Combination chemotherapy with large dose of bacteriocidal antibiotics for severe infectious episodes of patients with acute leukemia was studied. One antibiotic was selected from either Carbenicillin (CB-PC, 15∼20 Gm/day) or Cephalothin (CET, 4∼12 Gm/day) and the other from Kanamycin (KM, 2 Gm/day), Streptomycin (SM, 2 Gm/day) or Gentamicin (GM, 120∼160 mgm/day) and two antibiotics combined were administered intravenously at regular intervals, i.e., CB-PC or CET every 8 hours by 1 hour infusion and KM, SM, or GM every 12 hours by push. Among 106 infectious episodes in 42 leukemia patients, 46% showed excellent response, 26% good response and 28% failure to these combination antibiotic treatment. There was no difference in response rate between CB-PC group and CET group. Response rate of KM-group (80.5%) was superior to that of SM group (64.7%) and GM group (65.2%). Peripheral granulocyte counts of these patients were markedly reduced, the median of which was only 270/cmm. There was no positive correlation between response rate and the number of peripheral granulocytes in infectious episodes with marked granulocytopenia. There seemed to be no serious organ toxicity by present combination antibiotics therapy, judging from BUN and SGPT levels.

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The effect of dipyridamole derivatives (RA 233 and VK 744) on human platelet aggregation in vitro was studied. Blood was collected from healthy volunteers who had no drugs for at least one week. Platelet aggregation in citrated platelet rich plasma (PRP) was studied by the turbidometric method of Born using aggregometer (Bryston, Model AG-2) and continuous recording of changes in optical transmission. 0.9 ml of PRP was pre-incubated at the room temperature for 10 min., transferred to the instrument and stirred at 1,100 rpm before adding 0.05 ml or 0.1 ml of aggregating agent. RA 233 and VK 744 were tested in 4 concentrations between 1×10^-5 M and 1×10^-4 M. RA 233 and VK 744 inhibited ADP-, collagen-, adrenalin-, thrombin- and calcium-induced platelet aggregation.
ADP -induced platelet aggregation (final concentration: 5×10^-6 M) was inhibited by RA 233 at 2.5×10^-5 M (t-test: p<0.05) and by VK 744 at 5×10^-5 M (p<0.02). Collagen-induced platelet aggregation was likewise inhibited by RA 233 at 2.0×10^-5 M (p<0.02) and by VK 744 at 5×10^-5 M (p<0.01). RA 233 and VK 744 caused active disaggregation when added during ADP and collagen aggregation.
RA 233 and VK 744 inhibited both first and second phase of adrenaline-induced aggregation. At the same concentration RA 233 caused greater inhibition than VK 744, and both drugs greater than dipyridamole (RA 8) and adenosine. RA 233 and VK 744 (dipyridamole derivatives) proved to be very powerful inhibitors of human platelet aggregation in vitro.

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The effect of dipyridamole dreivatives (RA 233 and VK 744) on platelet function was studied.
A. In vitro studies:
The tests were carried out after incubation of citrated PRP, PPP or whole blood prepared from healthy donors with the inhibitors for 10 min. at the room temperature. Concentrations of both drugs up to 1×10^-3 M had no effect on coagulation and fibrinolysis.
Platelet adhesiveness in citrated whole blood according to the glass bead filter method was inhibited by RA 233 at 5×10^-5 M and by VK 744 at 2.5×10^-5 M. And platelet adhesiveness to glass beads according to Morris was also inhibited by both drugs at 2.5×10^-5 M. The availability of platelet factor 3 according to the kaolin clotting time method was inhibited by RA 233 at 2.5×10^-5 M and by VK 744 at 1×10^-5 M. Prothrombin consumption was likewise inhibited at 1×10^-4 M. The release of platelet factor 4 induced by ADP and collagen aggregation was inhibited by RA 233 and VK 744 at 5×10^-5 M. Plasma clot retraction was inhibited by RA 233 at 1×10^-3 M but not by VK 744 at the same concentration. There were no changes in all parameters of the TEG in citrated whole blood with the exception that the k-time was significantly sheortend at 1×10^-3 M (p<0.001).
B. In vivo studies in the rabbit.:
When a single dose of ADP (1.0 ml of 10^-3 M) was infused into rabbits, weighing 2.0-2.5 kg, it produced a sudden fall in the circulating platelet count, which was reached ca. 20 sec. after beginning the infusion of ADP with a maximum, ca. 25% of the pretreatment level, and rapidly followed by a return to pretreatment levels. An intravenous administration of a dose of 10 mg/kg RA 233 and VK 744 one minute prior to infusion of ADP (1.0 ml of 10^-3 M) had no or little inhibitory effect on a rapid fall in the platelet count.
On the other hand, platelet adhesiveness to the glass bead filter according to Hellem II method was performed at intervals for 8 hours with native whole blood collected by the technique of Rodriguez- Erdmann. An intravenous administration of a dose of 10 mg/kg VK 744 had no effect on platelet adhesiveness in the rabbit.
RA 233 and VK 744 powerfully inhibited human platelet function in vitro, whereas both drugs had no effect on platelet function in the rabbit.

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A 55-year-old male patient with pure red cell aplasia was reported. This patient's disease had several interesting features. Firstly, his moderate anemia became very severe immediately after removal of his thymoma which had been discovered incidentally 2 months before surgery. Secondary, he had many immunological abnormalities; false positive STS, positive LE cell phenomenon, positive antinuclear antibody, negative tuberculin reaction and inability to react to typhoid vaccine. Thirdly, reticulocytes began to appear in the peripheral blood after splenectomy, while corticostoroids and anabolic steroids were totally ineffective. Fourthly, his plasma had a high erythropoietic activity and no neutralizing activity to erythropoietin or inhibiting activity to normal erythropoiesis could be demonstrated in it.

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A 34-year-old man was admitted because of pallor, fatigability and bleeding tendency in March, 1970. After admission, sternal marrow aspirations showed normocellularity with erythroid hyperplasia and iliac crest aspirations were hypocellular. Pancytopenia persisted. A reticulocyte count was 2.0% and red cell survival with ⁵¹Cr was 19 days (T 1/2). Both Ham and sugar-water tests were negative. Neither hemoglobinuria nor hemosiderinuria was noticed throughout the hospital stay at least up to July, 1973. Treatment with adrenocortico steroid and anabolic steroid hormones and bone marrow transfusions brought no hematological improvement. In February, 1973, 3 years later from the onset of the disease, Ham and sugar-water tests turned to be positive without hemoglobinuria, hemolytic crisis, nor thrombosis during the 3 years. However, apparent shortened red cell life span and combined ferrokinetic pattern of aplastic and hemolytic anemia were again detected on admission in March 1973.
It is likely that this case was on transitional phase from so-called “atypical” aplastic anemia to PNH and had signs of apparent hemolysis in spite of the absence of hemoglobinuria.

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A 45 years old man with acute ulcerative colitis received subtotal colectomy for the treatment of the massive colon bleeding. Postoperatively continuous intraabdominal oozing and oliguria developed. Two weeks later, the patient expired by acute renal failure, lung edema and hemorrhage from the remnant rectum, despite the reexploration of abdomen to control oozing in retroperitoneum, massive fresh blood transfusion and Trasylol administration. Autopsy revealed the presence of widespread fibrin microthrombi in kidney, lung, liver, spleen and colon. Blood coagulation studies showed marked decrease of antithrombin III, transient decrease of α₂-macroglobulin and α₁-antitrypsin in immediate postoperative period suggesting that these studies may give an early warning for the development of DIC. The pathogenesis and the treatment of DIC are also discussed.

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A 6 years old boy with congenital non spherocytic hemolytic anemia and neurologic disease was found to have erythrocyte and leukocyte phosphoglycerate kinase deficiencies.
He was treated with exchange transfusion, because of severe jaundice at birth, but growth development was normal until about 2 years old when he was suddenly suffered from convulsion and found to be anemic. Speech and gait disturbunce were noted at 4 years old and tremor of extremities also became apparent. Then he had repeated hemolytic episodes with marked hemoglobinuria.
On admission, he was anemic with slight jaundice but there was no hepatosplenoomegaly. The hematologic examination showed RBC 3.67×10⁶/mm³, Hb 9.3 g/dl Ht 26% and reticulocytes 12.5%. The peripheral blood smear revealed anisocytosis, target cells and acanthrocytes. ⁵¹Cr half life of RBC was 12 days. No abnomalities were noted in studies on hemoglobin, antibodies and osmic fragility of erythrocyte.
Biochemical studies of glycolytic enzymes and intermediates of his hematocyte showed that PGK-ase activity of these erythrocytes and leukocytes was remarkably reduced and elevated levels of red cell FDP, DHAP, GA3P and 2,3-DPG were documented as well. The RBC enzyme levels of his father and elder brother were within normal range, although another brother was died of severe jaundice soon after birth.

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A 68-year-old man was admitted to the Hiraki Medical Clinic of the Okayama University in May, 1973, because of severe anemia. In 1969, he noted muscle weakness of bilateral arms and difficulty of mastication. When he had consulted his physician with signs of upper respiratory infection in 1972, a roentogenogram of his chest revealed a left hilar mass to be made a diagnosis of malignant thymoma. He developed progressively severe general fatigue and anemia since two months.
Physical examinations were unremarkable except for the presence of muscle weakness, pallor and systolic heart murmur.
Laboratory studies revealed hemoglobin 46%, hematocrit 21%, white blood cell count 10,500 per cmm with 66% neutrophils and 30% lymphocytes, platelet count 76,000 per cmm and red blood cell count 2,560,000 per cmm. Reticulocyte counts were 0%. Sternal bone marrow aspiration revealed hypoplasia of the erythroid precursore. Antinuclear and anti-erythroblast nucleus antibodies were found by indirect immunofluorescence method. Direct Coombs' test was positive though indirect was negative. The other immunological examinations examined were all negative.
Pneumomediastinography demonstrated a smoothly circumscribed mass arising from the anterior-inferior mediastinum.
In May, 1973, a thymectomy was performed and a well encapsulated tumor measuring 15×9×7 cm was removed from the anterior mediastinum. Histology of the tumor revealed a thymoma consisted with lymphoepithelial cells.
Postoperatively the patient did well in myasthenia gravis, but there was no evidence of a reticulocyte response. Direct Coombs' test became negative, but the other examinations were unchangeable.
Eighteen case reports concerning a syndrome with thymoma, pure red cell aplasia and myasthenia gravis have been reported since 1939. From these data, thymus seems to have some immunological effects on hematopoiesis and skeletal muscle organs.

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A 46-year-old male, manager, was admitted to the hospital because of right hypochondrial pain. He had been well until 8 years previously, when this pain began and he was diagnosed as cholelithiasis. He had not received surgical operation.
The examination of blood revealed white blood cell count of 7200 (for 2 weeks before admission, he was treated with 6 MP and steroids on suspicion of AML) with 11% basophils, thrombocyte count of 150×10⁴ and neutrophil alkaline phosphatase (NAP) activity was 85% positive and score 219. Repeated examination revealed remarkable basophilia, thrombocytosis and high NAP activity. In bone marrow, basophilia was observed, atypical megakaryocytes were not seen and also normal in number, cytogenetic study of bone marrow gave positive Ph^I chromosome.
We consider this basophilia as accompanied phenomenon or basophilic leukemoid reaction in the early stage of CML and thrombocytosis as the same phenomenon rather than thrombocythemia by the reason of no atypical megakaryocytes in bone marrow. Although low NAP activity is characteristic of CML, many cases with high NAP activity have been reported.
Ultimately presence of Ph^I chromosome was the key for diagnosis in this case.

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