Naoyuki Katano

Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan

This report presents a retrospective study of 26 Japanese children with recurrent anaplastic large cell lymphoma. The first relapses were documented at a median of 10·5 months after the initial diagnosis. Twenty‐four patients achieved a second remission. After a median follow‐up period of 47 months, 18 patients are still alive: 15 patients are in second complete remission (CR), three patients are in third CR or later. The 5 year overall and relapse‐free survival rates were 61 ± 12% and 51 ± 12% respectively. The patients who received allogeneic haematopoietic stem cell transplantation during second CR showed a superior outcome to other patients.

Improvement in CNS protective treatment in non–high‐risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group

BACKGROUND Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable. PROCEDURE To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Childrens Cancer and Leukemia Study Group (CCLSG) ALL874 (1987-1990) and ALL911 (1991-1993) studies. They received risk-directed therapy based on age and leukocyte count. In the ALL 874 study, the non-high-risk (low-risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high-dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18-Gy CRT plus 3 doses of intrathecal (i.t.) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B). RESULTS The 7-year probabilities (+/- SE) of CNS relapse-free survival were 97.3% +/- 2.6% (L874A, n = 41) vs. 90.3% +/- 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% +/- 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease-free survival (DFS) rates were 79.4% +/- 6.5% vs. 74.4% +/- 7.3% (P = 0.62) in the LR group and 63.3% +/- 6.8% vs. 58.3% +/- 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse-free survival (98% +/- 1.9% at 7 years) and a favorable DFS (85.5% +/- 5% at 7 years) in the IR patients. The patients in the high-risk (HR) group in both ALL874 and ALL911 studies received the 18-Gy or 24-Gy CRT with intensive systemic chemotherapy. Their 7-year probabilities of CNS relapse-free survival ranged from 88% to 95%, among which the T-ALL patients had a risk of CNS leukemia, which was 3-4 times higher compared with B-precursor ALL patients. CONCLUSIONS These results indicate that long-term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non-high-risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation.

BCL-2 Expression and Prognosis in Childhood Acute Leukemia

Bcl-2 expression and its prognostic value were evaluated in 42 children with acute leukemia. The Bcl-2 expression of the leukemic blast cells was measured quantitatively by flow cytometry and was further analyzed by the simultaneous immunostaining of Bcl-2 with the surface membrane antigens, DNA, Ki-67 antigen. All of the cases showed a consistent expression of Bcl-2 protein; virtually all leukemic lymphoblasts were Bcl-2 positive. Although the expression of Bcl-2 varied widely from 7 to 80 × 103 MESF units, no significant difference was found, in the mean value between the patients with acute lymphoblastic leukemia and those with acute myeloblastic leukemia. In more than half of the patients with AML, intraclonal heterogeneity of Bcl-2 expression was observed. The expression of Bcl-2 showed no apparent fluctuations during the different phases of the cell cycle. However, the proportion of Bcl-2-positive and -negative cells during the cell cycle was different between ALL and AML patients. In the ALL patien...

Survival outcome after the first central nervous system relapse in children with acute lymphoblastic leukemia: a retrospective analysis of 79 patients in a joint program involving the experience of three Japanese study groups.

In a retrospective review of the survival outcome of children with isolated central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL), we identified 79 patients with CNS relapse among the eligible patients enrolled in ALL trials of 3 Japanese pediatric oncology study groups (Japanese Children’s Cancer and Leukemia Study Group [JCCLSG], Tokyo Children’s Cancer Study Group [TCCSG], and Japan Association of Childhood Leukemia Study [JACLS]) between 1989 and 1999. CNS relapses were diagnosed as the first adverse event between 1991 and 1999. The median age at the time of CNS relapse was 5.0 years (range, 0.7-15.1 years). The duration of the first remission ranged from 1.4 to 54 months (median, 12.4 months), and the observation period after CNS relapse ranged from 1 to 131 months (median, 27 months). Overall, 75 of the 79 patients achieved a second complete remission, 44 of whom had second relapses in the following sites: CNS, 18 patients; bone marrow, 15 patients; combined sites, 8 patients; and testis, 2 patients. Rates of overall survival and event-free survival at 4 years were 43.7% ± 5.8% (mean ± SE) and 32.9% ± 5.5%, respectively.The probability of remaining in second remission was significantly correlated with the leukocyte count (P = .005) and age (P = .02) at the initial diagnosis.

Methotrexate Cytotoxicity as Related to Irreversible S Phase Arrest in Mouse L1210 Leukemia Cells

ABSTRACT The association between cytotoxicity and cell cycle perturbation caused by methotrexate (MTX) was investigated in mouse L1210 leukemia cells by flow cytometric bromodeoxyuridine/DNA assay. In the range of concentrations of MTX from 10‐7M to 10‐6M, in vitro exposure to the drug for 6 h caused a dose‐dependent suppression of clonal growth of the tumor cells and S phase arrest in the cycle progression, resulting in an accumulation of cells in early S phase, in which they showed no definite increase of DNA content above G1 levels. The surviving fraction of the clonogenic cells corresponded with the fraction of cells which recovered from the S phase arrest in MTX‐free medium. In mice bearing L1210 ascites tumors, a bolus injection of MTX caused the S phase arrest of the tumor cells as shown in suspension cultures, and cytokinetic recovery was observed in parallel with the regrowth of the tumor. These results showed that irreversible S phase arrest is a critical cytokinetic event associated with the cytotoxicity of MTX.

Prognosis and DNA Aneuploidy in Children with Acute Lymphoblastic Leukemia

Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease with respect to immunophenotype and karyotype of the blast cells, and so the biological features of the cells appear to have a strong influence on the prognosis. DNA analysis by flow cytometry (FCM) is an ideal way to detect abnormal DNA content of the leukemic cells (DNA aneuploidy), since it rapidly provides a DNA index (DI) that is independent of the mitotic index and is reliably correlated with the karyotype for DNA aneuploidy [1]. Although a favorable outcome for patients with aneuploidy has been commonly reported from our [2] and other working groups [3–5], there are some apparent differences in the prognostic value among the results of each group. In the present study we report the independent prognostic significance of the cellular DNA content in high-risk children who were stratified by WBC count and age at time of diagnosis.

Intramedullary Neutrophil Phagocytosis by Histiocytes in Autoimmune Neutropenia of Infancy

We describe a case of autoimmune neutropenia of infancy in which active phagocytosis of mature myeloid cells by bone marrow histiocytes was observed. This finding in the routine hematological investigation has not been reported so far and might be helpful in suggesting the diagnosis of autoimmune neutropenia of infancy, and also in understanding the pathogenesis of peripheral neutropenia in this disease.

Flow cytometric analysis of marrow cell kinetics in children treated with high-dose MTX and CF rescue.

SummaryNormal marrow cell kinetics were studied by flow cytometry with computer analysis in 11 children with malignancies who received high-dose MTX followed by CF rescue. Nine children with hematological tumors in remission each received an infusion of MTX over 24 h, followed by delayed CF rescue. In 8 of the 9, an accumulation of cells in early to mid-S phase and a decrease of cells in G2/M phase were observed at 24–48 h after the beginning of the MTX infusion. At 144 h after MTX infusion this kinetic perturbation disappeared and the DNA histogram returned to the same state as before therapy. Two children who had malignant bone tumors without marrow infiltration each received an infusion of MTX over 6 h with early CF rescue following an initial IV injection of vincristine. They did not have any prominent perturbation of marrow cell kinetics after MTX exposure, except for a transient increase of cells in G2/M phase.These results confirm that with the high-dose MTX therapy described above for hematological malignancies the impairment of marrow cell kinetics was much more severe and was soon followed by complete recovery, whereas with the therapy for solid tumors the impairment was much slighter.

Hepatitis C virus infection and chronic liver diseases after treatment of malignant disease in children: A multicenter study from the Children's Cancer and Leukemia Study Group of Japan

BackgroundWe studied the prevalence of chronic liver diseases, including hepatitis C virus (HCV) and hepatitis B virus (HBV) infection, as late effects of therapeutic regimens against childhood malignancies in Japan.MethodsPatients were long-time survivors of acute lymphoblastic leukemia (ALL), acute non-lymphoblastic leukemia (ANLL), non-Hodgkins lymphoma (NHL), neuroblastoma, and osteosarcoma, who had been treated and completed the Childrens Cancer and Leukemia Study Group (CCLSG) protocols for more than 6 months at CCLSG participating institutions. The study was initially done in 1993, and as a follow-up study using a retrospective questionnaire in 1997.ResultsThe overall prevalence of HCV infection in the 1993 study was 8.1% of 443 children. Among those long-term survivors in the 1993 study, 36 (8.1%) children (24 with ALL, 6 with ANLL, 2 with NHL, and 4 others) showed liver dysfunction. The details of the HCV-positive long-term survivors were 26 (13.3%) with ALL, 4 (12.9%) with ANLL, 1 (2%) with NHL, and 5 (3%) with others. The overall prevalence of HCV infection in the 1997 study at the same institutions was 0.6%. Only a slight reduction (5.6%) of HCV antibody positivity was noted in the 1997 follow-up study, while marked reduction (77.2%) of chronic liver disorders was noted during the same follow-up period in 623 children.ConclusionsThe high frequency of HCV hepatitis among ALL children is thought to be related to frequent blood transfusions. The 1997 study is the lowest reported prevalence of HCV hepatitis among children with leukemia and malignant diseases.