Enzyme target chemotherapy is a concept by which to investigate the biochemical changes due to cellular transformation, mainly at the level of enzymes, and by which to develop a treatment specific against cancer cells by targeting these enzymes. First, on the assumption that cancer cells are highly proliferative, enzymes which increase their activity depending on cell proliferation are considered to be good targets. Among them are ribonucleotide reductase, dihydrofolate reductase and thymidylate synthase, the inhibitors of which, such as hydroxyurea, methotrexate and 5-fluorodeoxyuridine, respectively, are already in clinical use. In this article, I introduce two enzymes as new targets, IMP dehydrogenase (inhibitor : tiazofurin) and topoisomerase I (inhibitor : camptothecin). A second group of targets are enzymes which are specifically deficient in cancer cells. I mention MTA phosphorylase and asparagine synthetase as examples and discuss a strategy whereby these cells can be killed selectively. Enzyme target chemotherapy promises to be a good approach to scientific cancer chemotherapy.

View full abstract

We studied the influence of congestive heart failure (CHF) on erythropoiesis clinically and experimentally. Clinical cases studied were classified into mild, moderate and severe CHF. The group of severe CHF showed a tendency to have macrocytic anemia as compared with the groups of mild and severe CHF. Two cases in severe CHF that measured erythropoietin (Epo) showed no response to hypoxia, that is, no increase in hemoglobin (Hb) and Epo. We used aortic constricted rat (AC-rat) and cor pulmonale rat induced by monocrotaline (M-rat) as the experimental models of CHF, regarded as left ventricular failure and right ventricular failure respectively. In the study of AC-rat the younger age group showed a significant lower value of Hb than the control group and also had a tendency to be low value of Epo, though it was not significant statistically. One possibility was suggested that in the younger age group erythropoiesis might be more profoundly influenced by CHF in which inadequate secretion of Epo might be present in no response to hypoxia. In the study of M-rat the cases with poor secretion of Epo were evidently confirmed in spite of a low value of Hb.

View full abstract

It has been believed that normal hemopoiesis would be suppressed by the proliferation of malignant cells in acute leukemia. We reported that many residual circulating CFU-C were detected in the peripheral mononuclear cells (MNCs) which were shared by a high percentage of malignant cells from five patients with acute B-cell lineage lymphoblastic leukemia (3/5 cases were newly diagnosed and 2/5 cases were relapsed after conventional chemotherapy). These lymphoblasts were studied by 2-step culture method. First in liquid culture system, MNCs which include variable rate of lymphoblast were incubated with or without 40 ng/ml of recombinant human interleukin-3 (rhIL-3) for 14 days. During a second step, CFU-C derived colonies were observed in methylcellulose with 20 ng/ml of G-CSF for the next 7 days. No erythroid colonies were detectable using methylcellulose media in the presence of 2 U/ml of erythropoietin. The mean number of circulating CFU-C in the culture with rhIL-3 was higher than that without rhIL-3. In two cases who expressed the abnormal chromosome population, there were no abnormal chromosomes in their CFU-C derived colonies. These studies show that liquid cultures may offer a new approach to the assessment of residual normal hematopoietic stem cells with chromosomally normal population in the patients with acute B-cell lineage lymphoblastic leukemia.

View full abstract

With the advance of cytotoxic chemotherapy, sepsis is one of the important complications in the treatment of pediatric patients with malignant diseases. We analyzed the organisms causing sepsis in 48 patients with malignant. disease who were admitted to the Department of Pediatrics of Showa University Fujigaoka Hospital from 1985 to 1989. Positive blood culture was found in 14.0% (18/129). And sepsis was frequently found in the patients who were admitted for re-consolidation therapy (25.6%). The organisms causing sepsis were as follows : grampositive cocci 63%, gram-positive bacilli 5%, gram-negative bacilli 32%. Among those organisms, Streptococcus viridans was the most dominant in frequency (58.3%). Furthermore, we have compared this study with a previous study performed during 1981 to 1984. In the previous study, gram-negative bacilli were the most dominant, and the organisms now causing sepsis are clearly different.

View full abstract

To improve the life circumstances of the children with malignant tumors, we investigated the manegement of imparting the diagnosis of those patients. Seventy-five cases were studied who were treated at our hospital. We are telling the diagnosis only to parents of the patients with malignant tumors. The incidence of imparting the diagnosis to the patients of school age by their parents was low (9.3%). But there were many cases where parents told their children's diagnosis to their family members, especially to their grandmothers or grandfathers. Furthermore, many parents told their children's diagnosis to the staff at work with high incidence. Ten children knew their own diagnosis without their parents imparting it; they had learned of it through the careless management of life-threatening illness by school staff. This study proved that it is necessary to improve the circumstances of school life for the patients of school age prior to telling the diagnosis to them.

View full abstract

A 9-year-old boy was admitted to Shizuoka Children's Hospital because of cervical lymphoadenopathy and leukocytosis. WBC in his peripheral blood was 298, 000/, cd with 87.2% lymphoblasts. Bone marrow aspirate showed hypercellular marrow with 95% blast cells of L 1 morphology. Surface marker analysis on bone marrow cells disclosed that tumor cells were positive for CD2, CD5, CD7, and HLA-DR. A diagnosis of acute lymphoblastic leukemia of T-cell type was made. He entered in complete remission by Children's Cancer & Leukemia Study Group 874 protocol for highrisk ALL. Twelve months after initial admission, when he was in complete remission, he developed cutaneous Langerhans' cell histiocytosis (LCH). Six months later, LCH spread to bone and lungs. He died from intestinal pneumonitis 21 months after initial diagnosis of ALL. To our knowledge this is a second report of LCH complicating lymphoproliferative disorders.

View full abstract

We had a 9-year-old female patient with hereditary spherocytosis, who was admitted for severe anemia due to aplastic crisis by parvovirus B19 infection without erythema. Her father had probably the same crisis because of hereditary spherocytosis, and interestingly her siblings had erythema infectiosum simultaneously.

View full abstract

This report described a girl with anorexia nervosa which was complicated with megaloblastic anemia. A 14-year-old girl was admitted because of remarkable weight loss and anorexia. In spite of her being treated with intravenous hyperalimentation, she was found to have megaloblastic anemia during pyrexia. The anemia was improved with folic acid therapy. Gastrointestinal bleeding or bone marrow hypoplasia or blood loss from catheter are well-known causes of anemia accompanied with anorexia nervosa. Megaloblastic anemia is thought to be rare but this clinical case suggested that this kind of anemia may be induced in anorexia nervosa.

View full abstract

Two cases of aplastic anemia in childhood treated with high dose methylprednisolone were reported. One case of moderate-type aplastic anemia achieved full hematological recovery and maintained it. Another case of severe-type aplastic anemia recovered with mild thrombocytopenia. These two cases were complicated with hyperglycemia, emotional disturbance, urolithiasis, subcutaneous abscess and necrosis of femoral heads. However, this therapy can be performed under close observation.

View full abstract

Macroamylasemia was detected in a 4-year-old boy who complained of transient abdominal pain. His pain was relieved, but serum amylase level remained at 800-2000 IU// for 2 years thereafter, and his amylase creatinine clearance ratio (ACCR), 0.09%, was extremely low. Acetate membrane-electrophoresis of serum amylase showed broad abnormal mobility on the anodic side of the salivary (S) -amylase fraction, in addition to only trace pancreatic (P) and S fractions. The amylase elution pattern on a Sephadex G-200 column showed the region of amylase peak activity to be located between those of IgM and IgA-IgG globulin fraction, indicating that the amylase had a molecular structure larger than that of normal amylase. The patient's amylase was immunoprecipitated with anti-human IgA and anti-human A antiserum, IgA was immunopurified with anti-IgA coupled CNBractivated Sepharose 4B beads, and amylase bound to IgA was dissociated under acidic conditions. The IgA refined from the patient formed a complex with purified S-amylase which showed electrophoretic pattern similar to that of his original serum. There was no change in the activity of the patient's amylase under the condition of high temperature at 60°C for 1 hour. In addition, amylase from the patient's father showed the same characteristics as the propositus, although amylase from other members of his family did not.

View full abstract

We reported a case of a 4-year-old female with bone marrow necrosis at presentation with acute lymphocytic leukemia. She complained of fever and leg pain on onset. Laboratory data revealed a high level of serum LDH. Bone marrow aspirations showed massive bone marrow necrosis in bilateral iliac crest. After one month, bone marrow in sternum showed complete remission and in iliac crest was not necrotic, but hypoplastic. Bone marrow in iliac crest recovered completely after nine months of complete remission.

View full abstract

An infant treated with Adriamycin (ADR) for malignant histiocytosis (MH) developed congestive heart failure (CHF) at 6 months after 8 ADR courses (total dose : 280 mg/m2 body surface). The CHF improved transiently, exacerbated 3 months later, and persisted subacutely with remarkable elevation of serum CPK and liver origin enzymes. In the active stage of MH, serum interferon-γ and interleukin-6 levels were elevated. When the CHF occurred, these levels remained within normal, indicating that the patient was in remission for MH. Further studies will be required in many cases to define that the cytokines exert some roles in the early development of ADR cardiomyopathy.

View full abstract

A four-year-old boy was admitted to our hospital because of persistent fever and lymph node swelling. The white blood cell count was 28, 100/μl, 76% of which were blasts. He was diagnosed as having acute lymphoblastic leukemia (FAB L1). He was treated according to the high-risk ALL regimen of the TCLSG (Tokyo Children's Leukemia Study Group) protocol. Following the remission induction, whole skull irradiation and intrathecal chemotherapy were initiated as the prophylaxis of central nervous system leukemia (CNS-L). In a few days from the beginning of this treatment, he was suspected of having central nervous system leukemia. Intrathecal chemotherapy was continued following the treatment for the prophylaxis of CNS-L. Five months after the diagnosis of his leukemia, he developed severe mental retardation with marked low densities in the white matter region of the CT scan. The diagnosis of leukoencepha lopathy was made. The chromosomal analysis of his blast cells revealed the abnormality of t (1; 19) (q23; p13). To our knowledge, three other childhood ALL patients with both acute leukoencephalopathy in the early remission and t (1 ; 19) have been reported. It is suggested that t (1; 19) itself may be one of the risk factors of acute leukoencephalopathy of childhood ALL.

View full abstract

A case of AML with rare chromosomal abnormality, presenting with facial diplegia is reported. A two-year-old boy was referred to our hospital because of the left facial nerve palsy following transient right facial nerve palsy. The leukocyte count of peripheral blood was 1.38×10⁴/μl, 24% of which were myeloid blast cells (FAB, M2 type). Bone marrow was occupied with 78.5% blasts cytochemically positive for myeloperoxidase. Cytogenetic analysis showed them to be 3p^-, 8q^- 10p⁺, 17q⁺ with or without-Y; surface markers, CD 13 and CD 19, were simultaneously expressed on the same blast cells by two-color flow cytometry. Lumbar puncture revealed initial CNS leukemia ; brain CT and MRI revealed chloromas in the right temporalis and posterior fossa and leukemic infiltration and inflammation of mastoid. The facial nerve palsy and abnormal pulse site in MRI disappeared after induction chemotherapy and cranial irradiation. He has been in remission for 10 months after diagnosis. MR studies are likely to be useful in diagnosis and assessment of treatment of masoitditis due to leukemic infiltration.

View full abstract

A 10-month-old girl underwent radical operation for tetralogy of Fallot. Subsequently, she developed persistent pyrexia and skin rashes, and was diagnosed as having measles. Laboratory examination disclosed pancytopenia and liver dysfunction. Two days after admission, she became lethargic and then comatose. Bone marrow aspirate showed many foam cells with hemophagocytic changes. She developed pneumonia during a period of severe neutropenia, which was successfully treated by intracutaneous rhG-CSF (recombinant human granulocyte colony stimulating factor). The injection of rhG-CSF is a good treatment for agranulocytosis caused by VAHS.

View full abstract

A case of transient abnormal myelopoiesis (TAM) with hypothyroidism is reported. A female newborn who had marked hepatosplenomegaly and Down's syndrome was admitted to our hospital. White blood cell count was 343, 000/μl with 86% abnormal cells, whereas in her bone marrow, 69.8% of cells were found to be abnormal. These blasts were positive for platelet peroxidase, KORP77, and CD_w41. These findings suggested that the abnormal cells in this patient had the characteristics of megakaryocytes. The DNA histogram showed normal 2C-4C pattern and these blasts revealed 47XX, +21 in chromosomal analysis. We could confirm the diagnosis of TAM by these findings. The patient has been well for more than a year with supportive treatment only, and the abnormal cells had disappeared from peripheral blood within three months. Her anemia gradually improved, which might be related to thyroid hormone therapy given for hypothyroidism.

View full abstract

A 9-year-old girl was admitted to our hospital because of epistaxis. Physical examination revealed short stature (<-3.0 SD) and cafe-au-lait-like spots. The diagnosis of MDS (RA) was made based on pancytopenia in peripheral blood and micromegakaryocytes, hypersegmented erythroblasts and karyotype aberrations with trisomy 1 in bone marrow cells. Due to refractoriness to G-CSF and mPSL pulse therapy, allogeneic BMT from HLA-identical male sibling was performed using busulfan and cyclophosphamide as conditioning regimen. Although successful engraftment was confirmed by the karyotype analysis on day 28, her clinical course was complicated with hemorrhagic cystitis, intestinal hemorrage, convulsion and temporal cardiac arrest during conditioning therapy and immediately after the BMT. The patient died on day 76 after grafting due to grade IV GVHD with toxic epidermal necrolysis, massive bloody diarrhea and severe hepatic dysfunction. After the BMT, the chromosome fragility was demonstrated by the mitomycin C stress test. Modified conditioning regimens to reduce the risk of GVHD will be needed for the successful BMT on patients with Fanconi anemia complicated with MDS.

View full abstract