Iron overload is found clinically in such conditions as hemochromatosis and sideroblastic anemia, and after long term repeated transfusion in aplastic anemia.
An animal model of iron overload was successfully developed in rats and rabbits by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe³⁺-NTA). This procedure induced a diabetic state with hyperglycemia, ketonemia, glycosuria and ketonuria. Blood venesection on these rats reduced the iron load in the liver and pancreas, and ameliorated the general diabetic symptoms.
A single injection of Fe³⁺-NTA in rats induced a temporary elevation in plasma iron concentration, lipid peroxidation in the perfused liver homogenate expressed by malondialdehyde (MDA) formation, blood GOT, GPT, ALP and γ-GTP sequentially. Fe³⁺-NTA uptake in the liver caused membrane lipid peroxidation, and subsequently produced a transit liberation of liver cell enzymes, although the incorporated liver Fe³⁺-NTA was only 1% of the injected dosage (7.5 mg iron/kg BW) at 3 hr after injection.
The direct toxic effect of Fe³⁺-NTA to living cells was examined using cultured normal rat liver parenchymal cells (RL-34). Marked cytolysis was found in cells exposed to more than 25 μg of iron through Fe³⁺-NTA/ml. At 50 μg iron of Fe³⁺-NTA/ml, most cells were lethally injured and the remaining cells were piled up and aggregated at 15 days. They grew on soft agar culture, and when inoculated subcutaneously to five newly born rats a subcutaneous tumor developed in all animals within three weeks. Lung metastases were found in three of five inoculated rats.
A spin trapping technique with electron spin resonance (ESR) on Fe³⁺-NTA employing 5, 5-dimethyl-l-pyrroline-N-oxide (DMPO) yielded a spin adduct with three doublets (DMPO-Z) which corresponded to singlet oxygen. By ESR in the presence of H₂O₂, the Fe³⁺-NTA solution strongly generated hydroxyl radical. The production of active oxygen species by Fe³⁺-NTA solution may explain the toxicity and carcinogenicity of Fe³⁺-NTA.
The majority of stainable iron in the iron overloaded tissue was hemosiderin (Hs). We tried to purify the Hs from multi-transfused human spleen by the method of Weir et al. The purified Hs did not show a DMPO-OH adducts in the presence of H₂O₂ and DMPO on ESR measurement. The Hs iron was solubilized with several biological ligands in an acidic state in the presence of a reducing reagent like glutathione. Solubilized Hs iron produced iron chelate complexes which resulted in OH radicals production in the presence of H₂O₂ in acidic conditions below pH 5.5. The hydroxy radical may damage the DNA as well as the cell organella. Lysosomes and anoxic conditions, as well as inflammatory conditions attain pH 5.5.-5.0. Our results may elucidate the toxic Hs effects in iron overload tissues.

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One of the major problems in cancer chemotherapy is the development of drug resistance during treatment. The nature of drug resistance in cancer patients is complex. Recently, it has been found that tumor cells can acquire resistance to anticancer drugs. It is now generally accepted that drug resistance at the cellular level (cellular resistance) is also an important mechanism of drug resistance in patients.
The elucidation of the resistance mechanisms has progressed well recently owing to the application of cellular and molecular techniques in addition to the usual biological and biochemical techniques. In this article, I describe the mechanisms of cellular resistance, especially those of multidrug resistance at the molecular level, and I also discuss possible approaches to overcoming drug resistance.

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The thymic epitheliums educate the pre-T lymphocytes from bone marrow by either direct contact or humoral stimulation and support their differentiation, proliferation and maturation. Thymic abnormalities include pathological involution, germinal center formation and tumor. Historically, many disorders associated with thymic abnormality have been reported. In this lecture, the structures and functions of human thymus, and immunological and hematological disorders related to thymic abnormalities such as myasthenia gravis, pure red cell aplasia, immunodeficiecy syndromes, immunoglobulin dyscrasias, acute T cell-leukemia, Hodgkin disease and lymphocytic lymphoma were reviewed. These extensive reviews suggested “Pharyngeal Pouch Syndrome” and it's significant roles in hematology.

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One hundred and thirty one different hemoglobin (Hb) variants and 134 families with thalassemia syndrome were reported during 30 years search for hemoglobinopathy in Japan. Studies on their molecular pathology and gene abnormalities have elucidated the effects of base substitution in the genomic DNA. The expression of the abnormal gene products decreases in a graded manner as follows: hemoglobinopathies due to stable Hb variants→unstable Hb disorder→hyperustable Hb disorder→thalassemic expression of Hb variants→thalassemia syndorome without abnormal gene product.

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One hundred ninety six previously untreated patients of adult acute nonlymphocytic leukemia (ANLL) were treated with B-DOMP therapy. 102 patients were treated in the conventional rooms and 94 patients were in the laminar airflow rooms.
The complete remission (CR) rates were 78.4%, and 84.0% respectively. The CR rate of the groups whose age was 60 years or older was higher for the patients treated in the laminar airflow room than those is conventional rooms (75.8% versus 60.0%), and the fatality from fungal infection was substantially lower for the laminar air-flow room patients.
Non cross resistant chemotherapy based on alternate administration of Daunorubicin (DNR) and Aclarubicin (ACR) was given to 54 pationts with ANLL in remission. The median duration of remission was 48.0 months, with 38.4%, patients in remission at 8 years. A plateau phase indicating freedom from the risk of leukemic recurrence is not clearly apparent yet. The most serious toxicity was drug induced cardiotoxicity from increased total dose by long term maintenance therapy.
Newly planned post remission chemotherapy that incorporated Etoposide and Mitoxantrone with ACR and DNR was given to 35 patients with ANLL in remission. Seventy nine percent (79%) of patients were remaining in remission at 2 years. Because many patients experienced significant side effects after each course of therapy, intensive post remission chemotherapy should be used in a setting where the physician is alwasy attending and ready to serve the patients.

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Based on bone marrow findings and bone marrow stem cell kinetics and response to treatment, we have developed individualization of intensive induction and postremission chemotherapy for adult acute nonlymphocytic leukemia (ANLL). Thirty-four consecutive adults with ANLL were treated with an intensified induction regimen and a high dose sequential postremission therapy consisting of daunomycin, Ara-C, 6-MP and prednisolone (DCMP). The first course of remission induction was continued till achievement of a complete marrow aplasia which resulted in a decrease of leukocyte count less than 0.6∼0.8×10⁹/L, a decrease of marrow nucleated cell count to less than 8×10⁹/L, and a decrease of marrow leukemic cell to less than 5%. Postremission therapy consisted of 4 courses of DCMP and a course of high-dose Ara-C. The first postremission course was initiated within 2∼3 weeks subsequent to the last induction course. Twenty-eight of 34 patients (82.4%) achieved complete remission. The 4 year disease free survival rate was 64.4±14.0%.
The results convinced us that individualized intensive induction and postremision therapy of adult ANLL given at the time of minimal residual leukemic disease in early remission might be sufficiently effective to produce long-term DFS to be considered potential cured.

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Since April, 1978 to October, 1988, 66 acute lymphocytic leukemia (ALL) patients aged 15 to 79 (21 L1, 43 L2, 2 L3/6 Ph¹+) were treated with 3 different therapeutic protocols. The drugs used for induction were VCR (VDS)+Pred, followed by DNR+VCR (VDS)+6MP+Pred and VCR (VDS)+L-asp+Pred in protocol I, Ad+VCR+Pred in protocol II and DNR+VCR+Pred in protocol III. Complete remission (CR) was attained in 72.7% of 66 patients. The CR rate of each group as followings; 71.4% in protocol I and 75.0% in protocol II and III, respectively. The median duration of remission was 10.2 months+and the probability of being in continuous CR at 3 years was 21.9%. For the 48 patients in remission the median survial was 17.8 months and the probability of being alive at 3 years was 24.3%. The intensified induction and consolidation therapy is expected in the cure oriented treatment of adult ALL.

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The overall event-free survival of childhood acute leukemia has increased to 60∼65% in ALL, and to 40∼60% in ANLL. This progress has resulted from a closely integrated scientific effort, including drug development, pharmacology, preclinical modeling, experimental design with respect to clinical trials, quantitative criteria for response, and a series of clinical trials in which the importance of complete remission, of dose and schedule, of sequencing chemotherapentic agents, of pharmacological sanctuaries, and particularly of combination chemotherapy was studied.
In this paper, recent treatment results of acute childhood leukemia made by the Children's Cancer and Leukemia Study Group of Japan were reviewed, and current challenges and future perspectives are discussed.

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We designed a short term intensive chemotherapy (DCMP-85 regimen) that completed 4 courses of postremission therapy without maintenance therapy in an effort to improve remission durations for adult patients with AML. Twenty six patients aged 14-65 yr were entered into this study. The rate of complete remission is 76.9%. A Kaplan-Meier analysis of patients entering remission predicts that 56% of patients will remain in remission at 3 years (median follow-up is 12 mo).
Comparison three different conventional chemotherapies (DC (M) P, DCMP Two Step and BH-AC DMP), DCMP-85 has achieved higher CR rate and 3-year leukemia-free survival rate, so far. Therfore, we conclude short term intensive chemotherapy is getting better results.

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Our analysis of the 9th investigation for long-term survivors of acute leukemia (1988) is based on the answers to the questionnaire sent to about 1400 hospitals all over the country.
This result makes it clear that there exist 2202 long-term survivors in Japan, now, with a recent increasing tendency; that is, 1607 children and 595 adults, and it documents also that the long-term survivors without relapse have extremely better prognosis than the relapsed long-term survivors.

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Prognostic significance of disease features obtained at the time of initial diagnosis was analyzed in 90 patients with chronic myelogenous leukemia (CML) in chronic phase. Median survival of this population was 45.9 months. Univariate analysis revealed that splenomegaly, bone marrow basophils, bone marrow blasts, peripheral blood blasts, and bone marrow eosinophils were significant prognostic factors for survival, and that peripheral blood leukocytes counts, hemoglobin concentration, performance status, age and lymphadenopathy were factors with border line significance. There were multiple interrelationship among these disease features. Multivariate regression analysis identified that age, hemoglobin concentration, and bone marrow blasts were independent primarily significant prognostic factors for survival. The Cox model generated with three variables of age, hemoglobin concentration, and percent blasts in bone marrow provided a useful representation of risk status in the population. A hazard function derived from the patients population segregated patients into three groups with significantly different survival patterns: A lower risk group, an intermediate group and a high risk group of patients with median survival of 57.8, 49.8 and 38.4 months respectively.
Survival after CML blast crisis was short and overall median survival of 54 patients with CML blast crisis was 6.4 months. A sole prognostic factor for survival in blast crisis identified by multivariate analysis was blast cell type at CML blast crisis and patients with lymphoid phenotype had a good prognosis with median survival of 9.8 months. Median survival of myeloid crisis was 4.2 months. No other disease features were identified as significant prognostic factors in the present patient population.

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Eighty-three patients in the chronic phase of Ph¹-positive chronic myelogenous leukemia (CML) have been treated with busulfan or other alkylating agents in a conventional way hitherto acknowledged. During its chronic phase, 31 cases of these 83 had received an additional intermittent therapy every 4 to 6 months, consisting of vincristine 2 mg or vindesine 3 mg per week, prednisolone 20 to 30 mg per day, and partly 6-mercaptopurine 50 to 100 mg, combined with allopurinol 200 to 300 mg per day for 2 to 3 weeks. The 50% survival of these patients using the Kaplan-Meier's method was 73.7 months and 5-year survival was 70.2%, while those of the remainig patients were 41.2 months and 13.4%, respectively.
The second nation-wide survey of long-term survivors of CML in Japan was attempted. CML totalling 195 surviving over 7 years from the initial diagnosis and 113 of CML surviving over one year from the blastic crisis had been collected by the end of March 1988. The longest survivors of the former group was for 21.3 years, while the latter 4.6 years. In addition, recent increase of the annual incidence of the above both groups was clarified. These results strongly support the progress of chemotherapy of CML in recent years.

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At Kanazawa University 28 patients with Hodgkin's disease were treated between 1975 and 1988. Ten patients underwent staging laparotomy by which we had to change the pathological stage in 3 patients because occult splenic lesions were detected histologically. Patients with early disease were treated mainly with radiotherapy (RT) and those with advanced disease received modified MOPP chemotherapy with or without RT. Twenty-six patients entered complete remission, and relapse occured in 7 including 5 patients with stage III disease. Four patients died of the disease and 4 of other causes. The actuarial survival at 5 and 10 years were 80.1% and 47.1% respectively. The actuarial relapse free rate at 10 years was 65.8%. Fourteen patients are in good health after completion of treatment, and 9 healthy babies were born to 5 patients including 3 female patients. The goal of therapy in Hodgkin's disease is cure. Treatment strategy must be based on proper staging and consideration of iatrogenic morbidity such as sterility and second malignancy.

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The long-term survivors of malignant lymphoma who had been treated in Saitama Cancer Center since September 1976 were evaluated. The primary treatment was scheduled as follows; radiotherapy alone was to be delivered to the involved field only in stage I lymphoma with less than 5 cm in diameter, the remaining lymphoma was mainly treated with anthracycline-based combination chemotherapy. 25 patients were treated with primary radiotherapy, and the actuarial 5-yr relapse-free survival rate was 83%. Primary adriamycin-based chemotherapy was given to 20 patients with nodal localized lymphoma. 10 patients died with this treatment and actuarial survival rate at 5 years was 41%. 36 patients with stage II lymphoma involving Waldeyer's ring were treated with primary chemotherapy. Complete response was obtained in 92% with 83% of 5-yr actuarial survival rate. 5-yr actuarial survival rate of 50 patients with advanced stage of lymphoma was 36%, but 69% of responders who obtained complete response had long-term survive. 20 patients aged 70 or older had a 31% actuarial 5-yr survival rate, however, the older patients with localized lymphoma who received primary chemotherapy had a 77% actuarial 5-yr survival rate. 10 older patients of the localized lymphoma arising from Waldeyer's ring are all surviving.

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In order to assess the curability of diffuse non-Hodgkin's lymphoma, a total of 93 patients who had entered into protocol studies in our institution was anlysed retrospectively. Between 1977 and 1988, 53 large cell lymphoma (DL), 16 mixed cell lymphoma (DMx), and 24 medium-sized cell lymphoma (DM) patients with advanced disease were treated with CHOP, CHOP-Bleo, or CHOP-Bleo alternating with POEM-Bleo (5-drug combination of mitoxantrone, etoposide, vincristine, bleomycin, and prednisolone). The complete response rate was 70% for DL, 69% for DMx, and 54% for DM. The response was most durable in DL, compared with DMx and DM: the relapse-free survival rate at 5-year was 71% for DL, both 38% for DMx and DM. Almost all the relapses had occurred within 2 years in DL, DMx and DM, as well, thus responding patients over 2 years after sessation of chemotherapy appeared to have been cured. Relapse-free survival rate was almost the same for T-and B-lymphoma, however, the 5-year survival rate of T-lymphoma was lower than that of B-lymphoma, reflecting the poor complete response rate of the former. Finally, the disease-free survival rate at 5-year was 39% for all the 93 pationts, with a trend favoring for DL histology with a rate of 51%. The alternating CHOP-Bleo/POEM-Bleo regimen appears beneficial compared with conventional regimens such as CHOP and CHOP-Bleo on the basis of response rate and response durability, and these results warrant further clinical trials.

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Major prognostic factors were analyzed by Cox proportional hazard model in 311 patients with B-lymphoma and 141 with T-lymphoma, who were treated with combination chemotherapy as the initial therapy during 1975 to 1987. Poor prognosis was associated with high grade pathology, increaing number of extranodal lesions, advanced stage, initial combination chemotherapy without doxorubicin, low total protein and intestinal lesion in B-lymphoma, but with increasing number of involved lesions, high LDH, low total protein, anemia, skin lesion and patients treated before 1982 in T-lymphoma. First three factors of each disease were the most important with risk ratio more than 2.5. New risk group was made from combination of the factors, which was ordered from low to high hazard rate. The new risk groups for T- and B-lymphoma are usefull for estimation of prognosis and determination of adequate chemotherapy of the patients. The prognostic factors of T-lymphoma were completely different from those of B-lymphoma, suggesting that T- and B-lymphoma are different disease and should be analyzed separately.

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128 cases of ATL (adult T-cell leukemia/lymphoma) were divided into 3 subgroups, 70 cases of acute type, 19 cases of chronic type and 39 cases of lymphoma type, and their prognosis were evaluated.
Median survival time from the oncet of acute type using Kaplan-Meier method was 8 months, that of lymphoma type was 14 months and that of chronic type was 50 months.
Median survival time from the start of treatment of acute type was 5 months, that of lymphoma type was 11 months and that of chronic type was 22 months. Reratively short median survival time of chronic type may be due to they had some duration with observation only at first.
No significant elongation of survival time could be obtained when acute type was devided into 2 stages, before and after 1982.
Twelve patients with non-Hodgkins' lymphoma unresponsive to the first line combination chemotherapy were treated with combination therapy with cis-dichlorodiammineplatinum (CDDP). Ten patients were evaluable for responce (4 cases of CR, 6 cases of PR).
To stop the HTLV-1 carrier mothers milk for giiving their children seems to be effective method to decrease the occurrence of ATL in future.

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Progress in the treatment of multiple myeloma can be considered from several points of view: (1) advent of new therapeutic agents and regimens; (2) the differentiation from variant forms; and (3) the prevention or early treatment of myeloma-associated complications. The author have discussed the following problems connected with the treatment of myeloma patients studied from 1984 to 1988, including (1) ten-year survival in multiple myeloma; (2) complete remission in multiple myeloma; (3) complete remission in primary plasma cell leukemia; (4) systemic amyloidosis in multiple myeloma as the presenting symptom; (5) treatments for patients resistant to standard therapies; (6) treatments and courses of patients with IgD myeloma; (7) multiple myeloma in the aged; (8) treatments for patients with primary extramedullary plasmacytoma; (9) long-term observation of a patient with smoldering multiple myeloma; (10) the outcome of idiopathic Bence Jones proteinuria; and (11) supportive therapies for multiple myeloma.
Since the introduction of melphalan and cyclophosphamide more than two decades ago, progress in the treatment of multiple myeloma has been slow. To overstep the limits in the current chemotherapy, therapeutic strategies for individual cases should be exploited by understanding their biological properties.

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Between 1971 and 1985, 133 patients were diagnosed as symptomatic multiple myeloma. Recently the number and percentage of patients, who were older (70 years old) and type of diffuse proliferation, were remarkably increased.
In 132 previously untreated patients who received chemotherapy, the 50% Survival time was 32 months; thirty-nine (29%) survived more than five years after treatment and 4 of them (3%) survived more than ten years. Among the prognostic factors related to survival time, serum albumin level, M-protein type, bone marrow plasma cell (%), clinical stage and classification according to tumor distribution were considerd to be significantly important.
Clinical responses were evaluated in 120 patients who received combination chemotherapy for at least 3 months. A 50% or more reduction of M-protein was obtained in 58% and a marked improvement in bone pain or motor-disturbance was found in 54%. Overall response rate evaluated by the effects of both objective and subjective symptoms was 43%. New criteria for response defined by the level of serum albumin and M-protein after treatment were proposed.

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The probability of long term survival for allogeneic graft patients was 63% for ALL, 64% for ANL and 40% for CML in the 1st remission or 1st chronic phase of each leukemia. The major causes of death were interstitial pneumonia, relapse of leukemia and infections. On relationship of GVHD and the long term survival, the probability of 5 years survival was 38%, 47% and 25% in grade O, I and II∼IV of acute GVHD respectively.
And the relationship between the relapse rate and GVHD, the patients with both of acute and chronic GVHD showed the lowest relapse rate 15.9%, the patients without GVHD showed the highest relapse rate 37.8% and the patients with either of GVHD showed the rate of between those of two groups. This may suggest that GVHD both acute and chronic might have an ability that can suppress the relapse of leukemia, i.e. GVL reaction.
Interstitial pneumonia occured in 32% of allograft patients and was often lethal complication (53%). Among many of prophylaxis tested, the followings were effective, a lower dose rate of total body irradiation, the selection of CMV-seronegative platelets donor, and the prophylactic administration of anti-CMV high titer globulin. Colony stimulating facter of human urine was also effective for shortening the granulopenic period after transplantation to prevent severe infections.

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Recent progress in biotechnology has uncovered the presence of trace substances which participate in the immunological response between cancer and host, they are cytokines, monoclonal antibodies, and immunomodulating agent which are called as biological response modifiers (BRM).
The genetic engineering anables mass production of these substances, and their clinical application in treating hematological malignancies is expected.
The role of biologically active substances as important pharmacological reagents was initially explored in human with purified interferon. The most recent example of such rapid progress has been with IL-2 and TNF. Clinical trials with recombinant IL-2 and TNF have begun in 1984. Although IL-2 is effective for the activation of T lymphocyte, intravenous injection of IL-2 was not so effective for treatment of hematological malignancies. On the other hand, IL-2 activated Killer cells were potent effectors of adoptive immunotherapy. Tumor necrosis factor, a cytotoxin derived from macrophages showed marked decreases in percentage of leukemic cells of peripheral blood in treating leukemic patients.

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Tissue blocks and vascular casts of the human spleen were studied by scanning electron microscopy. Splenic pulp was composed of white pulp packed with lymphocytes and red pulp which consisted of three dimensional reticular meshwork and splenic sinus. There were at least three types of microcirculation with defferent functions in the human spleen. First, open circulation in the red pulp is engaged in highly sensitive clearance of foreign materials in blood by numerous macrophages resided in splenic cord (culling function). It is also engaged in pitting function by narrow slits of the sinus. The second is the closed circulation occurred in the red pulp in the human spleen. It was represented as an arteriolar labyrinth whose endothelial cells connected with those of sinuses. Blood flow through this circulation is exposed to small number of macrophages in the sinus. It probably corresponds to the fast blood flow in the spleen. Third, microcirculation to the white pulp and marginal zone is engaged in phagocytosis of foreign materials in blood and carriage of their antigenic portions to lymphocytes in the white pulp. Therefore variation of the blood flow through their circulation may bring about a change of the splenic function. Relationship among blood flow, nerve stimulation and immune reaction was discussed.

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In order to investigate the role of the human spleen on hematopoiesis, hematopoietic stem cells and stimulaters were evaluated in fetal and adult spleens. BFU-E and CFU-C were existed in 20 weeks and 23 weeks fetal spleens (BFU-E 145±45/10⁵ mononuclear cells, CFU-C 55±6/10⁵ mononuclear cells). In adult spleen, a few stem cells were recognized, which may be contaminated from peripheral blood in sinus of the spleen. We tested conditioned media from adult spleen cells for the stimulative activity on the in vitro growth of BFU-E and CFU-C from bone marrow mononuclear cells. Spleen conditioned medium stimulated proliferation of these precursor cells. It seemed that PHA-stimulated spleen conditioned medium augmented BFU-E, whereas CFU-C growth was suppressed. Adult and fetal spleens were studied immunohistochemically using anti-G-CSF, GM-CSF and erythropoietin anti-bodies. The cells with G-CSF and GM-CSF were shown in fetal spleens. In adult spleens, however, only GM-CSF was detected.

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The mechanism by which senescent red blood cells (SRBCs) are eliminated from circulation by the reticuloendothelial system was investigated using the newly developed phagocytosis assay.
Phagocytosis of SRBCs and Vibrio cholera neuraminidase (VCN) treated RBCs by autologous macrophages were significantly higher than that of unfractionated RBCs. The phagocytosis of VCN-treated RBCs was enhanced by pre-treatment of RBCs with freshly prepared autologous serum, but not with heat inactivated serum. These results suggest that the erythrophagocytosis is mediated by lectin-like receptors and complement receptors which are present on the surface of macrophages. We also studied the erythrophagocytic capacity of macrophages in the presence of tumor necrosis factor (TNF) as a model of the anemia due to acute inflamation. The phagocytosis of VCN-treated RBCs was enhanced with the addition of a small amount of TNF (1 U/ml). This result suggests that TNF enhances the destruction of damaged RBCs by activating the reticuloendothelial system.

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Clinical and experimental studies on hereditary spherocytosis (HS) and high red cell membrane phosphatidylcholine hemolytic anemia (HPCHA) were performed in relation to lipid metabolism in plasma and in red cells of these patients.
In HS, red cell (RBC) membrane lipids (free cholesterol (FC) and phospholipids (PL) such as phosphatidylethanolamine, phosphatidylcholine (PC), sphingomyelin (SM) and lysophosphatidylcholine (LPC)) were markedly decreased in unsplenectomized HS. Plasma lipids (total cholesterol, FC, HDL-cholesterol, PL) were also decreased in these patients. After splenectomy, substantial normalization of plasma and RBC lipids were observed. Concerning lipid kinetics, the extents of ¹⁴C-PC synthesis in RBC from ¹⁴C-LPC in medium and of ¹⁴C-PC exchange between RBC and the medium were almost identical to those in normal control in the in vitro incubation conditions. These observations indicate that the decreased RBC lipids may be induced by the shortage of lipid materials in plasma in the presence of the spleen.
In unsplenectomized HPCHA, plasma lipids were also decreased same as in HS. In contrast, membrane lipids (FC and PC) were markedly increased. Even after splenectomy, increased PC contents were rather enhanced in their membranes concomitant to developing of hemolytic anemia, although plasma lipids were almost normalized. Thus RBC membrane lipids in HPCHA appeared not to be affected by plasma lipids.
In experimental studies on HPCHA, ¹⁴C-PC synthesis from ¹⁴C-LPC and ¹⁴C-PC uptake in these RBC were increased, in spite that large amounts of PC were already accumulated in these RBC. Thus, increased uptake of LPC and PC from the enviroment appears to be the major cause of the accumulation of PC in the RBC of HPCHA patients.
In addition, it should be noted that splenectomy in HPCHA showed no beneficial effect (rather worsened clinically), and therefore the procedure should be avoided in the HPCHA.

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The mean intrasplenic blood cell transit time (STT), splenic blood cell volume (SV) and the slow mixing splenic blood cell volume (SSV) have been measured in normal subjects and patients with congestive and infiltrative splenomegaly. The normal red cell SV was 0.47±0.14 (mean±SD)% of the circulating red cell volume (RCV). In patients with congestive and infiltrative splenomegaly, SV was 9.82±3.55% and 0.96±0.71% of RCV, respectively. The SSV was 69.1±8.4% of the SV in normal subjects, but in patients with splenomegaly, its value was lower than that of normal SSV. The STT was 0.43±0.11 min in nomal subjects. In the patients with splenomegaly, it prolonged. But, the STT/SV and STT/SSV were rapid in patients with congestive splenomegaly and low in infiltrative splenomegaly It seemed that SST/SV and STT/SSV were useful to distinguish between congestive and infiltrative splenomegaly. In the intrasplenic granulocyte kinetics, SV was similar to that of red cell. The STT was longer than that of red cell, in normal subjects and patients with splenomegaly. In the intrasplenic platelet kinetics, the ratio of cellular splenic volume to general circulation was the largest in platelets. The STT of platelet was the slowest in blood cells.

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The role of splenectomy in the management of hemolytic anemias seems to be established. However, when we decide the indication of this procedure in individual patients, we should make the final judgement after evaluating the following items. The items to be discussed include 1) cause and mechanism of hemolysis, 2) predominant site of red cell destruction, 3) evaluation of splenomegaly, 4) the age of the patient and the time of splenectomy, 5) complications of splenectomy and their proper management, and 6) alternative treatments (including drug therapy) to splenectomy.
After splenectomy, it is important to advise the patients and their families to seek immediate medical attention for febrile illnesses.

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A case of polycythemia vera with an inhibitor against factor XII was reported. A 60-year-old female was admitted to Hokkaido University School Hospital because of erythrocytosis and hepatosplenomegaly. The hemoglobin was 22.5 g/dl and white cell count was 9,500/μl without immature cells. The platelet count was 484,000/μl. Bone marrow specimens showed marked hypercellularity. Philadelphia chromosome was not found on chromosome analysis. She was diagnosed as polycytemia vera according to the criteria of polycythemia Vera Study Group.
Activity of factor XII was found to be decreased on the initial examination, but she had no personal and familial history of bleeding. In order to clarify the cause of decreased activity of factor XII, her plasma was mixed with normal plasma, and then examined PTT using factor XII deficient plasma. Her plasma mixed with equivalent normal plasma did not show the correction of prolonged PTT. It was suggested that an inhibitor of her plasma was included in the IgG fraction using gelchromatography. The patient was treated with phlebotomy and administration of N⁴-palmitoil (1- -D-arabinofurasyl) cytosine (derivative of cytosine arabinoside; PLAC) 200 mg/day and Busulfan (1 mg/day). Factor XII was not corrected by phlebotomy, but corrected gradually by administratin of PLAC and Busulfan.

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A 56-year-old male presented with fever of unknown origin and subacute dementia which progressed to death with seizure, coma and acute deteriaration of general conditions. He had splenomegaly but not skin eruption or lymph node swelling. Autopsy findings showed that mononuclear tumor cells were widespread within the lumens of small blood vessels, indicating the features of neoplastic angioendotheliosis. The involved organs were shown to be brain, lung, adrenal grand, testis, bone marrow, heart and thyroid gland. To determine the origin of tumor cells, an immunohistochemical study was carried out using a panel of monoclonal antibodies. The results indicated that the tumor cells were of B-lymphocyte origin. These findings support the possibility that neoplastic angioendotheliosis is a lymphoma with proliferation in small blood vessels throughout the body.

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A 71-year-old female was diagnosed as hypoplastic leukemia (ALL, L2). VitaminD₃ (D₃) therapy with alfacalcidol was successful and remission continued for approximately 4 months. However, the leukemia became refractory to D₃, and low dose Ara-C combined with D₃ was ineffective.
Combined chemotherapy with vincristine, cyclophosphamide, L-asparaginase and prednisolone, low dose aclarubicin, OK-432 and etretinate ended in a failure.
Treatment with mepitiostane was started and 1 month later obviuos elevation of hemoglobin concentration, white cell and platelet count was observed. A bone marrow aspirate showed distinct recovery of normal hemopoiesis without residual leukemic cells. The patient has been staying in the complete remission for over 15 months with mepitiostane therapy (30 mg, daily).
Androgen therpy, such as mepitiostane, appears to be effective in some patients with hypoplastic leukemia which does not indicate intesive chemotherpy.

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A 13-year-old girl with preB-ALL was admitted because of headache during maintenance therapy including L-asparaginase. Magnetic resonance imaging revealed cerebral thrombosis. Coagulation studies showed decreased levels of fibrinogen, antithrombin-III and plasminogen. The patient was treated with antithrombin-III concentrates and fresh frozen plasma and recovered quickly. These findings suggest that coagulopathy induced by L-asparaginase is associated with the pathogenesis of cerebral thrombosis.

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Currently, there is no satisfactory therapy available for patients with chronic idiopathic thrombocytopenic purpura (ITP) who are unresponsive to conventional therapeutic modalities. In this report, we describe a patient with chronic refractory ITP treated with immobilized protein A in an extracorporeal system. The patient was a 74 years old male diagnosed as ITP in 1980. Despite steroid therapy, the disease progressed and the patient exhibited ecchymosis and gum bleeding which was unresponsive to intravenous gammaglobulin therapy. Severe gastrointestinal bleeding was evident and administration of danazol was discontinued due to liver dysfunction. The patient was treated with extracorporeal protein A immunoabsorption. The patient's whole blood (200∼300 ml per treatment) was separated into plasma and cellular components and the plasma was passed through an immunoabsorption column containing 200 mg of covalently bound protein A. The treated plasma and cellular components were returned to the patient. After 4 immunoabsorption treatments, the platelet counts elevated and there was evidence of improvement in gastrointestinal bleeding. This report indicates that protein A immunoabsorption therapy should be considered in patients with chronic refractory ITP.

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We describe two cases of gastrointestinal lymphoma associated with rapid bone marrow dissemination after surgical resection.
Case 1: A 73-year-old male was diagnosed as having malignant lymphoma originating from ileocaecal region (diffuse medium-sized, B cell type). Tumor (8×8 cm) was resected but infiltrated to the peritoneum and curative operation could not be done. Two weeks after operation, elevation of LDH, pancytopenia and bone marrow infiltration of lymphoma cells developed and he died of respiratory failure.
Case 2: A 69-year-old female was diagnosed as having remnant gastric lymphoma (diffuse large, B cell type). Tumor size was 5×4 cm and swelling of the third lymph nodes was found, so curative operation could not be done. Two months after operation bone marrow infiltration of lymphoma cells was observed and she is now undergoing chemotherapy.
Surgical resection is perfomred in the majority of patients with localized gastrointestinal lymphoma. But the operation of the advanced case must be carefully done, because the operative procedure may sometimes facilitate growth and metastasis of tumor.

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A 14-year-old boy was admitted to Department of Pediatrics at Mie University Hospital with a 12-day history of facial cervical edema associated with venous dilatation on the upper chest wall. On admission anterior mediastinal mass was found on chest X-ray film and computed tomography. A needle biopsy revealed non-Hodgkin's lymphoma, diffuse lymphoblastic type and he was staged as III. He was treated with High-risk lymphoma protocol and achieved complete remission.
At relapse he developed various manifestations unusaual for lymphoblastic lymphoma including peripheral lymphadenopathy, an intramuscular mass of the lt-lower leg, multiple subcutaneous nodules at anterior chest wall and upper abdomen, and pericardial effusion. No lymphomatous infiltration into bone marrow or central nervous system was observed throughout his clinical course. Immunological phenotype of lymphoma cells from pericardial effusion was quite compatible with that of common thymocytes. However cytogenetic analysis showed unique translocation: (2; 5) (q33; q35). Translocations with a break at 5 q 35 have been reported in peripheral T-cell lymphoma and malignant histiocytosis.

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A 60-years-old female with fever and general lymphadenopathy was admitted to our hospital in 1979. By histological examination of cervical lymph node, she was diagnosed as B-cell malignant lymphoma, diffuse, large, stage IV B (Ann Arbor classification). In 1984, the complete remission of malignant lymphoma was observed after MOPP, COPP and VAPP chemotherapies.
After 3 years, she was readmitted because of leukocytosis in which 64% immature abnormal cells were detected. By conventional cytological and cytochemical evaluations, the immature abnormal cells were identified as secondary AML cells with M 2 type (FAB), peroxidase (+), My 7 (+) and chromosomal abnormality; 48, X, -X, +4, -9, +21, del (1) (p 34), i (17q), +M1, +M2. Analysis of Ig and TcR genes showed TcR-β rearrangement.
It has been reported that secondary leukemia frequently causes chromosomal abnormalities and therapy resistance. Ig gene and TcR gene analysis of secondary leukemia combined with chromosome examination, which has reported little, may be useful in predicting prognosis and therapy resistance.

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A case of Kaposi's sarcoma developing during corticosteroid thrapy for idiopathic thrombocytopenic purpura is reported. The patient is a 58-year-old female who was admitted to Sapporo City General Hospital for bleeding tendency in March 1987. She had been treated before admission with prednisolone (over 40 mg/day) for idiopathic thrombocytopenic purpura since October 1986, but her platelet count was below 40,000/ul.
In April 1987, several dark red or blue nodules appeared on the tip of her nose, left forearm, right shoulder, trunk and tongue. These nodules rapidly grew. Biopsy specimens from the nodule of the left forearm showed the histologic changes of Kaposi's sarcoma.
She was treated with irradiation. Splenectomy was done in May 1987 and predinsolone was decreased to 5 mg/day. Her platelet count was continually kept 50,000/ul or more. Her Kaposi's sarcoma completely regressed in January 1988. The relationship of immunosuppressive therapy to Kaposi's sarcoma is discussed.

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A 66-year-old female was diagnosed to have severe aplastic anemia. Remission was not achieved by the ALG-oxymethorone therapy, and she was in need of RBC multitransfusion. After receiving a total of 42 units (16,800 ml) of red blood cells, it was found that her serum agglutinated strongly her own group BI cells at 4°C. This agglutination disappeared in DTT solution. An eluate from her red cells also agglutinated BI panel cells, wheras Bi, 0 I, 0 i cells failed to react. It was apparent that the cold agglutinin in her serum had special affinity for I cells, which also contain B. Analysis of lymphocyte subset in peripheral blood showed T 3 (CD 3) 70.18%, T 4 (CD 4) 70.92%, T 8 (CD 8) 7.08%, T 4/T 8=10.1, T4(+)2H4(+)/T4(+)2H4(-)=1.05. Although relationship between appearance of anti-BI antibody and relative increment of CD 4 positive cells was not clear, we considered that these findings were caused by an abnormal autoimmune reaction in the patient with aplastic anemia.

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A case of methicillin-resistant staphylococcal (MRSA) enterocolitis following combination chemotherapy for acute promyelocytic leukemia is presented. MRSA enterocolitis has characteristic clinical features of high fever, frequent vomiting and watery diarrhea, and its mortality rate is very high without a proper antibiotic therapy. When the patient with hematological malignancy has the above-mentioned clinical manifestations during antineoplastic chemotherapy, appropriate antibiotics for MRSA should be promptly begun before a bacteriological diagnosis.

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