To improve the therapeutic results of children with high-risk malignancies, high-dose therapy and autografts with peripheral blood hematopoietic stem cell (PBSCT) has been developed. PBSC collection is easily applicable without the risk of anesthesia or invasive multiple marrow aspirations. Rapid hematopoietic recovery and fewer complications related to PBSCT have eliminated the need of strict aseptic patient care protocol and made cure-oriented high-dose therapy far safer and easier to apply. Introduction of G-CSF-combined mobilization of PBSC further facilitated the popularity of PBSCT. Our preliminary data with children with early relapsing acute lymphoblastic leukemia suggest that application of PBSCT results in increase in the salvage rate of patients, while avoiding toxicities of allogeneic bone marrow transplantation. Development of an effective procedure for allogeneic transplantation with PBSC or ex vivo expansion of cells to eliminate the pancytopenic period following high-dose therapy has been underway. Its role outside of cancer therapy will continue to evolve and the procedure may become critical in the development of a realistic protocol for gene therapy.

View full abstract

Human cord blood (CB) and bone marrow (BM) CD34⁺ cells were enriched and incubated in liquid culture medium with stem cell factor (SCF), interleukin-3 (IL-3) and interleukin-6 (IL-6). Every 6 days, cells were harvested and prepared for hematopoietic progenitor cell assays for colony-forming unit of granulocyte-macrophage (CFU-GM), burst-forming unit of erythroid (BFU-E) and colony-forming unit of erythroid (CFU-E). After 12 days of culture, CFU-GM in CB were expanded by 98-fold, while BFU-E and CFU-E were expanded by three-and fivefold, respectively, after 6 days of incubation. The number of self-renewal CD34⁺ stem cells was also amplified by approximately fivefold at the peak of the 6-day incubation. In contrast to CB cells, stem and progenitor cells in BM were not amplified under our culture condition. Anti-c-kit antibody, SR-1, significantly suppressed BFU-E and CFU-E growth before and after 12 days of liquid culture with IL-3 plus IL-6 plus SCF. However, CFU-GM growth was less affected by SR-1 before and after 6 days of liquid culture, and after 12 days of incubation no suppressive effect of SR-1 on CFU-GM was observed. These findings suggested differential requirements for c-kit function in the growth of erythroid and myeloid hematopoietic progenitor cells.

View full abstract

To evaluate the uroprotective efficacy and safety of mesna in pediatric patients, a prospective investigation was performed. 135 patients who received oxazaphosphorines and mesna at high-dose chemotherapy (ifomide (IFO); total 161 courses, cyclophosphamide (CPM); total 165 courses) and 73 patients conditioned by oxazaphosphorines with mesna at bone marrow transplantation (BMT) were analyzed. The incidence of [a] total hematuria (gross hematuria) and [b] irritative voiding symptoms at chemotherapy in IFO-treated patients were [a] 8.7% (2.5%), [b.] 5.0%, respectively, and those in CPM-treated patients were [a] 4.2% (0%), [b] 0.6%, respectively. At BMT, these incidences were higher with ([a] 29.2% (16.7%) and [b] 18.1%). No allergic symptoms or adverse effects caused by mesna were observed. We conclude that mesna is effective without any side effects in pediatric patients for the uroprotection at oxazaphosphorine chemotherapy ; however, at BMT, further supportive care and refinement of mesna administration are required.

View full abstract

We report a retrospective analysis of children who underwent stem cell transplantations and subsequently developed a varicella-zoster virus (VZV) infection. Among 44 patients successfully transplanted between 1988 and 1994, 11 patients, aged 3 to 14 years, developed VZV infections (6 allogeneic BMT, 1 syngeneic BMT and 4 PBSCT); there were 9 herpes-zoster and 2 chicken-pox. In 6 cases, VZV infections occurred within 6 months after transplantation, and they appeared between 7 to 12 months in 4 patients. The ratio of CD4/CD8 decreased in lymphocytes from 3 out of 9 patients, and lymphocyte-response to PHA and Con. A depressed in 5 of 10 cases, but there was no significant relation between these laboratory data and the clinical courses.Acyclovir was administered with or without high-VZV-titer immunoglobulin to all the patients, and they were cured without any remarkable complication except postherpetic neuralgia which was observed in 2 older children.However, relapse of leukemia was recognized in 3 cases between 0.5 and 6 months after transplantation. Even though the mortality rate is low, VZV infection after stem cell transplantations should be carefully treated especially in patients with acute or chronic GVHD.

View full abstract

From January 1984 to June 1994, 46 children with non-Hodgkin's lymphoma (NHL) or leukemia lymphoma syndrome (LLS) were treated at Kanagawa Children's Medical Center. Eleven patients were classified as stage I or II according to Murphy's classification, 27 had advanced disease (stage III or IV), and 8 were LLS. By surface marker analysis, 14 patients were T NHL/LLS, 21 B NHL/LLS, 6 Ki-1 lymphoma and 5 surface marker unknown. All patients with T NHL/LLS had a mediastinal mass. Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) at 10 years in all patients were 42.1% and 61.8%. In patients with localized disease, EFS and OS at 10 years were 80% and 100%. In advanced cases, both EFS and OS at 5 years were better for B NHL/LLS than T NHL/LLS (EFS : 29.4% vs. 14.3%, OS : 54.1% vs. 35.1%). Eighteen patients underwent hematopoietic stem cell transplantation. Of the 13 cases transplanted in their first or second complete remission, 10 are alive without disease. In conclusion, the prognosis of advanced NHL or LLS, especially T cell phenotype, is still poor, and we need a more effective treatment program.

View full abstract

We experienced a 5-year-old girl who showed hyperlipidemia after bone marrow transplantation (BMT). The donor was her younger brother. Engraftment was seen at the 20th day after BMT. One month after BMT, diarrhea appeared and lasted until the 60th day. A lot of fat was contained in her diarrheal stool. At 2 months after BMT, serum total cholesterol and triglyceride levels increased remarkably, reaching the maximum levels of 401 mg/dl and 1, 292 mg/dl, respectively, at 2.5 months. This hyperlipidemia was classified as type III on the basis of the presense of a broad β-band and abnormal elevation in the E band. We attribute her hyperlipidemia to side effects of corticosteroid hormones and cyclosporin. Moreover, her taste for hyperlipidemic foods (eg. butter, cheese, etc.) exaggerated her hyperlipidemia. Because her hyperlipidemia decreased after discontinuance of oral intake of these hyperlipidemic foods and a reduction in dose or discontinuance of the above drugs. Thus, attention should be paid to secondary hyperlipidemia due to side effects of drugs and high intake of hyperlipidemic foods after BMT.

View full abstract

Transient abnormal myelopoiesis (TAM) is sometimes seen in neonates with Down's syndrome. Firstly, the characteristic phenomenon in TAM is the more conspicuous excess of blasts and leukocytosis in the peripheral blood than in the marrow. Secondarily, these blastic cells spontaneously disappear within several weeks. Recently, there were some patients who developed acute leukemia after spontaneous regression of TAM reported in the literature. We report an infant with mosaic Down's syndrome (normal phenotype and partial 21 trisomy in PHA-stimulated peripheral lymphocytes) who transformed to MDS at 16 months after spontaneous regression of TAM. The only chromosomal abnormality in the neonatal period was trisomy 21 in hemopoietic cells. Although the trisomy 21 of bone marrow disappeared as TAM regressed, he showed transformation to MDS, namely refractory anemia with an excess of blasts in association with a hyperdiploid chromosome of 54, XY, 21 tetrasomy in the peripheral blood. In the repeated chromosomal analysis, the patient showed clonal evolution of 54, XY, +21, 7p^- and 12p^- in the bone marrow cells. Chemotherapy-induced marrow remission successfully and the abnormal clones disappeared from both the bone marrow and the peripheral blood. The trisomy 21 was not found in the PHA-stimulated peripheral blood lymphocytes any more.

View full abstract

We report a 14-year-old boy who developed acral erythema due to the chemotherapy for the conditioning of bone marrow transplantation (BMT). He was admitted to our hospital with the complaint of pancytopenia and diagnosed to have RAEB-T. When CR was achieved with low-dose Ara-C plus G-CSF therapy, allogeneic BMT was planned from his one-locus mismatched sister. Soon after the completion of conditioning regimen, sharply demarcated erythema became evident on the palms. For the treatment of severe pain, morphine was administered. The erythema gradually became dusky and resolved with marked desquamation over 10 days without any complication. Ara-C was suspected for the causative agent in our case. Acral erythema is known to be a complication in the patients treated with high-dose chemotherapy. It should be careful for its differentiation from GVHD in the recipients of BMT.

View full abstract

We describe a 4-year-old girl with Fanconi anemia associated with myelodysplastic syndrome (MDS). The diagnosis of Fanconi anemia was made by the clinical characteristics and further supported by chromosomal breakage in peripheral lymphocytes following treatment with mitomycin C. Bone marrow examination showed hypocellular marrow and dysplastic features in erythroid, granulocytic, and megakaryocytic lineages. A diagnosis of MDS was made with assignment to FAB class : refractory anemia (RA). The rare association between Fanconi anemia and MDS (RA) in this patient is discussed.

View full abstract

Two cases of hemolytic uremic syndrome (HUS) following allogeneic bone marrow transplantation (BMT) are presented. Case 1 is a 14-year-old boy with acute leukemia who underwent allogeneic BMT from an HLA-matched sibling. His conditioning regimen was total body irradiation, L-PAM and thiotepa, and graft versus host disease (GVHD) prophylaxis consisted of short-term methotrexate (MTX) and cyclosporin A (CyA).At 7 months after BMT, he was admitted with edema on the lower extremities, hypertension, proteinuria, microhematuria and hemolytic anemia. He was diagnosed as having HUS. By stopping CyA administration, symptoms disappeared within 4 weeks. Case 2 is a 13-year-old girl with severe aplastic anemia who underwent allogeneic BMT from an HLA-matched unrelated donor. Her conditioning regimen was thoracoabdominal irradiation, cyclophosphamide and busulfan. GVHD prophylaxis consisted of short-term MTX and CyA. At 7 months after BMT, she showed pancytopenia, hemolytic anemia, proteinuria, microhematuria and hypertension.Similar to Case 1, administration of CyA was discontinued and anticoagulant therapy was employed with rapid improvement of clinical and laboratory findings. Although various factors such as chemotherapy, irradiation and infections are considered to be causal agents, the pathogenesis of HUS following BMT is still unknown. In the present cases, irradiation and viral infections might be involved in the pathogenesis of HUS.

View full abstract