The antigens directed against anti-platelet antibodies detected in 5 patients with EDTA-dependent pseudothrombocytopenia were analyzed. Washed donor platelets suspended in PBS containing 10 mM EDTA were treated as follows. a) incubation for 1 hr at 37°C, b) treatment with trypsin, c) treatment with hetergenous anti-platelet antibody, d) treatment with antiglycoprotein (GP) IIb/IIIa monoclonal antibody, e) treatment with anti-GP Ib monoclonal antibody. These treatments were done at room temperature except treatment a). Treated platelets or that of a patient with thrombasthenia resuspended in PBS containing 10 mM EDTA were incubated with the sera of the patients with psudothrombocytopenia or normal serum at room temperature. Five hours later, platelet counts and platelet-associated immunoglobulin were determined using PL-100 (Symex) and flow cytometry (Spectrum III, Ortho), respectively.
The counts of the non-treated platelets from normal donor were decreased by addition of the sera of 5 cases, indicating agglutination. The sera of case 3, 4, and 5 have IgG antibodies, and those of case 1 and 2 have IgM antibodies. The platelets treated with anti-platelet antibody and trypsin were not agglutinated by addition of the sera of 5 patients. And the platelets treated with anti-GP IIb/IIIa and the platelets from a patient with thrombasthenia were not agglutinated by addition of the sera of case 3 and 5, whereas the platelets treated with anti-GP Ib were not agglutinated by addition of the serum of case 4. These results indicated the antigens drected against EDTA-dependent antibodies in the sera of case 3 and 5 were considered platelet membrane, especially GP IIb/IIIa and that of case 4 was considered GP Ib. On the contrary, the precise antigens directed against IgM antibodies (case 1 and 2) were not determined.
Agglutination with sera of patients was not observed, when donor platelets were incubated for 1 hr at 37°C under the condition containing EDTA (Treatment a)). This phenomenon would suggest that the temperature of 37°C might alter antigenicity directed against the sera in the patients with EDTA-dependent pseudothrombocytopenia.

View full abstract

Cells of a human myeloma cell line, KMM-1, established from a patient with Bence Jones (λ) type myeloma, were fractionated by a Percoll density gradient method. Three fractions of cells were separated to fraction 1 at 1.034 g/ml, 3 at 1.068 g/ml and 2 were at 1.034 to 1.068 g/ml. Regarding growth potential of cells, the fraction 3 cells showed most vigorous growth, while the fraction 1 cells were degenerative. No significant difference was detected by immunoflorescent method in the amout of cytoplasmic λ-chain protein among three cell fractions. The generation time of fraction 3 cells was about 15 hours measured by autoradiographical determination, but it was about 32 hours examined by their growth curve. Our current findings indicated that the Percoll density gradient fractionation of cells was useful to obtain the proliferative cells efficiently at high concentration.

View full abstract

We studied retrospectively in how grade of hepatic reserve the patients of acute leukemia with severe liver dysfunction could be taken chemotherapy in safety.
1) Twelve cases of 119 patients of acute leukemia had severe liver dysfunction and seven cases of twelve died due to chemotherapy. Six cases of seven were in complete remission hematologically.
2) Four cases of seven with severe liver dysfunction of hepatotoxic type died and three cases recovered. In the dead group, cholinesterase levels decreased less than 0.4 ΔpH and hepaplastin test less than 40% irreversively, in the recovery group, the decrement of cholinesterase and hepaplastin test were transient and those levels increased more than 0.1 ΔpH and 10% within a month. Therefore, when hepatic reserve decreased irreversively, chemotherapy should be discontinued, but transiently, chemotherapy can be started again.
3) Three cases of five with severe liver dysfunction of cholestatic type died. Gluco-corticoid could not improve the icterus of these three patients.

View full abstract

Comparative study of 46 patients with acute leukemia and myelodysplastic syndromes was performed on chromosomal analysis and FAB classification. Adequate mitoses were obtained in 41 out of 46 patients, and a detectable clonal chromosomal abnormality was present in bone marrow cells or blood cells of 37 patients [4/6 ALL, 19/30 (63.3%) AML, 4/5 MDS]. When the AML patients were separated into those with and those without a chromosome abnormality, the difference in remission rates was not significant (normal: 9/11; abnormal: 11/19).
Two patients associated with t (8; 21) were M2 and those with inv (16) were M4 and M5. But all patients with t (15; 17) were M3 and this translocation was not found in any other types. These results may follow that FAB classification is based only on morphology but reflects the origin of leukemic cells to some degree.

View full abstract

ATLA antibody was determined in patients with various hematological and collagen diseases using the PA and the IF method. Of a total of 181 patients with hematological disease, 20 and 16 proved to be positive with the PA and the IF method respectively. All the positive patients except 3 with ATL and 1 with NHL proved to have had past records of blood transfusion. On the other hand, of a total of 187 patients with collagen disease, 9 and 6 proved to be positive with the PA and the IF method. Of these, only two with SLE had past records of blood transfusion. More specifically, 4 patients with hematological disease and 1 with collagen disease who were all 16∼64 times positive with the PA method were found to be negative with the IF method. However, ATLA-bearing cells were detected in short-term cultures of peripheral blood lymphocytes from one AML patient who was 16 times positive with the PA method but negative with the IF method. Thus the sensitivity of the PA method seem to be higher than that of the IF method. The two patients with collagen disease who were 128 times and 256 times positive with the PA method could hardly be evaluated due to the non-specific reaction using the IF method. But ATLA-positive cells were detected in the cultures from one of these two case with difficulties in the evaluation. Therefore, this case was identified as ATLA positive.
The positive ratio of the healthy control group was 0.3% with both the PA and the IF method. As the PA method is characterized by its simple operation, this method was deemed to be useful as the ATLA antibody screening method for donated blood so as to prevent possible ATLV infection by blood transfusions.
A higher positivity was found, irrespective of blood infusion, with both PA and the IF method in patient with collagen disease, especially those with Sjögren's syndrome. Furthermore, ATLA-bearing cells were found in the cultures from 5 of 6 ATLA-antibody positive collagen disease patients.
Taking into consideration the possibility that viral factors are involved in the onset of Sjögren's syndrome and the fact that the disease is most often complicated by lymphoma, it would be likely that ATLV may essentially be replaced to the onset of this disease via its reaction upon the functions of T-cells.

View full abstract

Forty-six cases of collagen diseases (CD) were examined on their plasma F. XIII (a) levels assayed by anti-XIII (a) antibody neutralization method, and on the presence of soluble fibrin monomer (FM) by FM test. The results obtained were as follows:
1) F. XIII (a) level: Although the SLE cases having no vascular manifestations tended to show low levels (P<0.1), no significant differences were found among the kinds of CD, nor between the groups with/without Raynaud's syndrome, bleeding-thrombotic complications, or lung fibrosis. F. XIII (a) levels less than 60% were observed in seven among the total 46 CD cases; i.e. 6/24 (25.0%) for SLE and 1/4 for RA.
2) FM test: Positive FM test was obtained in 11 of the total 46 CD cases (24.6%), while the origin of FM could not be identified in four of them. No significant differences as to the incidence of positive FM test were found among the kinds of CD, nor between the groups with/without Raynaud's syndrome, bleeding-thrombotic complications or lung fibrosis.
3) F. XIII (a) levels showed no significant correlation with the platelet count, AT-III, fibrinogen and FDP, nor with the glucocorticoid administration; and the positive FM test, too, did not correlate with them, except for the platelet count.

View full abstract

A retrospective analysis of 13 children with hematological malignancy who underwent percutaneous silastic catheter insertion is presented. Twenty catheters were placed by the subclavian approach, percutaneously. Nine of 20 insertions were performed in the children with platelet count of less than 30,000/μl, most of them were in neutropenia of less than 500/μl either. Before the insertion, platelet transfusions for the children with thrombocytopenia were done. There were no prolonged bleeding after insertion, no infection and no morality related the catheter insertions. Six complications were occured, one spontaneous dislocation, two occulusions related to the thrombosis, 3 fever episods related to the catheters, without no serious sequelae. The percutaneous siliastic catheter insertion is a safe and reliable tecnique for the thrombocytepnic children with hematological malignancy.

View full abstract

Two sisters with extreme neutrophilia and recurrent infections are reported.
The neutrophils of the younger sister exhibited impaired adhesion, chemotaxis and phagocytosis, but hyperresponse of O₂ production and membrane potential changes by the stimulants. Her neutrophils and mononuclear cells (mostly lymphocytes) lack 110K and 98K dalton membrane proteins and 95K dalton membrane protein, respectively. The cells of the parents contained an approximatley half amount of these proteins, supporting that the disease is probably transmitted by an autosomal recessive trait.
Mo1 positive neutrophils and monocytes were 1.4% and 33% respectively, indicating significant decreases compared with controls.
The marked neutrophilia may result from an increase of CFU-C and a reduced ability of neutrophils to invade into tissues.
The lymphonodes of both patients were found to be hypoplastic with lymphocyte depletion in the lymphatic parenchyma. These findings seemed to be the hallmark of the disease.

View full abstract

Interstitial pneumonia (IP) occurred among 14 of 31 leukemia patients received allogeneic bone marrow transplantion (45.2%) and it was fatal at 9 cases. IP was clinically suspected by symptoms, chest roentgengram, blood gas analysis and CT scan, and pathologically diagnosed on the specimens obtained by transbronchial lung biopsy or autopsy. At 11 out of 14 cases, the association of cytomegalovirus (CMV) was identified by the positive viral cultures from bronchoalveolar fluid or CMV inclusion body in autopsy specimens. The other 3 cases were diagnosed as idiopathic IP.
Significant risk factors for IP included the sex of recipient (the incidence of IP was 13 of 21 cases in male and one of 10 cases in female. p<0.025) and the additional preconditioning with cytotoxic agents and/or splenic irradiation other than cyclophosphamide (CY) and total body irradiation (TBI) (5/5, 100% compared with 7/25, 28% in cases received conditioning with CY and TBI. p<0.05). Insignificant predisposing factors were the type of disease (5/7, 71.4% with chronic mylogenous leukemia) and the clinical status of patients at the time of BMT (5/17, 29.4% in remission v.s 9/14, 64.3% in relapse or non-chronic phase).
The use of blood donors seronegative for CMV antibody (CF<8) and high-titered CMV immune globulin were not preventive for IP in our cases. As therapy for IP, high-titered CMV immune globulin, acyclovir and corticosteroid (standard dose or high-dose methylprednisolone) were used. Seven cases responded to the corticosteroid therapy and 5 of them survived.

View full abstract

A 78-year-old male with hypoplastic acute myeloid leukemia developed a transient change in his blood group. On admission, his red cells agglutinated weakly against anti-A with twenty percent free red cells, although his blood group was essentially A, while his serum reacted with only B red cells. The agglutination titer to Ulex europaeus (anti H) was high and that to Dolichos biflorus (anti A₁) was low compared with the control red cells. Moreover, the A and H antigens were contained in his saliva. Activity of the glycosyl A transferase in his serum was lower than the control on admission, while his red cells were transformed to typical A in the presence of the normal A transferase. In our case, therefore, the modified A of his red cells was probably due to the decreased activity of the A transferase. The similar changes in the blood group examination were observed at the relapse after 10 months remission.

View full abstract

A-45-year old woman was admitted to the National Defense Medical College Hospital in January 1984 because of high fever. She had experienced the symptom repeatedly since August 1982 and had absolute monocytosis (WBC 8,000/mm³, monocyte 39.5%) with hypercellular bone marrow (NCC 60.5×10⁴/mm³).
The peripheral blood showed Hb 5.5 g/dl, RBC 201×10⁴/mm³, reticulocytes 4.0%, platelets 33×10⁴/mm³ and WBC 7,500/mm³ with 25% of monocytes. A bone marrow smear was normocellular but showed various morphological abnormalities in myelocytes, erythroblasts and megakaryocytes. Combined esterase stains were positive in 11.5% of myeloid or monocytoid cells in bone marrow. Serum V.B 12 level was elevated. Serum and urinary lysozyme levels were not increased. NAP score was markedly low. Bone marrow culture for CFU-C was not obtained.
She was diagnosed as CMML and treated with low-dose cytosine arabinoside unsuccessfully and died of pneumonia in September 1984.
Cytogenetic studies on two different occasions showed a loss of chromosome 7 without any other abnormality.

View full abstract

An 81-year-old woman was admitted, complaining of gingival bleeding and purpura. She had severe anemia and bleeding tendency. In the peripheral blood many abnormal cells were observed. Bone marrow aspiration revealed a nucleate cell count of 620,000/cmm with 85.4% of leukemic cells containing coarse azurophilic granules and many Auer's rods in their basophilic cytoplasms. A diagnosis of acute promyelocytic leukemia (APL, M₃) was made, and daunorubicin and prednisolone were administered. However, the remission was not able to be obtained and she died of pneumonia. On hopitalization, proteinuria and hypoalbuminemia were recognized and the former increased with the progression of APL; the maximal amount was 25 g/day. Although her illness was diagnosed as nephrotic syndrome, prednisolone was not effective. At autopsy, neither of renal vein thrombosis, amyloidosis nor disseminated intravascular coagulation was observed in her kidneys. However, the microscopic finding of diffuse proliferative gromerulonephritis and the electron microscopic finding of minimal change were detected. Recently many cases of nephrotic syndrome complicating malignant neoplasms, especially malignant lymphoma and lymphocytic leukemia, were reported. This is the first case showing a complication of nephrotic syndrome in APL.

View full abstract

A 8-year-old boy was admitted to our hospital because of epistaxis and cervical lymphadenopathy. The peripheral blood showed RBC 283×10⁴/mm³, hemoglobin 8.1 g/dl, platelet count 5.2×10⁴/mm³, WBC 16,300/mm³ with 19% myeloblasts, 37% monocytoid cells, and 3.5% eosinophils. A bone marrow aspirate was normocellular with 33.2% myeloblasts, 23.5% promyelocytes, 13.6% monocytoid cells and 15.8% eosinophils. The eosinophils contained large coarse basophilic granules in their cytoplasm on Wright-Giemsa stain. Cytochemically, the eosinophils were PAS and specific esterase (naphthol AS-D chloroacetate) positive. Bone marrow chromosome study with G-banding method by short term culture technique revealed that the karyotype was 46, XY, inv (16) (p13q22) in all 20 banded cells analyzed.
Complete remission, which was accompanied with disappearance of abnormal eosinophils and inv (16), has been continued for 16 months after two courses of chemotherapy consisted of BHAC, doxorubicin, vincristine and prednisolone.
This is the second case of childhood AMMoL with bone marrow eosinophilia associated with inv (16) reported in Japan.

View full abstract

A 76-year-old man was admitted to our hospital because of purpura. The hemoglobin was 10.4 g/dl, the platelet count 5,000/μl, and the white-cell count 31,500/μl with 66% neutrophils and 11% monocytes. Bone marrow aspirate showed a marked hypercellularity with 2.8% blastic cells differentiating toward both granulocytic and monocytic cell lines. The bone marrow also showed marked proliferation of megakaryocytes, 82% of which were micromegakaryocytes. Serum lysozyme level was highly elevated. A diagnosis of chronic myelomonocytic leukemia (CMMoL) was made.
Thrombocytopenia less than 10,000/μl in this patient is exceptionally rare in CMMoL. In contrast to the marked thrombocytopenia, the marrow megakaryocyte count was about 20 times as many as normal. In addition, the proportion of micromegakaryocytes was extremely high, compared with those in other cases of myelodysplastic syndrome and myeloproliferative disorder. Thus, the patient seems to be an unusual case in respect of remarkable dysmegakaryocytopoiesis.

View full abstract

A 52-year-old man was admitted to our hospital because of leukocytosis. Physical examination on admission revealed moderate hepatosplenomegaly. The white blood cell count in the peripheral blood was 16,100 with 86 percent lymphocytic cells.
His peripheral blood leukemic cells were characterized by surface marker analysis as well as functional assays. The leukemic cells had both the helper/inducer (OKT4) and the suppressor/cytotoxic (OKT8) phenotype, and showed helper function in the pokeweed mitogen-induced imunoglobulin production of normal B cells.
As for as we Know, this is the first report on the case of T-cell chronic lymphocytic leukemia with double marker (OKT4, 8) and helper T cell function.

View full abstract

A 2-year-old boy was admitted to our hospital with thrombocytopenia and bleeding tendency on May 17, 1983.
Bone marrow aspiration and biopsy showed decreased megakaryocytes with an otherwise normal marrow.
Platelet survival study showed normal result and platelet associated immunoglobulin G showed normal value. Bleeding tendency and thrombocytopenia were recognized in early infancy, and no underlying disorder nor any drug could be incriminated, so we assumed that this patient was suffered from a congenital and idiopathic form of amegakaryocytic thrombocytopenia.
The patient died 8 months after first hospitalization. No useful therapy was identified.

View full abstract

A 17-year-old male with severe aplastic anemia became refractory to platelet concentrates which were harvested from random donors by plateletpheresis using blood cell separator (IBM 2997). Then, platelet concentrates from an HLA-identical brother were used. The patient had excellent response to HLA-matched platelet transfusions and bleeding stopped. The HLA-matched platelet concentrates from his brother were effectively transfused to the patient every 7 to 10 days 48 times in total for 16 months. A regimen of androgen was continued and the patient obtained partial remission. The patient has been living over 38 months since he suffered from severe aplastic anemia.
This case suggests that androgen therapy may be effective in some patients with severe aplastic anemia if bleedings are prevented by proper platelet transfusions.

View full abstract

Two patients with severe aplastic anemia who had not responded to conventional therapy resulting in refractriness to platelettransfusions were transplanted with marrow from their HLA-identical siblings. As they were sensitized to alloantigens such as HLA-matched platelets, TBI (1.5Gy×2) and cyclosporine were added to the conventional immunosuppressive regimen. Cytomegalovirus-hyperimmune globulin was given for prevention of interstitial pneumonia and HLA-matched platelets were transfused for maintenance of platelets. Their posttransplant course were uneventful and the bleeding was not seen. They are well 13 and 16 months after transplantation (Karnofsky score 100%). Bone marrow transplantation for high risk patients with severe aplastic anemia was possible by improved immunosuppressive regimen and supportive therapy.

View full abstract

A 3-month-old girl was admitted to our hospital with complains of poor milk uptake and jaundice. The diagnosis of autoimmune hemolytic anemia (AIHA) was made from severe anemia (hemoglobin 2.7 g/dl), hyperbilirubinemia (total bilirubin 6.1 mg/dl), and positive direct Coombs' test. Since the patient showed a steroid (glucocorticoid)-dependent chronic course, high dose gamma globulin (400 mg/kg/day) was administered for 5 days from the 115th hospital day. Increase of hemoglobin was transient, therefore, we combined the high-dose gamma globulin with methylprednisolone (28 mg/kg/dose) pulse therapy. After 3 courses of the combination therapy, the patient achieved complete remission.
Survey of previously published reports revealed that the prognosis of infantile chronic AIHA was poor in 6 out of 9 cases. For such patients, our treatment, described here, is recommended, because of its effectiveness and minimal side effects, compared to the traditional therapy of steroid alone or steroid plus immunosuppressive agents.

View full abstract

In the last 16 years we have seen four cases of Burkitt's lymphomas. Two of them had died from bowel bleeding and perforation during the initial treatment. Bowel bleeding and perforation occurred only in the children with Stage C or D disease. They were treated with COMP protocol. Bowel bleeding and perforation occurred when the white blood cell count was under 500/μl and the platelet count was under 40,000/μl.
Just before the bowel bleeding and perforation, the septic fever over 40°C and the waterry diarrhea were seen. After the diarrhea, the bleeding and then the perforation of bowel were occurred. Bowel perforation is a devastating complication of childhood Burkitt's lymphoma. When the children with Burkitt's lymphoma have initial treatment, we should be alert to its possible occurrence.

View full abstract

A case of primary acquired sideroblastic anemia terminating in chronic myelomonocytic leukemia is reported. A 52-year-old man was admitted to our hospital with complaint of anemia in September, 1983. Blood studies showed moderate anemia and eosinophilia with occasional myelocytes, metamyelocytes and nucleated red cells. His bone marrow was characterized by erythroid hyperplasia with megaloblastoid changes and ringed sideroblasts accounting for 16% of nucleated marrow cells. Pyridoxine was not effective, and repeated blood transfusions were required throughout the clinical course. His peripheral blood picture disclosed an appearance of a few blast cells in December. Marked progression of anemia and thrombocytopenia were noted in March, 1984. Peripheral monocytosis over 1,000/cmm was also observed. We employed lowdose cytarabine, however, peripheral leukocytes rapidly increased up to 78,500/cmm with 60% monocytoid cells, and 36% maturing granurocytic cells without blast cells in July. Bone marrow aspirates showed hypercellularity without proliferation of blast cells or monocytoid cells. Combination chemotherapy failed to induce remission, and he died of respiratory failure. Necropsy revealed leukemic infiltration in the lungs and liver.

View full abstract

A 43-year-old man with blastic crisis of chronic myelocytic leukemia was admitted to our hospital for diplopia and weakness on June 20, 1985. He had previously been given vincristine (VCR) 2 mg 7 time and began to feel numbness of fingers in the middle of May. Double vision, palpebral ptosis, and dysarthria developed in June. Cerebrospinal fluid and brain CT findings revealed no abnormality. Neurological examinations showed complete flaccid quadriplegia, sever sensory disturbance, and cranial nerve palsy (III-VII and IX-XII). Diagnosis of VCR neuropathy was made and he was placed on artificial respiration. Peripheral nerve conduction velocity was diminished slightly on June 27 and markedly on July 20. Neuropathy slowly improved in the end of July but there was a progression of leukemia and he died of pneumonia on September 21. Postmortern examination revealed marked axonal degeneration of the posterior fasciculi of the spinal cord and peripheral nerves. The reason why he developed such sever VCR neuropathy is unknown but liver dysfunction may have been one of the contributing factors.

View full abstract

Transport mode of 6-MP and ara-C by leukemic cell was investigated. 6-MP was incorporated into the cell by facilitated transport mechanism and the small part of 6-MP was converted to its nucleotide. The efflux of 6-TUR, which was produced from 6-MP by xanthine oxidase, and residual 6-MP was shown. The cytotoxic activity of 6-MP, accordingly, is enhanced by the long time retention of drug in the plasma and the increase in PRPP content rather than the increased concentration of 6-MP. Ara-C incorporated in the cell by active transport mechanism was well converted to its nucleotide. The higher concentration of extracellular ara-C resulted in the increase of ara-C transport. It was apparent that 1 μg/ml of vitamin A derivatives facilitated the ara-C influx. In order to enchance the cytotoxicity, high dose administration of ara-C and combined administration of ara-C with vitamin A derivative are effective. Pharmacokinetics of behenoyl ara-C (BH-AC) and palmitoyl ara-C (PL-AC) was also investigated. The both drugs which are resistant to ara-C deamination were retained in the plasma for a longer time than ara-C and released ara-C gradually. The effective cytotoxic activity of ara-C is expected by the administration of these drugs.

View full abstract

Fifty one adult patients with acute non-lymphocytic leukemia (ANLL) received BHAC-DMP remission induction therapy, and 42 patients achieved complete remission (CR). Prognostic factors of these 42 CR patients were analyzed by generalized Wilcoxon method and Cox's multivariate regression method. % of blast in bone marrow at 2 weeks of chemotherapy, white blood cell count at the start of treatment and days required till CR (or number of courses required to CR) were shown to be significant prognostic factors in this order. Eight patients who failed to receive maintenance therapy (BHAC-DMP and VEMP) for more than 2 months due to hepatitis, hepatic abscess or old age had tendency to show early relapse, and no long term survivors were observed in this group. Among other 8 patients whose maintenance therapy was discontinued after 2 years, 4 patients relapsed. These 4 patients achieved CR again by the same BHAC-DMP therapy. These data suggest that the maintenance therapy has some effect for the prolongation of CR period, although it is uncertain that whether the maintenance therapy may play a role in complete cure of ANLL.

View full abstract

Mechanisms of resistance to MTX and ara-C in leukemic cells and some trials to overcome their resistance were discussed.
The mechanisms of resistance to MTX were considered as follows. 1) Decreased membrane transport 2) Increased DHFR activity 3) Activated salvage pathway 4) Expantion of nucleotide pools 5) Decreased polyglutamation. Therapy to overcome these resistance contains administration of high dose MTX, continuous infusion of moderate dose MTX, 6TG and 6MP. Because 6TG and 6MP are phosphorylated by the activated salvage enzyme of the cells resistant to MTX.
On the other hand, the mechanisms of resistance to ara-C were as follows. 1) Decreased membrane transport 2) Increased deamination 3) Decreased activity of deoxycytidine kinase 4) Increased level of intracellular dCTP pools. Deficiency of deoxycytidine kinase was considered most difficult to be overcome among these mechanisms. In the present study, we could suggest that administration of deoxycytidine and thymidine was selectively cytotoxic to ara-C resistant R1.1 cells. High dose ara-C therapy would be effective to cells with decreased membrane transport or increased deamination of ara-C. On the other hand, MTX-ara-C sequential therapy would be effective to cells with increased dCTP pools.

View full abstract

Five patients with refractory AML (3 of them were complicated CNS-L) and 13 patients in remission with AML were treated with high dose cytarabine therapy (HD-AC) as re-induction and consolidation therapies, respectively. Three of 5 refractory cases treated with HD-AC achieved complete remission. Decreasing number of leukemic cells and improvement of CNS symptoms were seen in all of 3 patients with CNS-L. Nine of 11 patients treated as consolidation therapy relapsed 1-17 months after HD-AC (median 3.5 months). Three M3 patients out of those 9 patients relapsed 1, 3, 3.5 months after HD-AC, respectively, Two out of those 9 patients relapsed in CNS, 9 and 14 months after HD-AC respectively. Symptoms which suggested systemic inhibition of DNA synthesis, i, e. skin erythema with itching and corneal ulceration, were seen.
Ara-C concentration in plasma was 29.67±5.91 μg/ml at the end of 1 hour infusion (3 g/m²), and 0.20±0.17 μg/ml at 240 minutes after 1-hr infusion.
The in vitro sensitivity of leukemic cells to ara-C was assessed in acute myeloid leukemia, by means of incorporation of H-thymidine. According to the in vitro result, inhibition of DNA synthesis of ara-C at high dose suggests not only the time dependent effect but also the dose response to the cells.

View full abstract

An analysis of clinical course, therapy and prognosis was performed in 46 patients with myelodysplastic syndromes (MDS).
In either group of patients with refractory anemia or chronic myelomonocytic leukemia, chemotherapy was unnecessary and they should be given conservative therapy. For refractory anemia with excess of blasts (RAEB), the prognosis in the conservative therapy group might be longer than that in the chemotherapy group.
Because of the high risk to transform into overt leukemia in patients with RAEB in transformation, young patients should be given intensive chemotherapy, but in old ones the efficacy of treatment was not clear.
Our results in MDS patients demonstrated that low dose Ara-C treatment was not more effective than expected, and the danger of the treatment should not be underestimated.

View full abstract