There is no evidence that cancer cells including leukemic cells are immortal. It has been clearly indicated that certain cytokines can significantly stimulate leukemic cell proliferation in vitro, and sustain the circuit of autocrine or paracrine stimulation. More interestingly, DNA fragmentation and specific morphologic changes including chromatin condensation and nuclear fragmentation can be demonstrated and programmed cell death (apoptosis) is rapidly induced in the majority of primary leukemic cells, when they are placed in culture, indicating leukemic cells still maintain the suicide program for cell death that can be activated. Leukemic cells require specific factors (surviving factors) to remain viable and removal of these factors results in programmed cell death. Additionally, deregulated expression of genes such as c-myc, bcl-2, and tumor-suppressor gene p53 may suppress programmed cell death of leukemic cells. Reduction of surviving factors to activate the suicide program in leukemic cells, and alteration of sensitivity to cytotoxic drugs by cytokine stimulation may be the new strategy for biologic therapy of acute leukemia.

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The 8511 protocol was designed to answer the following questions for children with standard-risk acute lymphoblastic leukemia (SR-ALL). (a) What is the frequency of central nervous system (CNS) leukemia in SR-ALL without presymptomatic cranial irradiation therapy ? (b) Could intensive rotational combination chemotherapy improve overall outcome of SR-ALL ? (c) Could the active immunotherapy have any beneficial effect on the clinical outcome ? Eighty-five evaluable patients were registered and complete remission was successfully achieved in 83 out of 85 cases. All responders were randomized to standard maintenance regimens with or without immunotherapy (protocol A or B respectively), or intensive rotational combination regimen (protocol C). No difference was found in both the rate of event-free survival (EFS) and the site of relapse between protocol A and B, indicating that immunotherapy has no beneficial effect on the overall outcome, although long-term follow-up is apparently necessary. The overall rate of solitary CNS relapse was 9.6% (8 of 83 cases). The frequency of CNS relapse was similar in each maintenance protocol. Interestingly, EFS rate of the patients with lower leukocyte count (<10, 000/μl) was significantly higher than that with higher leukocyte count (≥10, 000/μl) in protocol A and B, but not in protocol C. In the group with lower leukocyte count, estimated EFS rate in protocol A and B (74.8% and 79.2% respectively) was higher than that in protocol C (50.6 %). In contrast, in the group with higher leukocyte count, EFS rate within 5 years in protocol C was significantly higher than those in protocol A and B (p < 0.05). These data suggest that SR-ALL could be further divided into subgroups according to the leukocyte count. Intensive rotational combination chemotherapy might be more effective for the group with relatively higher leukocyte count.

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We analyzed salvage therapy in 34 relapsed cases of 83 standard risk ALL patients who have obtained 1 CR in the Tokai POSG protocol 8511 which omitted cranial irradiation. Relapse of 23 cases occurred on bone marrow (BM), 3 cases on BM + central nervous system (CNS), and 8 cases on CNS. Initial leukocyte count of relapsed cases was significantly higher than that of 1CR maintained cases (p=0.040). Mean duration of 2CR was 474 days in 10 patients treated with chemotherapy alone and 1, 141 days in 10 patients treated with bone marrow transplantation (BMT). Disease-free survival (DFS) rate after 676 days of 2CR in chemotherapy group and in BMT group was 26.7% and 65.6%, respectively (p=0.097). The results of this study suggest that allogenic BMT may be better therapy than chemotherapy in patients with donor, and that autologous BMT using monoclonal antibody plus complement treated BM may be better therapy for patients who relapsed on BM or BM + CNS without donor. Patients with isolated CNS relapse were treated with craniospinal irradiation (CSI) or BMT with TBI+ CSI. Although the period of observation was still limited, mean duration of 2CR in this group of 1, 233 days and DFS rate of 64.3% were acceptable.

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Interleukin-2 receptor (IL-2R) expression on peripheral blood monocytes was enhanced by incubation with lipopolysaccharide (LPS), but not with IL-2. IL-2R expression enhanced by LPS was inhibited by pretreatment with hydrocortisone (HDC). Proliferation of HL-60 cells was inhibited by monocytes cultured in the presence of IL-2 or LPS. Also, the culture supernatant from the monocytes incubated with IL-2 or LPS for 48 h (IL-2-Mon-Sup, or LPS-Mon-Sup) had an inhibitory effect on HL-60 cell proliferation. Morphological observation of the HL-60 cells cultured with IL-2-Mon-Sup or LPS-Mon-Sup revealed agglutination of chromatin and collapsed nuclei. Treatment of the monocytes with HDC suppressed all the above effects of IL-2 and LPS on HL-60 cell proliferation, and that with anti-TNF-a antibody suppressed the effect of LPS.

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Testicular function was investigated by testicular biopsy, testicular volume, testosterone and LH-RH test in 16 prepubertal boys with 15 cases of acute leukemia and one case of malignant lymphoma after chemotherapy and/or testicular irradiation. One of 2 cases who had infiltrated in testes received irradiation at onset. With another 2 cases, testis was resected at testicular relapse and irradiated on opposite side. All continued complete remission for 1-9 years after cessation of chemotherapy. Basal levels of serum testosterone, FSH and LH were normal in 13 cases of unirradiated group recently but spermatogonia in testicular biopsy specimen decreased on cessation of chemotherapy in 8 cases. Primary gonadal dysfunction was detected in 3 cases of irradiated group. And so testicular irradiation induced damage of tubular system and Leydig cell function. It is necessary to follow up about sexual maturation.

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11 children with advanced neuroblastoma who had received autologous bone marrow transplantation (A-BMT) between 1985 to 1992, were given 13-cis-RA daily in oral dosage of 100 mg/m²/day, divided every 12 hours, to prevent relapse. We determined the pharmacokinetics and side effect of 13-cis-RA. The peak serum concentration of 13-cis-RA occurred at between 2-6 (average 4) hours after ingestion, and almost disappeared at 24 hours. The peak level increased linearly with increasing dose level ; but the patients with kidney dysfunction, showed the increase of peak level remarkably. All patients had a mild skin toxicity (chelitis and fissured lips), elevated ALP, TG, and some of them had elevated GOT, GPT, Ca, and cholesterol. Also patients with kidney dysfunction had more side effects. In our data, giving a 13-cis-RA 100 mg/m²/day divided every 12 hours daily, we could not find any bone marrow suppression even after A-BMT, and also side effects were not severe except in some patients. It might suggest that 13-cis-RA can be given safely.

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A 14-year-old girl was diagnosed as acute lymphoblastic leukemia (ALL) in May, 1988. She was treated with peripheral blood stem cell transplantation in first complete remission in December, 1989. But in June, 1990 she was found to be relapsed. Any chemotherapy was not effective afterward. She suffered from high fever and cough suddenly in January, 1991. A chest X-ray film showed pulmonary infiltration in the right lower field. She died of respiratory failure without improvement in her symptoms and hematologic findings in March, 1991. Autopsy revealed pulmonary alveolar lipoproteinosis and a large pulmonary infarction. The relation-ship between pulmonary alveolar lipoproteinosis and hematologic malignancies is discussed in this case and other reports.

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A 7-year-old boy with common ALL followed by secondary leukemia (ANLL, M5b) was reported. He developed common ALL in Jan., 1988 when he was 18 months old. Although a complete remission had been achieved by the TCLSG-11-H2 protocol chemotherapy, the bone marrow relapse developed soon after. After the re-induction therapy, multiple fungal liver abscess was developed. Liver cirrhosis, hypersplenism and portal hypertension has been following. Furthermore, he showed various complications such as pleural effusion and bleeding from esophageal varices. A CNS relapse was found in Apr., 1992. After being treated with intrathecal injections of MTX, HC and Ara-C and 28 Gy of cranial irradiation, additional chemotherapies including high dose MTX were performed and totally 750 mg/m² of VP 16 were given. ANLL (M5b) was developed in Jan., 1993. The leukemic cells were positive for HLA-DR, CD 13, CD 14, CD 11 and CD 18. They had phagocytic function and O₂^- producing ability. A chromosomal abnormality was observed as 45XY, -7, -21, +i (21q), t (6, 14) (p22 ; q23). P-glycoproteins were found in 58% of the cells. Although he has been intensively treated, no remission has yet been accomplished. It is now urgent to investigate the mechanisms of the secondary leukemias and to establish effective treatments.

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Two cases of refractory acute lymphoblastic leukemia with pulmonary aspergillosis were reported. Both cases died in spite of antifungal therapy. At the autopsy, massive infiltration of aspergillus without any cellular responses was found in their lungs. The analysis of 30 cases of reported childhood leukemia and malignant lymphoma with pulmonary aspergillosis, including the present two cases, revealed the following : (1) acute leukemia as the most prevalent of the primary diseases, (2) the frequent prophylaxis with antifungal agents, (3) higher survival rate in remission state of primary diseases, (4) development of aspergilloma and its surgical resection in most of the survival cases, (5) intravenous AMPH-B therapy in most of the survival cases, (6) massive hemothorax as the major cause of death in remission, and (7) definite diagnosis of pulmonary aspergillosis only by the resection or autopsy in most cases. These findings indicate the importance of reliable prophylaxis and early diagnosis of aspergillosis.

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A 4-year-old boy with Ki-1 lymphoma showing remarkable hyperferrtinemia is described. On admission, he complained of fever, wheezing and swelling of cervical lymph nodes but most of laboratory data including ferittin and LDH were within normal range. About 2 weeks later, the first biopsy of cervical lymph node was done, and the histological findings showed phagocytosis without malignant cells, suggesting VAHS (virus-associated hemophagocytic syndrome). In spite of treatment with prednisolone his clinical course got worse and laboratory findings indicated high level of serum ferritin (3, 595 ng/ml) and LDH (2, 891 IU/l). The second biopsy of cervical, temporal lymph nodes and skin revealed malignant cells with phagocytosis, suggesting malignant hisfiocytosis. Furthermore, immunohistochemical staining using cryosections of these tissues revealed positive labeling of Ki-1 (CD30), EMA (epithelial membrane antigen), IL-2R (interleukin 2 receptor, CD25), but negative labeling of Leu-Ml (CD25). These results could enable us to diagnose him as Ki-1 lymphoma. Radiation and chemotherapy with etoposide (VP 16), pirarubicin (THP-ADR), methylprednisolone (mPSL), cytarabin (Ara-C) had a partial remission, and he died of intracranial hemorrhage 3 months after clinical onset. Serum ferritin (35, 181 ng/ml) as well as LDH (7, 110 IU/ l) more remarkably increased at his terminal stage. Though hyperferritinemia is not always associated with Ki-1 lymphoma, this case might show that serum ferritin could be a good marker for clinical course in some patients with Ki-1 lymphoma.

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A 10-year-old boy developed, at 1 year of age, chronic ear discharge, hemorrhagic skin rash, osteolytic skull lesions and lymphadenopathy, and at age 2 the diagnosis of Langerhans cell histiocytosis (LCH) was made by skull and skin biopsies. While receiving multiagent chemotherapies, the patient showed new bone lesions and hepatosplenomegaly, but did not have major organ dysfunction. Etoposide (VP16) was found to be partially effective, but the patient did not respond to radiation, interferon-alpha and cyclosporine therapy. At age 6 he was found to have growth hormone (GH) deficiency, when MRI-CT revealed sphenoidal sinus filled by soft tissue, pituitary stalk thickening and absence of the normal posterior pituitary bright spot on T₁-weighted image. Six months later, he developed diabetes insipidus. At age 7, VP16 was withdrawn because of good partial response when a total dosage of VP16 reached 15, 400 mg/m². At age 8, the patient attained a complete remission and chemotherapy was stopped. He has kept complete remission since then with replacement of GH and DDAVP alone.

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Epstein's triad is a syndrome with a combination of macrothrombocytopenia, deafness and nephritis. We report a case of Epstein syndrome ; furthermore, we examined various platelet antibodies. A 14-year-old girl, who had been diagnosed as having chronic thrombocytopenic purpura at 3 years old, was first referred to our university hospital in 1991 for refractory thrombocytopenia. She had shown progressive sensorineural hearing loss bilaterally at 6 years old. Her platelet count was 1, 000/μl, and the peripheral blood smears showed giant platelet. At age 15, she developed glomerulonephritis. There were no abnormal inclusion bodies in the leukocytes. She was treated with interferon, prednisolone and high dose γ-globulin (400 mg/day X 5 days). But her platelet was not increased and hypermenorrhea continued. So she underwent splenectomy on August 12, 1992. Consequently the platelet count was not increased but hypermenorrhea was remarkably improved. Her platelet associated immunoglobulin G, platelet associated immunoglobulin M, and platelet binding immuno-globulin G were positive, 62.0% (control 4.6%), 41.8% (control 10.1%), and 68.5% (control 25.5%) respectively. On the contrary, specific antibodies to glycoprotein IIb/IIIa were negative. This data suggested that im-munological abnormalities have a part in mechanism of thrombocytopenia in Epstein syndrome.

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Although recombinant granulocyte colony stimulating factor (rG-CSF) improves a prognosis of congenital neutropenia patients, we report here a 5-year-old female congenital neutropenia who did not respond to rG-CSF therapy and received allogeneic bone marrow transplantation. Bone marrow cells were transplanted from her HLA-matched sister following a thoracoabdominal irradiation and cyclophosphamide preconditioning therapy. Her peripheral blood neutrophils reached 500/μl on day 19. Complete blood counts were normal and stable, and also a frequency of bacterial infection was markedly reduced. However, hemopoietic cells showed mixed chimerism on day 244 and thereafter. On day 540 she showed pancytopenia unexpectedly and was suspected of a late phase marrow rejection. Despite the neutrophil response to high dose rG-CSF, donor hemopoiesis did not recover. The second transplant was performed from the same donor and with conditioning regimen which included cyclophosphamide with total body plus total lymph node irradiation. Donor cells were rejected again and she died on day 51 of the second transplant. It is discussed that a preconditioning therapy for these patients should be intensified with other immunosupressants.

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We report a case of refractory acute lymphoblastic leukemia (ALL) who was successfully treated with Erwinia L-asparaginase (L-Asp). A 6-year-old boy with ALL had been treated according to Children's Cancer Study Group Protocol ALL-871. He relapsed after 31 months of complete remission, during which he had received Escherichia coli L-Asp at a dose of 2, 000 u/m² intravenously for 42 doses. During the reinduction therapy, he developed an anaphylactic reaction after injection of eighth dose of E. coli L-Asp. Other regimens without L-Asp failed to induce remission. Since the chemosensitivity test using MTT dye reduction assay showed that his blasts were still sensitive to L-Asp, he was administered the novel regimen with Erwinia L-Agp, Ara-C, methotrexate, vincristine and prednisolone. The remission was achieved without any hypersensitive reactions. His anti-L-Asp IgG antibody titer was as high as 94 U/ml. It is concluded that Erwinia L-Asp might be useful without significant adverse effects when hypersensitive reactions to E. coli preparation have occurred.

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