Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation is allo-reactive, acute, and chronic syndromes modified by toxicities of high-dose chemoirradiation. Regimen-related toxicities of the gut and skin, hepatic veno-occlusive disease, and cytomegalovirus gastroenteritis have long been the major problems to be distinguished from acute GVHD. Recently, the author et al. revealed that ischemic enterocolitis because of thrombotic microangiopathy (TMA) is another mimic of acute gut GVHD with hemorrhagic diarrhea. Since thrombonecrotic changes of arteriolocapillaries characteristic of TMA can also occur in the liver, stomach, and skin, it is now necessary to differentiate acute hepatic GVHD and that of upper gastrointestinal tracts from ischemic cholangiopathy and microangiopathic gastritis, respectively. The involvement of the target organs for acute GVHD with microangiopathy will encourage a reconsideration of therapeutic policy on acute GVHD thus far, because the use of angiotoxic drugs such as CSA or FK506 without the notice of these complications may worsen the ischemic process of these organs. Thus the detection of microangiopathy in the targets of acute GVHD raises a crucial ground for the need of a substantial revision of current ways on the diagnosis and treatment of acute GVHD. A genuine picture of chronic GVHD would appear through careful treatment of acute GVHD on the basis of more precise exclusion of nonalloreactive complications, including microangiopathic tissue injuries.

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Recent progress in molecular biology contributes to the detection of MRD during hematological remission in leukemia. The clinical value of MRD monitoring is confused because its detectability is variable according to the disease, the treatment, and the methods. In t (1 ; 19) ALL, t (8 ; 21) AML, inv (16) ANLL, and CML, there is controversy regarding MRD in which the positive and negative MRD results during the long-term remission were described. It is necessary to quantitate the level of MRD in these diseases, however, in most cases of leukemia there appears to be good agreement between the detection of MRD and relapse. It is useful not only for the prediction of a relapse, but also for evaluation of the efficacy of the treatment and the choice of other treatments. Furthermore, it is hoped that protocol including the result of MRD will be made.

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We investigated the frequency of cytomegalovirus (CMV) infection and the strategy of the treatment by monitoring antigenemia weekly in 15 patients who received allogeneic stem cell transplantation from November 1996 to July 1998. Antigenemia became positive in 7 of 15 (46.7%) patients on 20-49 (median 29) days after transplantation, and clinical symptoms associated with CMV infection occurred in 5 of 7 (33.3%) patients. These 7 cases received transplantations from unrelated or mismatched donors, and antithymocyte globulin was used for 6 cases as preconditioning. Treatment was started with ganciclovir (GCV) immediately after antigenemia turned out positive, but the 2 patients whose antigenemia was slight (2/300, 000 WBCs) were observed without treatment. However, the number of their antigen positive cells increased to 15 and 68/300, 000 WBCs in a week. GCV seemed to be tolerant in 3 of 7 patients, who improved with foscarnet (FOS). An early initiation of treatment may be necessary if antigenemia becomes positive, and FOS is recommended if GCV seems to be ineffective.

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We evaluated the clinical outcome of 11 hemophilia A patients with inhibitors from 120 patients in our hospital from 1977 to 1998. The overall incidence of inhibitor development was 11 (9.1%) of 120 patients with hemophilia A. Inhibitor developed in 4 (44.4%) of 9 previously untreated patients (PUPs group) and were treated with recombinant factor VIII (r-FVIII) : they developed in 7 (6.3%) of 111 patients previously treated with only plasma-derived factor VIII (pd-FVIII group). The incidence of high responder (HR) was 8 (6.7%) in 120, 2 (22.2%) in 9, and 6 (5.4%) in 111. By use of the intermediate-dosage regimen (50 to 100 units of FVIII/kg body weight, 2 or 3 times a week) for immune tolerance induction (ITI), the inhibitor titer was decreased in 2 of 4 patients in the PUPs group and in 2 of 3 in the pd-FVIII group. Anamnestic response was not observed in the 2 patients whose treatment was changed from pd-FVIII to r-FVIII for ITI therapy. The inhibitor was decreased in 1 of 4 patients treated mainly with FVIII bypassing agents.

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Children with acute lymphoblastic leukemia (ALL) were screened for TEL/AML1 fusion gene, using reverse transcription-polymerase chain reaction (RT-PCR) assay followed by Southern blot hybridization. The fusion mRNA was detected in 4 of 40 patients (10%), and the incidence was lower compared with previous studies in the United States and Europe. The patients were two boys and two girls 2-6 years old, and the initial leukocyte counts were 3, 200-29, 800/μ1. Leukemic cells in all 4 patients were CD10 positive and t (12 ; 21) (p13 ; q22) was not detected by chromosome analysis with G-banding. Minimal residual disease with TEL/AML1 had disappeared at the early phase of complete remission in all cases. Further study is needed to determine the relationship between TEL/AML1 fusion gene and the prognosis of ALL in childhood.

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Eighty-nine patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph¹ALL) who were registered with the committee of stem cell transplantation (SCT) of the Japanese Society for Pediatric Hematology were analyzed. Seventy-one patients received allogeneic bone marrow transplantation (BMT) (allo), including one syngeneic BMT, 9 autologous BMTs (auto), and 9 autologous peripheral stem cell transplantations (PBSCT). Relapses occurred in 27 allos, 4 autos, and 8 PBSCTs at a median of 6 months after transplantation. Five-year event-free survival (EFS) rates for allo, auto, and PBSCT were 26.0 + 5.7%, 51.9 + 17.6%, and 0%, respectively. Patients that received PBSCTs had the worst prognosis (p < 0.01), and no significant difference of EFS between allo and auto was noted. Transplant-related mortality occurred in 19 allos and one PBSCT. The main causes of death were hepatic veno-occlusive disease, sepsis, interstitial pneumonia, and graft-versus-host disease (GVHD). Status at BMT from matched sibling donors (p < 0.02) and the occurrence of chronic GVHD (p < 0.05) significantly affected the prognosis of patients after allo BMT. Multivariate analysis indicated that the occurrence of chronic GVHD was an indepentent prognostic factor for relapse-free survival. SCT should be carried out as early as possible by a less toxic method for Ph1ALL.

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We report here the therapeutic results of a combination of idarubicin/cytarabine treatment (IDA : 5 mg/m², 30 minutes infusion for 3-6 days, CA : 1 g/m², 6 hours infusion for 3-6 days) in 7 cases of refractory acute leukemia (AML, 3 ; ALL, 4) in childhood. When treated, all cases had active disease, with 2 induction failures and 5 relapses (1st, 3 ; 2nd, 1 ; 4th, 1). Following an induction treatment, 4 patients showed good response (GR), two of which maintained GR after consolidation by using the same IDA/CA. As for adverse effects of this therapy, bone marrow suppression and infections were noted in all cases. Severe leukocytopenia with a nadir of WBC ≤200/μl and delayed recovery over a period of median 15 days (range 7-30 days) occurred at every course of treatment. Other toxicities included mild nausea, vomiting, and liver dysfunction. Cardiac dysfunction was also observed in 2 cases. The IDA/CA therapy was thought to be useful to attain a GR in childhood refractory acute leukemia, but careful management is needed for infectious complications and cardiac toxicity.

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We report a case of congenital Langerhans cell histiocytosis with skin and digestive tract involvement that resulted in severe growth retardation. A congenital herpetic infection was initially suspected because papulovesicles were intermixed. However, the skin eruptions persisted and later severe growth retardation developed as a result of prolonged diarrhea containing blood and mucus, and hypoproteinemia and edema caused by protein-losing enteropathy. The skin and colon biopsy established the diagnosis of LCH, and no infiltration to other organs was found. Administrations of vinblastine and prednisone with central venous alimentation were very effective. Congenital self-healing LCH (CSHLCH) with spontaneously involuting skin lesions and generally good prognosis has been known as a unique entity of rare congenital LCH. A computer search revealed several case reports very similar to ours, and thus it is suggested that a subtype of congenital LCH that is characterized by skin and digestive tract infiltration and is different from CSHLCH may exist.

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An 8-month-old girl with refractory acute lymphoblastic leukemia with del (11q23) underwent a purified CD34⁺ peripheral blood stem cell (PBSC) transplantation from her HLA-haploidentical mother. PBSC were mobilized with G-CSF (10 μg/kg/day for 5 days) and collected at day 5 of G-CSF treatment. The CD34⁺ cells were separated by using an immunomagnetic cell-separation system (Isolex 300^®). The conditioning regimen consisted of busulfan (600 mg/m²), etoposide (60 mg/kg), melphalan (195 mg/m²), and total lymphoid irradiation (7.5 Gy/6 fractions). The number of infused CD34⁺ cells, colony forming unit-granulocyte/macro-phage (CFU-GM), and CD3⁺ cells were 3.4 × 10⁶/kg, 2.6 × 10⁶/kg, and 2.8 × 10⁴/kg, respectively. Neutrophil counts increased above 500/μl by day 18. No serious acute GVHD was seen without graft versus host disease (GVHD) prophylaxis. However, the patient died of respiratory failure on day 22. Autopsy findings revealed disseminated aspergillosis, but no evidence of leukemia or GVHD. Purified CD34⁺ PBSC transplantation from HLA-haploidentical related donors should be considered for patients with refractory leukemia without an appropriate donor. Overcoming lethal infectious complications is crucial to the establishment of this method.

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We report a case of an 11-year-old girl with aplastic anemia who was treated repeatedly with combined therapy. This treatment consisted of antilymphocyte globulin (ALG, Lymphoglobulin) and cyclosporin A, danazol, and granulocyte colony-stimulating factor. Methylprednisolone and antihistamines were used for prophylaxis of serum sickness of ALG. The side effects of ALG at the first course were transient pyrexia and urticaria. Because the evaluation at 6 months revealed no response, she was treated again with ALG from the same source. The side effect of the second course was as mild as that of the first course. We safely completed a readministration of ALG. Retreatment with ALG from the same source could be one choice for the failure or relapse case of ALG treatment.

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We have reported a 3-month-old boy with acute renal failure following high-dose methotrexate (HD-MTX) treatment. The patient was diagnosed as having acute lymphoblastic leukemia (early-B cell type). Southern blotting and FISH analyses showed MLL gene rearrangement. Complete remission was achieved by combination chemotherapy, according to the protocol of the Japan Infantile Leukemia Study Group since 1996. Anuria and disseminated intravascular coagulation (DIC) developed 'after an intravenous infusion of 100 mg/kg HD-MTX for 24 hr, although renal function tests were normal before this treatment. Renal failure and DIC recovered, but renal tubular acidosis continued. Acute renal failure following HD-MTX therapy occurs rarely in infants, because the serum clearance of MTX in infants is usually higher than that in older children. It is considered that possibly frequent measurements of renal function tests during HD-MTX therapy is important even in infantile leukemia.

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Selective malabsorption of vitamin B₁₂, or Imerslund-Gräsbeck syndrome, is a rare congenital disease usually found in infancy. We had a case of Imerslund-Grasbeck syndrome that was diagnosed at 17 years of age. The patient was transferred to our clinic for further examinations of his anemia by a pediatric clinic. During the physical examination, he had partly gray hair on his head. Hyperchromic macrocytic anemia, throm-bocytopenia, and low serum vitamin B₁₂ level were found in the first medical examination. The bone marrow was hypercellular with megaloblastic changes in erythroid cells. Giant band and hypersegmented neutrophils were also noted in his bone marrow. Although superficial gastritis was found by endoscopic examination, neither anti-intrinsic factor (IF) antibody nor antigastric parietal cell antibody was detected in serum. A Schilling test revealed decreased absorption of vitamin B₁₂ and vitamin B₁₂-IF complex. The proteinuria had been noted during his clinical course. Besides these data, his parents were cousins. Taken together, he was diagnosed to have Imerslund-Gräsbeck syndrome. His anemia was improved by vitamin B₁₂ injection. It is interesting that the result of the Schilling test was only just as low as the control values. This may explain the late onset of the disease.

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We report a boy with Fanconi anemia presented with pancytopenia and minor abnormalities when one month old. Chromosome breakage was observed in a culture with mitomycin C. Multiple cardiac atrial tumor and left ventricle cardiomyopathy were also observed. A choledochal cyst and bilateral kidney hypertrophy became evident 3 months later. Hematological findings were improved with 2 mg/kg of prednisolone ; however, he contracted CMV pneumonia 2 months later. We did not proceed with bone marrow transplantation because of the positive results obtained with prednisolone, the uncontrolled CMV infection, and the lack of a family donor. The patient died of septicemia and capillary leak syndrome 5 months after his birth.

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