In an attempt to establish the treatment system for adult acute leukemia, the effects of multicombination regimens using new agents currently developed in Japan have been studied in a prospective randomized cooperative trial supported by a Grant-in-Aid from Japanese Foundation for Multidisplinary Treatment of Cancer (chaiman: Dr. Kiyoji Kimura). The combined drugs used for AML were as follows: regimenA; BH-AC+DNR+6MP+PSL (BH-AC·DMP) or regimen B; BH-AC+ACM+6MP+PSL (BH-AC·AMP). The drugs used for ALL were regimen C; ADM+VCR+PSL (AdVP) or regimen D; ADM+VCR+L-ASP+PSL (L-AdVP). The 58 institutions are involved in this study. Since April, 1983 to August, 1984, 505 adults with acute leukemia, previously untreated, have been entered. of them the remission induction therapy have been completed in 253 patients, of whom 94 evaluable patients had regimen A, 87 regimen B, 36 regimen C and 36 regimen D, respectively. There were no statistical differences as to age, sex, FAB classification or hematological findings between group A and group B or group C and Group D. The remission rate of each group was as follows: 68% in group A, 55% in group B, 58% in group C and 67% in group D. Although there were no statistical differences as to remission durations between group A and group B or group C and group D, the survival time of group A was superior to that of group B at the present time (p<0.01).

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Results of combination chemotherapy were analysed in 17 patients with Hodgkin's disease and 110 patients with non-Hodgkin's lymphoma who were registered in the Department of Medicine, Okayama University Hospital between 1973 and 1983. Complete response rate was 88% for Hodgkin's disease and 53% for non-Hodgkin's lymphoma; 17% (1/6) for diffuse small, 60% (3/5) for follicular medium, 75% (3/4) for follicular large, 60% (15/25) for diffuse medium, 64% (27/42) for diffuse large, 45% (5/11) for diffuse mixed, and 38% (3/8) for lymphoblastic lymphoma. As for Hodgkin's disease, the actuarial relapse-free survival rate at 5 years was 61% for patients who achieved complete remission: the actuarial survival at 5 years was 84% for patients who achieved complete remission, and 71% for all patients. Patients with diffuse small or follicular medium lymphoma had a favorable prognosis than those with other histologic type of non-Hodgkin's lymphoma: 8 of the 11 patients are still alive between 1 and 8 years. For diffuse medium lymphoma patients, median survival time was 4 years and 8 months, and the actuarial survival rate at 5 years was 41%. The figures were 1 year and 10 months, and 29% for patients with diffuse large lymphoma, respectively. As for diffuse large lymphoma, median survival of patients who had complete remission was 4 years, with 43% of patients still alive and free of disease between 1.5 and 10 years, compared to only 9 months median survival for patients who failed to have complete remission. These results suggested that diffuse large lymphoma was potentially curable by intensive chemotherapy. Phase II studies of mitoxantrone, etoposide, and cisplatin conducted in our Departmant revealed that these drugs were non-cross-resistant to conventional drugs which had been used for malignant lymphoma. Based on the results, we have conducted a phase III study of a 4-drug combination of these 3 drugs plus prednisolone in refractory lymphoma patients, since January, 1984. Out of 14 patients, 3 responded completely and 4 did partially, so far. The regimen would appear useful as a salvage therapy for patients who are refractory to standard regimens.

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Forty nine patients, 43 with acute leukemia and 6 with chronic leukemia, were treated with chemotherapy, total body irradiation and bone marrow transplantation from allogeneic or syngeneic donors.
Among 43 patients with acute leukemia, 13 patients were given allogeneic marrow graft at the first complete remission stage and their relapse-free survival and relapse rate were 69.2% and 23.1% respectively. Another eight patients were given allogeneic marrow graft at the second or third remission stage and their relapse-free survival and relapse rate were 37.5% and 37.5% respectively. The remaining 22 patients received allogeneic or syngeneic marrow graft at the time of leukemia relapse and all died within 16 months after the transplantion.
Among six patients with chronic myelogenous leukemia, two patients were given allogeneic marrow graft at the chronic phase and the other four patients received allogeneic marrow graft at the time of blastic crisis, and one out of two patients transplanted at the chronic phase was alive.
Twenty out of 49 patients (40.8%) developed interstitial pneumonitis and 17 out of 20 patients died of this complication. Acute GVHD occurred at 59% of the patients and chronic GVHD developed at 63% of long-term (>100 days) survivors. Relapse-free survival rate of the patients who had experienced chronic GVHD was 62.5%, which was higher than that (20%) of the patients who lacked the sign of GVHD.

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In a biological viewpoint, a leukemic cell may be regarded as an abnormal cell deviated from a normal differentiation of hematopoiesis.
We succeeded in inducing an in-vitro differentiation of four in-vitro cultured leukemic cell lines (HL 60, NKM-1, U 937, KG-1) when treated with either retinoic acid (RA) and/or γ-interferon (γ-IF) or TPA. During this differentiation, antigeneic alterations on the surface of leukemic cells were examined with a panel of monoclonal antibodies named “HHM” series, which were produced in our laboratory and all of which are specific to myeloid cells. As a result, the cell surface antigens recognized by those antibodies varied qualitatively and quantititively in an accordance with the distribution of those antigens which were previously attested in various differentiation steps of normal hematopoietic cells. Amongst these findings, it is interesting that the antigen detected by HHM 5 antibody is expressed more while the one detected by HHM 6 and 7 antibody exists less on the cell surface as the leukemic cells mature in a vitro.

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As one of approaches for studying the curability of acute leukemia, we have bene investigating the clinical features of patients with acute leukemia for these 20 years who survived 5 years or longer after diagnosis of the disease. The data have resulted from the 862 patients with acute leukemia who were collected from main medical institutes throughout the country. There were 681 patients in children and 181 in adults, ranging from 0 year to 68 years of age. They included 261 in myeloblastic (ANLL), 593 in lymphoblastic (ALL) and 8 in unknown type. The predominant regimen for remission induction treatment was VCR+STH (VP) in children and DM+CA+6MP+STH (DCMP) in adults, respectively. In 57 patients who attained a CR with a single agent, their leukemic cells may have been remarkably sensitive to antileukemic agents.
The primary sites of leukemic relapse in adults were mostly in the bone marrow (95%), whereas those in children were not only in the marrow (39%), but also in the CNS (35.6%) and in the testis/ovary (16.5%).
With regard to prognosis of long-term survivors, the survival curves analysed by Kaplan-Meier's methods demonstrated that the longer the duration of maintenance treatment, the better the prognosis. The patients who had been treated for at least 5 years had a significantly longer survival than those who had been treated for less than 5 years. CNS prophylaxis was not likely to affect the prevention of CNS leukemia relapse, but contributed to prolongation of survival in patietns who received CNS prophylaxis.
Thus, when conventional maintenance therapy is utilized, there is no evidence at present of leukemic cure, but an initial 5 years maintenance treatment appears to be an important step for leukemic cure.

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M0-marrow is defined as a condition in which no apparent leukemia cell is seen in the bone marrow morphologically, cytogenetically or immunologically. However, M0-marrow may contain minimal residual leukemia (MRL) cells. Therefore, the treatment for MRL after complete remission is nessesary for curing the acute leukemia. Although it is not easy to evaluate the effect of treatment for MRL, the author conclude that the treatment would be effective if the prolongation of remission duration and the cure of the leukemia were achieved.
After reviewing patients with acute leukemia in remission, the treatment for MRL is considered to be effective if it is done more intensively and as early as possible after complete remission. Following therapies are in progress in our department; intensive post induction treatment similar to induction chemotherapy or high dose ara-C for AML, and intensive chemotherapy with severely myelosuppressive drugs (ADR or DNR, ara-C, CY and pred) after LVP regimen for ALL.

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Consecutive 208 patients with non-Hodgkin's lymphoma treated in National Cancer Center Hospital from 1975 to end of 1981 were analysed with respect to surface phenotype, primary site of tumor, and prognosis. Most of the non-Hodgkin's lymphomas that arose from the tonsil, digestive tract, breast, testis, brain and ovarium were found to be B-lymphoma, while most of the non-Hodgkin's lymphomas that arose from the thymus, skin and nasal cavity were T-lymphoma. In the cases of nodal non-Hodgkin's lymphoma, most lymphomas in stage 1 and 2 were found to be B-lymphoma, while lymphomas in stage 3 and 4 consisted of almost equal numbers of T- and B-lymphoma. Prognosis of non-Hodgkin's lymphoma was much influenced by cell lineage and its primary site: In general, prognosis of B-lymphoma was better than that of T-lymphoma. B-lymphoma that arose from the tonsil and stomach had the best prognosis, while that arising from the intestine, lymph node, breast, testis, brain, and ovarium had a poor prognosis. These results indicate that classification of non-Hodgkin's lymphomas should be based on their cell lineage for the purpose of establishing disease entity and elucidating prognostic factors based on new concept.

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Natural killer (NK) cell activity against K 562 target cells in a 6-hour chromium release assay showed a wide range of reactivities but was found decreased during chemotherapy (mean value: 29.8%) in peripheral blood mononuclear cells from 44 patients with malignant lymphoma, when compared to before chemotherapy (45.8%) and in remission (68.4%) (p<0.01). NK cell activity in responders, even with advanced disease, by VEPA therapy (vincristine, cyclophosphamide, prednisolone, adriamycin) recovered arround 20 th day and remained at an increased level despite of continued chemotheiapy. In contrast it was not restored in nonresponders with progressive disease and poor prognosis. At late relapse the restored value decreased again (30.9%). NK cell activities were similar in patients with Hodgkin's disease and with non-Hodgkin lymphoma. There were no statistically significant correlations between NK cell activity and site of origin, histology or cell surface markers. The distribution of NK cells in lymph nodes were determined with the use of monoclonal antibody (Leu-7) and immunohistologic methods (Avidin-Biotin-Peroxidase Complex). As compared with diffuse lymphoma, follicular lymphoma had more Leu-7+cells, which were found in the perifollicular areas as well as within the nodules. In a case of follicular lymphoma, however, the numbers of the Leu-7+cells decreased and the peripheral blood had lower NK cell activity, when the nodular pattern was lost. It is suggested that NK cell activity and its tissue distribution are additional prognostic factors in patients with malignant lymphoma.

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Forty nine patients with acute non-lymphocytic leukemia who had not been able to enter a complete remission were classified into 6 subtypes according to the classification of remission induction failures proposed by Preisler. The incidence of subtypes of failure were as follows, Type I (substantial drug resistance): 51.0%, Type II (relative drug resistance): 14.3%, Type III (regeneration failure): 0%, Type IV (hypoplastic death): 8.2%, Type V (inadequate trial): 26.5% and Type VI (extramedullary failure): 0%.
Although more than half of patients were classified into type I, some factors were associated with type V, such as M3 in FAB classification, DMP therapy, hyperleukocytic leukemia and thrombocytopenia under 20,000/cmm. Sixteen out of 49 (32.7%) were the elderly patients who were over 65 years old.
The causes of death in remission induction failures were infection (47.9%), hemorrhage (33.3%) and failure of major organs. Median survival was type I: 97 days, type II: 115 days, type IV: 25.5 days and type V: 5 days, respectively. This analysis provided useful informations concerning the treatment of adult acute non-lymphocytic leukemia.

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Fourteen patients diagnosed as having myelodysplastic syndromes (MDS) according to the classification of the French-American-British Co-operative Group are described. These patients consisted of three cases of refractory anemia, seven cases of refractory anemia with excess of blasts, and four cases of refractory anemia with excess of blasts in transformation. Three of them died due to infection or hemorrhage in preleukemic states. Nine developed overt leukemia within 1 to 31 months (median, 13 months) after the time of diagnosis of MDS. Only one of six patients treated with chemotherapy achieved complete remission. Median survival time of nine patients who developed leukemia was 4 months from the of diagnosis of leukemia. This was not significantly different from that of 26 senile patients with acute nonlymphocytic leukemia without preceding preleukemic states. Our study indicates that patients with MDS are always exposed to dangers such as infection and hemorrhage, and that most of them develop overt leukemia refratory to chemotherapy, and the prediction of the development of leukemia is difficult.

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A 63-year-old woman was diagnosed as non-Hodgkin's lymphoma (small cell type) by histopathological findings of the resected specimen of the rectum in 1980 and treated by some chemotherapeutics. In March 1983, she was pointed out to have the enlargement of mediastinal lymphnode and abnormal accumulation on Ga scyncygram. She was diagnosed as relapse of malignant lymphoma and treated with 2 courses of CHOP regimen. At that time, she was also pointed out the existence of carcinoma colli uteri and required hysterectomy. The operation was done after confirmation of the improvement by means of myelosuppresive chemotherapy. After the operation slight fever developed, and she was treated with cephazolin and micronomycin for 3 days, and then amoxicillin was administered. Next day, high fever developed and sore throat, hoarsness, exanthema, erosion in oral cavity, cheilitis, conjunctivitis, DIC, elevation of GOT, GPT and pancytopenia developed one after another. The findings of bone marrow biopsy revealed disappearence of hematopoietic cells. In spite of a large dose corticosteroid therapy, adult respiratory distress syndrome developed and died of respiratory and renal failure.
It was supposed that her various manifestations were induced by drugs, especially by amoxicillin, on judging from clinical course.

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A 4-year-old boy was referred to Shizuoka Children's Hospital with the diagnosis of acute lymphoblastic leakemia. At the age of 1 he had been diagnosed as idiopathic thrombocytopenic purpura (ITP) and treated with low dose prednisone without significant effects. Three years and 6 months later he developed cervical lymphadenopathy, hepatosplenomegaly and leukocytosis with excess of blasts. The determination of surface markers revealed that the blasts were T-cell origin. After intensive induction chemotherapy complete remission was obtained and the platelet count returned to normal. However, leukemia relapsed earlier both in central nervous system and bone marrow.
On the basis of review of literature we suggest the classification of leukemia related with chronic thrombocytopenia in the following cases;
1) Leukemia developed during the course of preleukemia manifested as thrombocytopenia.
2) Leukemia developed during the course of thrombocytopenia with decreased mgakaryocytes.
3) Leukemia developed during the course of almost typical ITP.
4) Leukemia developed as a second malignancy subsequent to treatment of ITP with immunosuppressive agents.
5) Leukemia followed by ITP.

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We report a patient with Burkitt's lymphoma who showed hypercalcemia at allogeneic bone marrow transplantation. A 12-year-old boy was admitted because of right neck tumor. The pathological diagnosis of Burkitt's lymphoma carrying IgM with λ was made. Cytogenetic analysis of infiltrated bone marrow showed t(8;14)(q24;q32). Chemotherapy of VEPA, AAAP and NIH75-6 regimen were performed without success. After intensive chemotherapy and conditioning of the administration of cyclophosphamide and total-body-irradiation, 6.2×10⁸/kg marrow nucleated cells from an HLA-identical sibling were infused. Between 2 days before and 3 days after grafting, there happened hypercalcemia up to 16.9 mg/dl.
Nineteen days after grafting, skin lesions like graft-versus-host disease appeared, but lymphoma cells increased in bone marrow. Although chemotherapy was performed he died of respiratory failure 43 days after grafting. Autopsy revealed infiltration of lymphoma cells into multiorgans and general candidiasis. At the end of his life, serum phosphate level decreased seriously to 0.4 mg/dl. Hypercalcemia and hypophosphatemia are though to be caused by acute tumor lysis syndrome and sequestration of phosphate into lymphoma cells, respectively. Because this syndrome is common to associate with hypocalcemia, hypercalcemia of this patient was thought to be quite rare.

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We report a reactive histiocytosis complicated with malignant lymphoma in two children.
A 3-year-old girl was admitted because of fever and hepatomegaly, Bone marrow aspiration showed cytological benign histiocytes with platelet and erythrocyte phagocytosis and leukopha-gocytosis. Exploratory laparotomy disclosed similar histiocytes with prominent hemophagocytosis in the spleen. There were no malignant cells in the marrow, spleen and paraaortic lymph nodes. She was treated with chloramphenicol and lincomycin, because a blood culture revealed anaerobic bacilli. There was a striking clinical improvement for three weeks. Autopsy demonstrated infiltration of malignant lymphoma cells in many organs.
A 8-year-old girl was admitted because of fever and cervical lymphadenopathy. Bone marrow aspiration and skin biopsy showed cytological benign histiocytes with phagocytosis. Histological examination of the cervical lymph nodes revealed striking necrosis with a few lymphoid cells. Epstein-Barr virus infection is likely to cause a reactive histiocytosis in the patient. Autopsy demonstrated infiltration of malignant lymphoma cells in many organs. Conclusively, immunodeficiency followed to malignant lymphoma might induce reactive histiocytosis in our caes.

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A 7-year-old boy with acute monocytic leukemia of which blasts carried sheep erythrocyte receptor and the antigens recognized by OKT 11, is reported. The leukemic cells were immature monocytic cells with negative peroxidase reaction, and positive α-naphthyl butyrate esterase reaction which was inhibited by the addition of NaF. Phagocytic activity of the leukemic blasts was absent. The majority of the leukemic cells expressed the myelomonocytoid phenotype in terms of the positive reactions of anti-Ia like antigen antibodies, anti-myeloid-monocytoid antigen antibodies, and IgG-Fc receptor. In addition, the leukemic cells apparently expressed SRBC receptor and the antigen recognized by OKT 11, although they did not express other T-lymhocyte specific antigens, B-lymphocyte antigens and CALLA. The karyotype of the leukemic cells was 48, XYY, +19, 8p^-. He died of intracranial hemorrhage at the 4th day after admission. This observation suggests the possibility that immature monocytic cells might possess sheep erythrocyte receptor and the antigen defined by OKT 11 monoclonal antibody during the maturation.

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A 17-year-old girl was admitted to our hospital on January 30, 1984 because of pancytopenia after acute non-A non-B hepatitis. A diagnosis of severe aplastic anemia after acute hepatitis was made from the following: granulocyte count 90/cmm, reticulocyte count 5,000/cmm, platelet count 15,000/cmm, and marked hypocellular marrow. Bolus methyl-prednisolone therapy was started. However, there was no clinical response to this therapy, and the patient devloped bacterial pneumonia and gastrointestinal bleeding. Pneumonia was improved by antibiotics with granulocyte infusions from random donors. She was conditioned for grafting with cyclophosphamide 50 mg/kg/day for 4 successive days and bone marrow cells (6.3×10⁸ cells/kg) from her HLA A, B, C matched sister were infused.
Hematological findings were gradually improved, and her blood cell type was changed to the donor's on day 75 after BMT. On day 82, GVHD appeared and lasted 2 months. She died with sepsis on day 137 after BMT.
In addition, we studied the effects of serial sera of the patint on colony formation of normal bone marrow cells. Bivef discussion is made on inhibitory effect in relation to pathogenesis of posthepatitic aplastic anemia.

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Adult T cell Leukemia-Lymphoma (ATLL) had attracted public attention because of its geographic distribution and familial aggregation. Recently, it was determined that ATL-virus (ATLV) play an important role in the occurrence of ATLL.
Up to the present day, 21 families were reported as aggregation of malignant lymphoma in Japan. Participation of the genetic and environmental factors has been emphasized. In this paper, five lymphoid malignancies in one family are reported and living healthy members were studies in respect to ATLV infection. ATLL associated antigen (ATLA) was 60% positive, anti-ATLA antibody was 73% positive in this family. These findings suggest that this family members have been frequently infected with ATLV.
Many questions have been unsolved about the way of ATLV infection and the mechanism of ATLV's oncogenesis. So it is worthwhile examining the familial outbreak of malignant lymphoma.

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Non-activated and activated prothrombin complex concentrates, Proplex and Feiba, were used for the treatment of bleeding episodes in a hemophilia B patient with high titer inhibitor against factor IX (40∼50 Bethesda units). 28 of 40 (70%) and 17 of 21 (81%) bleeding episodes were successfully treated with Proplex and Feiba, respectively. Prothrombin time and activated partial thromboplastin time were markedly shortened after infusion of both concentrates but the plasma level of fibrinopeptide A was significantly increased only after Feiba infusion, while that of activated factor VII was more elevated after infusion of Proplex than Feiba. Thus activated factor VII may not be so much implicated in the inhibitor bypassing activity of Feiba. Both Proplex and Feiba contain factor IX and were repeatedly infused but the level of factor IX inhibitor was scarcely increased. The presence of an immune complex of factor IX and its inhibitor was tested by crossed immunoelectrophoresis but was not detected in the plasma even after infusion of Proplex and Feiba. Feiba seems to be the most effective drug for the treatment of bleeding episodes in hemophiliacs with inhibitor but rapid infusion of large amount of Feiba might induce intravascular coagulation.

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A 65-year-old male was diagnosed as primary myelofibrosis on December, 1981, because of splenomegaly, peripheral blood leukoerythroblastosis and bone marrow fibrosis with increased megakaryocytes. He was admitted to our hospital because of marked splenomegaly and anorexia on February 5, 1983. We performed splenectomy when pancytopenia was progressing. On July 18, he complicated with nephrotic syndrome. Further, he was diagnosed as interstitial pneumonia with extramedullary hematopoiesis by transbronchial lung biopsy on November 7. Immature cells in the peripheral blood gradually increased in number and on January 4, 1984, 44% of leukocytes were blasts. The majority of the blasts were myeloblasts but occasionally, blasts suspected of immature megakaryoblasts were seen. Chromosomal analysis of the peripheral blood showed 46, XY, +C, -E. He died of heart failure on February 2. The autopsy revealed marked fibrosis in the bone marrow and extramedullary hematopoiesis of myeloid series and megakaryocytes in the liver, lung, kidneys and adrenal glands. Microscopic picture of the kidneys was focal glomerulonephritis and deposition of immune complexes in the glomerulus was not found by electron microscope. The clinical course of this case is suggestive of clonal proliferation of pluripotential myeloid stem cell.

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A 76-year-old man was admitted to our hospital because of exertional dyspnea and headache in June, 1983. Blood studies showed pancytopenia with an increase of lymphoid cells. Bone marrow aspiration was dry tap and biopsy of the marrow showed proliferation of lymphoid cells. A diagnosis of primary macroglobulinemia was made based on his laboratory findings. He was treated with VP-16, a semisynthetic podophyllotoxin derivative, and received frequent transfusions of blood. There was gradual symptomatic improvement and reduced M component. But he experienced anorexia and general fatigue in December, 1983. His serum transaminase level was markedly increased and HbsAg became positive. He became rapidly icteric and lapsed into Grade 3 coma. All efforts at treatment were unsuccessful and he died from GI bleeding. It was suggested that recovery of immunocompetence after the withdrawal of chemotherapy resulted in this fulminant hepatitis B.

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