DOI： 10.11406/rinketsu.57.2151

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P = 0.0066) and overall survival (OS) (P = 0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P = 0.015) and OS (P = 0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2015.03.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Disseminated intravascular coagulation (DIC) is often associated with infection and a poor outcome. In this study, useful markers for predicting poor outcomes were examined.
Methods The frequency of DIC and organ failure, outcomes and hemostatic markers were prospectively evaluated in 242 patients with infections.
Results Seventy-seven patients were diagnosed with DIC, 36 of whom recovered from the condition. The rate of DIC or resolution of DIC was highest in the patients with sepsis and lowest in the patients with respiratory infections. Mortality tended to be high in the patients with respiratory infections. The DIC score, sepsis-related organ failure assessment (SOFA) score, prothrombin time (PT) ratio and thrombin-antithrombin complex level were significantly high in the patients who did not recover from DIC. The age, DIC score, SOFA score, PT ratio and levels of thrombomodulin and plasminogen activator inhibitor (PAI)-I were significantly high in the non-survivors. Factors related to a poor outcome included resolution of DIC, the SOFA score, age and the PT ratio. Factors related to resolution of DIC included the SOFA score and age, while factors related to the SOFA score included the levels of PAI-I, leukocytes, fibrinogen, D-dimer and platelets.
Conclusion The outcomes of septic patients primarily depend on the SOFA score and the resolution of DIC, which are related to organ failure.

DOI： 10.2169/internalmedicine.52.0571

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

The generation of thrombin-antithromin (AT) complex (TAT) or soluble fibrin (SF) was prospectively compared with prothrombin fragment 1 + 2 (F1 + 2) generation in patients with disseminated intravascular coagulation (DIC). The plasma levels of TAT, SF, and F1 + 2 were significantly higher in the DIC group than in the non-DIC group. The differences in these levels between the DIC group and non-DIC group were significantly related to infections and hematopoietic tumors. There were no significant differences in the TAT/F1 + 2 ratio between DIC and non-DIC patients, but the SF/F1 + 2 ratio was significantly higher in the DIC group than the non-DIC group. The plasma AT activity was significantly higher in patients with DIC with resolution than in those without resolution, and in survivors than in nonsurvivors. These findings suggest that the ratio of TAT/thrombin is constant between the patients with and without DIC but that the ratio of fibrin formation/thrombin might increase in DIC.

DOI： 10.1177/1076029612451648

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), D-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, D-dimer, and SFMC were recommended to be 8.3 and 42.0 mu g/mL, 2.4 and 22.0 mu g/mL, and 3.4 and 138.0 mu g/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin-related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders.

DOI： 10.1177/1076029611429786

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Patients with suspected disseminated intravascular coagulation (DIC) were prospectively evaluated for various types of underlying diseases, and the usefulness of hemostatic markers were examined for each patient with DIC due to various underlying diseases.
The main underlying disease of DIC was infectious diseases, hematologic malignancies, and solid tumors, and a high resolution rate from DIC was observed in obstetric diseases and hematologic malignancies. The diagnosis of DIC was related to a poor outcome in trauma/burn victims and those with infectious disease. In the main underlying disease, it is suggested that DIC would be excluded in patients with hematologic malignancies or solid tumors with a platelet count of more than 100,000/mu l and in the patients with an FDP of less than 10 mu g/ml, and fibrinogen of less than 100 mg/dl, suggesting the presence of DIC. The prothrombin time was a sensitive marker, but fibrinogen levels were not sensitive for DIC due to infectious diseases. The plasmin plasmin inhibitor complex in hematologic malignancy, and soluble fibrin monomer complex, antithrombin and thrombomodulin in patients with infectious disease, were sensitive markers for the diagnosis of DIC.
Although hemostatic markers were useful for the diagnosis of DIC, the usefulness varied depending on the different underlying diseases. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.thromres.2011.02.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.

DOI： 10.1007/s12185-011-0774-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Diagnostic criteria for non-overt disseminated intravascular coagulation (DIC) have been proposed by the International Society of Thrombosis and Hemostasis, but are not useful for the diagnosis of early phase of overt-DIC (pre-DIC). Therefore, in the current study the non-overt DIC diagnostic criteria were modified using the global coagulation tests, the change rate in the global coagulation tests and molecular hemostatic markers to detect the pre-DIC state and were prospectively evaluated in 613 patients with underlying DIC disease. The frequencies of patients with DIC (DIC positive), late onset DIC, and without DIC (DIC absent) were 29.5%, 7.2%, and 63.3%, respectively. The modified non-overt-DIC criteria can correctly predict 43/44 patients (97.7%) who were DIC absent at admission and became DIC positive, within a week (late onset DIC state). The mortality rate was higher in DIC positive compared with pre-DIC (37.6% vs. 22.7%, P < 0.05) or DIC negative (37.6 vs. 13.7%, P < 0.01). It was also significantly higher in pre-DIC compared with DIC negative (P < 0.05). Thus, these modified non-overt DIC diagnostic criteria might therefore be useful for the diagnosis of early-phase DIC. Am. J. Hematol. 85:691-694, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/ajh.21783

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Disseminated intravascular coagulation (DIC) sometimes has a poor outcome, and therefore early diagnosis and treatment are required. This study prospectively evaluated the hemostatic abnormalities and the onset of DIC in 613 patients with underlying diseases to identify a useful marker for diagnosing Pre-DIC. Pre-DIC was defined as the condition of patients within a week before the onset of DIC. Initially, 34.4% of patients were diagnosed with DIC, and about 8.5% of the patients without DIC were diagnosed as DIC within a week after registration (pre-DIC). The mortality of DIC, Pre-DIC and "without DIC" was 35.3%, 32.4% and 17.2%, respectively. All hemostatic parameters were significantly worse in "DIC" than "without DIC" and the values of the prothrombin time ratio, platelet count and fibrin monomer complex could classify the three groups; "DIC", "pre-DIC" and "without DIC". No useful marker was identified that provided an adequate cutoff value to differentiate "pre-DIC" from "without DIC". A multivariate analysis identified clinical symptoms that were related to poor outcome. DIC must be treated immediately; there is no specific marker to identify pre-DIC. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.thromres.2010.03.017

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.thromres.2009.08.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocation involving the gene for retinoic acid receptor alpha (RAR). Most APL patients have a t(15;17) translocation that generates the PML-RAR fusion gene, and such patients respond well to treatment with all-trans retinoic acid (ATRA). Some APL cases also involve rearrangements that fuse RAR to partner genes other than PML, including nucleophosmin (NPM), promyelocytic leukemia zinc finger (PLZF), nuclear mitotic apparatus (NUMA), and Stat5b, but the clinical characteristics of APL without PML-RAR have not been fully clarified. We describe a 64-year-old man with NPM-RAR-positive APL who was receiving hemodialysis therapy for chronic uremia. Complete remission was achieved with ATRA monotherapy and was maintained for 18 months with consolidation chemotherapy. These findings suggest that ATRA can be used to treat APL patients with NPM/RAR as well as APL with PML/RAR.

DOI： 10.1532/IJH97.07036

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Introduction: Vascular endothelial cell damage plays an important role in microvascular thrombogenesis. In vivo administration of cyclosporin A or mitomycin C sometimes results in thrombotic microangiopathy in patients.
Materials and methods: The effects of cyclosporin A, mitomycin C and/or prednisolone on the cell cycle in cultured human umbilical vein endothelial cells were investigated to evaluate drug-induced endothelial cell damage and the protective effect of prednisolone on endothelial cells against the damage by cyclosporin A or mitomycin C in vitro.
Results: The addition of cyclosporin A to cultures caused proliferation arrest in the G1-phase in a dose-dependent manner, while mitomycin C inhibited DNA synthesis, which resulted in cell cycle arrest and inhibition of BrdUrd incorporation in the S-phase. The administration of prednisolone also caused cell cycle arrest in the G1 by itself, and protected the cells from the damage caused by mitomycin C. The inhibitory effects of cyclosporin A and prednisolone on the cell cycle were reversible, while mitomycin C was not. The highly phosphorylated retinoblastoma protein expressed in human umbilical vein endothelial cells decreased in the presence of mitomycin C. Soluble thrombomodulin levels in the culture supernatant were elevated by the addition of cyclosporin A.
Conclusion: These effects of the drugs may cause the cell cycle arrest and the prolonged repair of damaged endothelial cells in patients. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.thromres.2004.09.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Non-Hodgkin's lymphoma (peripheral T cell, unspecified, clinical stage IIIEA) was diagnosed in a 54-year-old male. He was treated weekly with chemotherapy consisting of pirarubicin hydrochloride, cyclophosphamide, methotrexate, vincristine sulfate, etoposide, and prednisolone. After 6 weeks of treatment in a state of partial remission, he exhibited sudden dyspnea, chest pain, fever, and drowsiness. The patient had received 100 mug/day of granulocyte colony stimulating factor (G-CSF) for 6 days before the onset. Laboratory data showed an elevated lactate dehydrogenase (LDH) level, leukoerythroblastosis in the peripheral blood, and no decrease in the serum haptoglobin level. There were no findings of acute myocardial infarction or pulmonary thromboembolism. Bone marrow specimen showed the characteristic features of necrosis without any signs of the involvement of lymphoma cells. No indications of infections were found. This patient was diagnosed as having bone marrow necrosis (BMN) during the recovery phase of bone marrow with G-CSF treatment after chemotherapy for malignant lymphoma. After conservative therapy, inhalation of oxygen and stopping the administration of G-CSF, all clinical symptoms subsided except that the elevation of LDH continued for I month. The plasma level of tumor necrosis factor-alpha (TNF-alpha) was high just after the onset of BMN. The thrombomodulin (TM) level was high just before the onset of BMN and continued to be high for 2 weeks. Cross-linked fibrin degradation products (D-dimer) were also high just after the onset of BMN and continued to be high for 3 weeks after the onset. Although dyspnea is a rare symptom of BMN, it is important to rule out in BMN during the recovery phase of bone marrow with G-CSF treatment after chemotherapy for malignant lymphoma. Activated neutrophils in the small vessels of the lung by G-CSF and microthrombl, suggested by the elevation of D-dimer, may participate in the onset of dyspnea, which is a rare symptom of the onset of BMN. Am. J. Hematol. 70:250-253, 2002. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ajh.10136

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Presentation type：Oral presentation (invited, special)  

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Presentation type：Oral presentation (invited, special)  

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