the open reading frame of the CCR5 gene are associated with HIV disease progression among Caucasians and African-Americans in North America and Europe. However, in populations other than Caucasians and African-Americans, SNPs have not been fully examined. In our study SNPs in CCR2 coding and CCR5 regulatory regions have been examined in 98 Japanese HIV-positive individuals. The alleles of CCR5 regulatory regions at -2135T and -2086G are associated with late onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 0.502 and 0.404, respectively). In contrast to this, the allele of CCR5 at -2086A is associated with the early onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 2.133). A haplotype including two alleles at -2135G and -2086G is associated with the late onset of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 0.372). Thus we found that a CCR5 SNP and haplotype polymorphism affect HIV disease progression even in the Japanese population. This indicates that the CCR5 genetic polymorphism affecting disease progression should be studied in a wider range of population.

Clinical pharmacological study of a plasma-derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors – Phase I trial

Summary.  MC710, a combined product of plasma‐derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non‐bleeding state. This was a multi‐centre, open‐labelled, non‐randomized, active controlled crossover, dose‐escalation study of five doses (20–120 μg kg−1 of FVIIa) with re‐administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 μg kg−1) and/or FEIBA (50 and 75 U kg−1) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (Cmax) of MC710 active ingredients increased dose‐dependently within the range of 20 and 120 μg kg−1. After administration of MC710, activated partial thromboplastin time (APTT) was dose‐dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 μg kg−1.