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Biomedical subjects

R Ohno

Publications and source records attributed to R Ohno.

At least 109 records · Page 6Linked to original sources
PubMed1999

No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group.

To assess the efficacy of etoposide added to the standard remission induction therapy for acute myeloid leukemia (AML), newly diagnosed adult AML patients were randomized to receive either daunorubicin (40 mg/m2/day x 4 or more), behenoyl cytarabine (200 mg/m2/day x 10 or more), and 6-mercaptopurine (70 mg/m2/day x 10 or more) (BHAC-DM), or the same three drugs plus etoposide (100 mg/m2/day x 5) (BHAC-EDM) for response-oriented individualized induction therapy. The patients achieving complete remission (CR) received the same 3 courses of consolidation therapy followed by 6 courses of maintenance/intensification therapy. M3 patients were excluded because all-trans retinoic acid was used. Of 667 patients registered, 655 were evaluable. The median age was 49 (range 15 to 85). CR rates were 77% in the BHAC-DM group and 75% in the BHAC-EDM group. In 173 M4 patients, CR rates were 86% and 69% (P = 0.009), and in 32 M5 patients, 80% and 77% (P = 0.810) in the BHAC-DM and the BHAC-EDM groups, respectively. The predicted 6-year overall survival rates were 30% and 38% (P = 0.925) for the BHAC-DM and BHAC-EDM groups, and the disease-free survival rates of CR patients were 25% and 35% (P = 0.352), respectively. Nonhematological toxicities after the first course of induction therapy were almost equal among the two groups, with the exception of a greater loss of hair (P = 0.024) and more frequent diarrhea (P = 0.013) in the BHAC-EDM group. We concluded that in the present study, the addition of etoposide to the standard individualized induction therapy showed no advantage in adult AML, even among M4 and M5 patients.

Acute Disease↗
PubMed1999

Infectious complications during remission induction therapy in 577 patients with acute myeloid leukemia in the Japan Adult Leukemia Study Group studies between 1987 and 1991.

The Japan Adult Leukemia Study Group analyzed infectious episodes in 577 patients with acute myeloid leukemia during remission induction therapy between 1987 and 1991. 542 patients (93.9%) experienced at least one infectious episode, 121 (21.0%) had microbiologically documented infection; there was clinically documented infection in 184 (31.9%) and unexplained fever in 237 (41.1%). Among 121 microbiologically documented infections, bacteremia/fungemia was observed in 68, pneumonia in 33, and other types of infections in 20. Among the bacteremia/fungemia, gram-negative bacteria accounted for 41.2% (Pseudomonas aeruginosa was the most common), gram-positive bacteria for 39.7%, fungi for 16.2% (Candida spp. being most frequent), and polymicrobial for 2.9%. The most frequent isolates among pneumonia were Pseudomonas aeruginosa and Aspergillus. A total of 70 patients (12.1%) died during remission induction. Mortality of 68 patients with bacteremia/fungemia was 26.5%; in these patients, mortality with concomitant pneumonia increased to 41.4%; without pneumonia, mortality was 15.4% (P < 0.05). Mortality according to the isolated microbes was 17.2% for gram-negative bacteria, 25% for gram-positive bacteria, and 54.5% for fungi. Mortality of 113 patients with pneumonia (33 microbiologically documented and 80 clinically documented), 20 with other microbiologically documented infections, 104 with other clinically documented infections, and 237 with unexplained fever was 25.7%, 5.0%, 5.8%, and 5.1%, respectively.

Acute Disease↗
PubMed1999

[Phase II clinical study of SH L 573 (fludarabine phosphate) in patients with chronic lymphocytic leukemia].

We conducted a multicenter phase II clinical study of fludarabine phosphate, a new purine nucleotide analogue, in patients with chronic lymphocytic leukemia (CLL). Fludarabine phosphate was administered at a dose of 20 mg/m2/day intravenously for 5 days every 4 weeks as one course. Six courses as a maximum were repeated. The response rate was 38.5% (95% confidence intervals: 20.2% to 59.4%), with 1 complete remission and 9 partial remissions out of 26 treated patients. Major drug-related adverse reactions were fever, nausea, weakness, and paresthesia of the fingers; as a grade-3 reaction, varicella was also reported. Neutropenia and thrombocytopenia were observed as manifestations of hematologic toxicity. Clinical laboratory test results revealed abnormalities in hepatic function, including increased GPT, but none of these was rated grade 3 or 4.

Adolescent↗
PubMed1998

A novel myeloid cell line, Marimo, derived from therapy-related acute myeloid leukemia during treatment of essential thrombocythemia: consistent chromosomal abnormalities and temporary C-MYC gene amplification.

A novel myeloid leukemia cell line, Marimo, was established from bone marrow cells of a patient with secondary acute myeloid leukemia (AML) that had developed during the treatment of essential thrombocythemia (ET) with busulfan. Karyotype at the ET phase was 46,XX,der(15)t(1;15) (q23;p12-13), but at the blastic phase changed to 44,XX,-5,del(8)(q22), add(17)(p11),+18, psu dic(18;9) (q23;p21) x 2 lacking t(1;15). In Marimo cells, C-MYC gene was temporarily amplified by double-minutes (dmin) but disappeared at 33 months, whereas t(10;14;11)(q22;q32;q13) and t(10;14)(q22;q32) were added in vitro psu dic(18;9) x 2 and add(17)(p11) were consistently found throughout the culture. These results suggest that this AML clone is not derived from ET but rather is therapy-related.

Cell Line↗
PubMed1998

Cooperative oncology groups in Japan: experience from the Japan Adult Leukemia Study Group.

To ensure reliable statistical analysis in clinical trials, a large number of patients is required and therefore multicenter cooperative studies are indispensable in clinical oncology. However, both in the field of oncology and other fields of medicine, well-functioning clinical study groups are rare in Japan. In this review, the reason why multicenter cooperative study groups are difficult to organize in Japan is analyzed. Subsequently, the experience of a self-supporting and successful cooperative study group, the Japan Adult Leukemia Study Group, is reviewed. Finally, in the absence of significant financial support and thus no financial benefit for participating institutions, how to organize a cooperative study group successfully is discussed.

Antineoplastic Agents↗
PubMed1998

A long term follow-up of a randomized trial comparing interferon-alpha with busulfan for chronic myelogenous leukemia. The Kouseisho Leukemia Study Group.

To evaluate the long-term effectiveness of interferon-alpha (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML) in chronic phase, we examined the updated outcomes of 159 patients who had been enrolled between 1988 and 1991 into a randomized trial comparing IFN-alpha with busulfan. At a median follow-up of 73 months, the median survival was 71 months in the IFN-alpha group and 55 months in the busulfan group (P=0.0563), and the median time of remaining in chronic phase was 58 months in the IFN-alpha group and 39 months in the busulfan group (P=0.4676). Landmark analysis showed a significant advantage in survival (P=0.009) and duration of chronic phase (P=0.0001) in patients with any cytogenetic response among the IFN-alpha group. About half patients were discontinued IFN-alpha administration in spite of cytogenetic response in this study. It appears that continuation of IFN-alpha might possibly confer a survival advantage. Pretreatment factors associated with cytogenetic response included high hemoglobin level, low percentage of peripheral basophils and low leukocyte counts. Multivariate analysis identified lower percentage of bone marrow basophilia (P=0.007) for survival advantage. If a group with a very good prognosis is predicted by a new prognostic model, it might be an option to wait for bone marrow transplantation.

Adult↗
PubMed1998

Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor in the treatment of acute myeloid leukemia and acute lymphoblastic leukemia.

The role of G-CSF, GM-CSF and M-CSF in the treatment of AML and ALL was reviewed. These CSFs significantly accelerate the neutrophil recovery after intensive chemotherapy, and reduce febrile neutropenia and documented infections. There is no clear evidence that CSFs accelerate early regrowth of AML cells at the doses and schedules presently used clinically except one study. Patients who have received CSFs tend to have a higher CR rate, which does not seem to be translated into definite survival benefit. There has been no prospective randomized study showing any beneficial priming effect of CSFs on AML cells with better clinical outcomes.

Granulocyte Colony-Stimulating Factor↗
PubMed1998

Pregnancy among long-term survivors of acute leukemia. A second nationwide survey.

A second nationwide survey was conducted to determine the outcome of pregnancy in long-term survivors of acute leukemia and to clarify the influence of treatment on the offspring of long-term survivors. In July 1996, 336 survey responses were received from the 498 Japanese institutions surveyed. A total of 89 cases (39 spouses of male patients and 50 female patients) who had babies during their first remission were analyzed, including 43 patients from the first survey in 1991. Median age at the birth of first baby was 30.7 years for male patients and 28.6 years for female patients. A total of 109 of the 117 pregnancies resulted in live births and eight resulted in abortions. A total of 58 cases had single children and 23 cases had two or more, generally from separate pregnancies, but including two pairs of twins. The infant was male in 59 cases, female in 37 and gender was not reported in 13 cases. Ages of children ranged from 2 months to 20 years at the time of this study and all children were in good health. There were two minor anomalies, both of which were surgically corrected. Of the 81 parents bearing live infants, 75 remained in complete remission. Five fathers died (four of relapse and one of another disease). In conclusion, there was no apparent increase in pregnancy complications or congenital anomalies in the children of long-term survivors with acute leukemia.

Acute Disease↗
PubMed1998

Response-oriented individualized induction therapy with six drugs followed by four courses of intensive consolidation, 1 year maintenance and intensification therapy: the ALL90 study of the Japan Adult Leukemia Study Group.

Adult patients with acute lymphoblastic leukemia (ALL) were treated according to the ALL90 study, the second prospective study for ALL of the Japan Adult Leukemia Study Group (JALSG). Its characteristics included response-oriented individualized induction therapy with six drugs (doxorubicin, mitoxantrone, vincristine, prednisolone, [corrected] cyclophosphamide and L-asparaginase), and a prospective comparison between allogeneic bone marrow transplantation (allo-BMT) and chemotherapy alone in patients below 45 years of age. The protocol consisted of one or two courses of induction, four courses of consolidation, and three courses of intensification including 12 month maintenance and six times of central nervous system (CNS) prophylaxis. Of 180 evaluable patients (median age, 43), 125 (69%) achieved complete remission (CR). Predicted overall survival (OAS), event-free survival and disease-free survival (DFS) were 15, 10 and 14%, respectively at the median follow-up period of 62 months. No specific toxicities were observed. Leukocytes < 30,000/microliter, normal karyotype, and blasts < 10% in bone marrow at day 15 of induction therapy were significantly favorable prognostic factors for the achievement of CR, DFS and OAS by univariate analysis. Multivariate analysis showed leukocytes < 30,000/microliter and blasts < 10% on day 15 was a significant factor for the achievement of CR, DFS and OAS. Ph-chromosome was found in 28% (36/130) of patients examined and was one of the worst prognostic factors. All Ph positive patients were predicted to die within 600 days. Allo-BMT was not significantly superior to chemotherapy with respect to DFS (P = 0.226). The overall results were inferior to those of the former ALL87 protocol. As reasons, the older median age of 43 years old (vs. 38 years old) and lower dose intensity, especially of l-asparaginase, etc. were suggested. However, patients with good prognostic factors (leukocyte < 30,000/microliter and age < 30 years old) showed better survival than others (P < 0.0001), and the result was similar to that of older children, the high risk group of childhood ALL, suggesting that ALL could be a disease of single entity, showing higher resistance to chemotherapy as patients become older.

Adult↗
PubMed1998

Response-oriented individualized induction therapy followed by intensive consolidation and maintenance for adult patients with acute lymphoblastic leukemia: the ALL-87 study of the Japan Adult Leukemia Study Group (JALSG).

The Japan Adult Leukemia Study Group conducted the ALL-87 study to determine whether response-oriented induction therapy and intensive consolidation and maintenance/intensification therapies could increase complete remission (CR) rate and survival in adult acute lymphoblastic leukemia (ALL). Of 121 patients registered, 116 were evaluated. Patients' ages ranged from 15 to 72 years (median, 38 years). Induction therapy, which consisted of doxorubicin, vincristine, cyclophosphamide, L-asparaginase and prednisolone, was given in a response-oriented individualized fashion. Patients were randomly allocated either to receive or not, intrathecal chemotherapy on day 8 of the induction therapy. Complete remission (CR) was obtained in 97 (83.6%) patients (90.2%) in patients of less than 50 years of age and 67.6% in patients 50 years of age or older). At a median follow-up period of 65 months, the predicted 6-year overall survival and event free survival (EFS) rates of 116 patients were 23.4 and 20.0%, respectively. Predicted 6-year survival and disease-free survival (DFS) rates of 97 CR patients were 28.2 and 24.5%, respectively. By multivariate analysis, patients under 40 years of age (P = 0.002) or those with a platelet count of more than 100,000/microliters (P = 0.004) were significant favorable prognostic factors for obtaining CR, and days to CR less than 50 (P = 0.003), patients under 50 years of age (P = 0.005) were significant favorable factors for longer DFS. There was no significant difference in CR rates and DFS between the two randomized groups according to the intrathecal chemotherapy on day 8. Response-oriented induction therapy produced a high CR rate, but fairly intensive consolidation and maintenance/intensification chemotherapies resulted in only a marginal effect on DFS in adult ALL. Although age is one of the most important prognostic factors in ALL, the outcome was unsatisfactory even in younger adult patients using chemotherapeutic regimen employed in this study.

Adolescent↗
PubMed1998

Chemotherapy vs HLA-identical sibling bone marrow transplants for adults with acute lymphoblastic leukemia in first remission.

There is controversy about whether chemotherapy or an HLA-identical sibling bone marrow transplant is better treatment for adults with acute lymphoblastic leukemia (ALL) in first remission. A previous study of patients treated in 1980-1987 showed similar leukemia-free survivals with these approaches. We re-examined this issue in more recently treated patients receiving different chemotherapy. Chemotherapy subjects (n = 76) participated in trial ALL-87 of the Japan Adult Leukemia Study Group (JALSG). Transplant subjects (n = 214) were reported to the International Bone Marrow Transplant Registry (IBMTR). Treatment-related mortality, relapse and leukemia-free survival were compared after adjusting for differences in subject- and disease-related variables and time-to-treatment. Outcomes differed in persons < or = and >30 years of age. Five-year treatment-related mortality in persons < or =30 years was 3% (95% confidence interval, 0-12%) with chemotherapy vs 32% (23-41%; P < 0.0001) with transplants. The difference was greater among persons >30 years, 13% (2-31%) with chemotherapy vs 57% (43-69%; P < 0.0001) with transplants. Five-year relapse probability in persons < or =30 years was 69% (50-84%) with chemotherapy vs 22% (14-32%; P < 0.0001) with transplants. Among persons >30 years, 5-year relapse was 70% (53-85%) with chemotherapy vs 32% (20-45%; P < 0.0001) with transplants. Leukemia-free survival at 5 years was significantly worse with chemotherapy than with transplants in persons < or =30 years (30% (15-48%) vs 53% (44-63%; P = 0.02)) but not in persons >30 years (26% (13-41%) vs 30% (20-41%; P = 0.70)). We concluded that transplants result in more treatment-related deaths but fewer relapses than chemotherapy. Leukemia-free survival is better with transplants than chemotherapy in persons < or =30 years of age but comparable in older persons.

Adolescent↗
PubMed1998

Reconstitution of peripheral blood lymphocyte subsets in the long-term disease-free survivors of patients with acute myeloblastic leukemia.

The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in complete remission (CR) were entered into the study. There were 12 males and 18 females; one M0, six M1, 14 M2, three M3, two M4 and four M5 according to FAB classification. The age ranged from 21 to 78 years (median age, 46 years) and the duration of disease-free survival after completion of chemotherapy ranged from 5 to 122 months (median, 35 months). The chemotherapy was performed according to the protocol designed by the Japan Adult Leukemia Study Group (JALSG). PBL subsets were analyzed by flow cytometry with the use of monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD16, CD20, CD45RA, CD56, CD57 and HLA-DR. There was a significant positive relationship between the absolute number of CD4+, CD45RA+ CD4+ cells and the duration of time post-therapy and a significant negative relationship between %CD5+ B, CD56+ cells and the duration of time post-therapy. The appearance of autoantibodies (rheumatoid factor and anti-DNA antibody) tended to increase after 2 years, however, there was no relationship between CD5+ B cells and the frequency of rheumatoid factor. These findings demonstrate that patients in CR have a low number of CD4+ and CD45RA+ CD4+ T cells at an early period after chemotherapy and that each subset recovered to a normal level in 2 years. %CD5+ B and CD56+ cells gradually decreased and returned to their normal level after 4 years. There were high numbers of DR+ T cells and NK cells for a long time, suggesting that activated T cells and NK cells may play a role in the immune surveillance system after chemotherapy.

Adult↗
PubMed1998

Serum thrombopoietin levels in patients correlate inversely with platelet counts during chemotherapy-induced thrombocytopenia.

We studied serum thrombopoietin (TPO) levels and circulating numbers of platelet during five courses of myelosuppressive post-remission chemotherapy in three patients with acute leukemia in complete remission. Serum TPO levels were measured by a newly developed and sensitive sandwich enzyme-linked immunosorbent assay. In all courses, serum TPO levels changed reciprocally with the platelet counts. When platelets were transfused into patients near the time of platelet nadir, the TPO levels dropped temporarily, while platelet counts temporarily increased. In addition, platelets obtained after transfusion in a thrombocytopenic patient showed lower binding to biotinylated TPO than donor platelets prior to the transfusion. The finding indicated that the TPO receptors were saturated with endogenous TPO of the patient with a high serum TPO level. These results suggest that the platelet mass directly regulates serum TPO levels by receptor-mediated absorption and is one of the major regulators of serum TPO levels in humans.

Adolescent↗
PubMed1998

Characterization of the immunoglobulin light chain variable region gene expressed in multiple myeloma.

We studied the organization, diversification and clinical significance of the immunoglobulin light chain (IgL) variable region genes expressed in 17 kappa-chain and 16 lambda-chain producing multiple myeloma (MM) samples. The V genes from 31 MM samples had over 84.9% homology to the known germline Vkappa/lambda genes, whereas one Vkappa and one Vlambda gene had only 75.5% and 65.9% homology, respectively. While all five Jkappa segments were equally used, only Jlambda-1 or Jlambda-2/3 was used among seven Jlambda segments. N nucleotide addition was found at two Vkappa-Jkappa and five Vlambda-Jlambda junctions. The lambda-chain complementarity determining region (CDR)-3 was longer and more variable than the kappa-chain CDR-3 mainly due to junctional flexibility of Vlambda and Jlambda segments. Somatic mutations were more frequent in the Jlambda than the Jkappa segments, and were distributed in the CDR-3 as well as the frame work region (FWR)-4. Those of the Jkappa segments, however, were limited to FWR-4. In FWR-4, replacement mutations were clustered at codon 106 of kappa-chain and 103 of lambda-chain. Thus nucleotide mutation or conservation was dependent on position, indicating a structural necessity of IgL for the development of myeloma cells in addition to a non-random distribution of mutations. There was no characteristic IgL sequence according to the isotype of M-protein, clinical stage or renal complication.

Adult↗
PubMed1998

The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms.

Arsenic trioxide (As2O3) has recently been shown to induce complete remission in acute promyelocytic leukemia (APL). As2O3 reportedly has dose-dependent dual effects on APL cells, triggering apoptosis at relatively high concentrations and inducing differentiation at lower concentrations. However, its effect is still controversial for other AML cells and hematological neoplasms. We studied the in vitro effect of As2O3 on lymphoid lineage cells: lymphoma cell lines, NOL-3, Raji and Daudi, a myeloma cell line, NOP-1, normal peripheral blood lymphocytes (PBL), non-Hodgkin's lymphoma (NHL) cells and chronic lymphocytic leukemia (CLL) cells, and compared it with the effect on APL cell line, NB4, as well as other myeloid cell lines, HL-60 and NKM-1. As2O3 at a concentration of 1 micromol/l markedly inhibited both proliferation and viability of NB4, NOP-1, NOL-3 and NKM-1 cells, but it reduced only viability in normal PBL, CLL cells and NHL cells. As2O3 induced apoptosis and down-regulated bcl-2 expression in NB4, NOP-1 and NKM-1 cells. On the other hand, in HL-60, Raji and Daudi cells, 1 micromol/l As2O3 inhibited only the proliferation weakly, and neither induced apoptosis nor down-regulated bcl-2 expression, but arrested only cell cycle at G1 phase. As2O3 at a low concentration of 0.1 micromol/l had no effect on proliferation and viability of these cells except for NB4. These results showed that As2O3 exerted variable and definite effects on lymphoid cells and indicated that As2O3 might be clinically useful in lymphoid neoplasms such as malignant lymphoma and CLL.

Antineoplastic Agents↗
PubMed1998

Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product.

An internal tandem duplication (ITD) of the FLT3 gene is found in nearly 20% of acute myeloid leukemia (AML) and 5% of myelodysplastic syndrome cases. Our serial studies on 51 samples with the FLT3 gene mutation indicated that the ITD was frequently (47/51) clustered in the tyrosine-rich stretch from codon 589 to 599 and rarely (3/51) in its downstream region, both of which are located within the juxtamembrane (JM) domain. One remaining sample had an insertion into the JM domain of nucleotides of unknown origin. To elucidate the biological relevance of the ITD or the insertion, we expressed various types of mutant FLT3 in Cos 7 cells. All mutant FLT3 studied were ligand-independently dimerized and their tyrosine residues were phosphorylated. The Y589 of FLT3 was essential for the phosphorylation in the wild FLT3, but a Y589F conversion did not affect the phosphorylation status of the mutant FLT3. These findings suggest that the elongation of the JM domain rather than increase of tyrosine residues causes gain-of-function of FLT3. Thus, ITD is a novel modality of somatic mutation which activates its product. Since the DNA corresponding to codon 593 to 602 potentially forms a palindromic intermediate, we propose that a DNA-replication error might be associated with generating the ITD of the FLT3 gene.

Acute Disease↗
PubMed1998

Quantitative expression of thrombopoietin receptor on leukaemia cells from patients with acute myeloid leukaemia and acute lymphoblastic leukaemia.

Using a non-isotopic ligand binding assay, we quantitatively examined the amount of human thrombopoietin (TPO) receptor (TPO-R) on leukaemia cells from 128 patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). The TPO-R was expressed in 53 (47%) of 114 AML cases, and an in vitro treatment with TPO led to proliferation (stimulation index >1 5) of leukaemia cells in 13 (20%) of 66 AML cases examined. The TPO levels had no relation to the FAB classification except for FAB-M7 AML. All five FAB-M7 cases expressed TPO-R, and one of three FAB-M7 examined showed in vitro proliferative response to TPO. Although there was no significant correlation (r = 0.3125) between the amount of TPO-R and the proliferative response, all of the AML cases which showed the in vitro response had TPO-R expression. There was no relationship between TPO-R amount and CD phenotypes, or the amount of granulocyte-colony stimulating factor (G-CSF) receptor. TPO-R was also expressed in two (14%) of 14 cases of ALL, and only these two cases had in vitro proliferative response to TPO. One had only lymphoid antigens, and the other had both lymphoid and myeloid antigens. Our results suggest that some leukaemia cells express functionally active TPO-R.

Acute Disease↗