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Biomedical subjects

K Ohyashiki

Publications and source records attributed to K Ohyashiki.

At least 19 recordsLinked to original sources
PubMed2004

Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia.

A multicenter open randomized trial was conducted to compare cefepime monotherapy with cefepime/amikacin combination (dual) therapy in treating febrile neutropenic patients with hematologic disorders. Among the 189 evaluable patients, 5.8% had microbiologically and 10.6% had clinically documented infections. Excellent response was seen in 32.6% and 45.7% of monotherapy and dual therapy recipients, respectively, at day 3 (P=.065). At day 3, patients with neutrophil counts of <500/ mu L receiving dual therapy had a better response than did those receiving monotherapy (45% vs. 27.6%; P=.024). The same was true for patients with leukemia. Adverse events were minimal, and early death was observed in 7 patients in the dual therapy group and 5 patients in the monotherapy group. Overall, cefepime monotherapy is as effective as dual therapy for the initial treatment of febrile neutropenic patients. Further study is warranted for patients with severe neutropenia and leukemia who may benefit from dual therapy.

Amikacin↗
PubMed2004

Monotherapy versus dual therapy based on risk categorization of febrile neutropenic patients.

Cefepime monotherapy was compared with cefepime-plus-amikacin dual therapy for treatment of febrile neutropenic patients. Response rates were significantly lower for patients receiving monotherapy who had neutrophil counts of <500 cells/mm3 but did not differ significantly between patients receiving dual therapy who had neutrophil counts of > or =500 cells/mm3 or <500 cells/mm3. Dual therapy is recommended for the initial treatment of patients with neutropenia with <500 cells/mm3. Dual therapy was significantly more effective in patients with neutropenia lasting <5 days. The response rates to monotherapy or dual therapy did not differ significantly when neutropenia persisted for > or =6 days, indicating that sustained neutropenia is a risk factor for failure of initial empirical therapy. The rate of response to monotherapy was lower in leukemic patients, whereas the rate of response to dual therapy did not differ between leukemic and nonleukemic groups. The rate of response to either monotherapy or dual therapy did not differ for patients with temperatures of > or =38 degrees C or 37.5 degrees C-38 degrees C. Overall, defervescence occurred in >80% of patients with mild infections, whereas only 32% of those with moderate to severe infection responded by day 3 and 69.8% by day 7.

Amikacin↗
PubMed2004

A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia.

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasias but not in normal somatic tissues. Therefore, the telomerase complex represents a promising universal therapeutic target in cancer. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells. Telomere length was determined by either the terminal restriction fragment method or flow-FISH, and apoptosis was assessed by flow cytometry. Moreover, chemosensitivity was examined in telomestatin-treated U937 cells before ultimate telomere shortening. Treatment with telomestatin reproducibly inhibited telomerase activity in U937 and NB4 cells followed by telomere shortening. Enhanced chemosensitivity toward daunorubicin and cytosine-arabinoside was observed in telomestatin-treated U937 cells, before ultimate telomere shortening. Telomere shortening associated with apoptosis by telomestatin was evident in some freshly obtained leukemia cells from acute myeloid leukemia patients, regardless of sub-types of AML and post-myelodysplasia AML. These results suggest that disruption of telomere maintenance by telomestatin limits the cellular lifespan of AML cells, as well. However, in a minority of AML patients apoptosis was not evident, thus indicating that resistant mechanism might exist in some freshly obtained AML cells. Therefore, further investigation of telomestatin as a therapeutic agent is warranted.

Acute Disease↗
PubMed2003

Telomerase inhibition enhances apoptosis in human acute leukemia cells: possibility of antitelomerase therapy.

Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. We examined the impact of telomerase inhibition by the dominant-negative human catalytic subunit of telomerase (DN-hTERT) on the biological features of acute leukemia. We introduced vectors encoding dominant- negative (DN)-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistant marker into a telomerase-positive human acute lymphoblastic leukemia cell line, HAL-01. Expression of DN-hTERT dramatically inhibited telomerase activity, leading to apoptotic cell death. Mutant telomerase expression also enhanced daunorubicin-induced apoptosis. Nude mice (n=5 per group) received subcutanous implants of HAL-01 cells expressing the control vector or DN-hTERT or WT-hTERT. Implantation of HAL-01 cells expressing control vector (n=5) rapidly produced tumors, whereas implantation of those expressing DN-hTERT (n=5) did not. Thus, telomerase inhibition both growth of HAL-01 cells in vitro and tumorigenic capacity in vivo. Furthermore, the G-quadruplex-interactive telomerase-specific inhibitor, telomestatin, shortened the telomere length and induced apoptosis in freshly isolated primary acute leukemia cells. These results suggest that antitelomerase therapy may be useful in some acute leukemias in combination with antileukemic agents such as daunorubicin.

Acute Disease↗
PubMed2003

Increased collagenase activity in macrophages from bronchial lavage as a diagnostic marker of non-small cell lung cancer.

BACKGROUND: The roles of matrix metalloproteinases (MMPs) in cancer metastasis have been studied. Macrophages are considered to release MMPs in the tissues of patients with lung cancer. METHODS: Intracellular collagenase activity was measured in CD14+ CD45+ cells from bronchial lavage fluid to establish a new diagnostic tool for lung cancer. Between August 2000 and November 2001 bronchoscopy and bronchial lavage were performed in 45 patients with abnormal shadows on the chest radiograph; 21 had lung cancer and 24 had non-malignant disease. RESULTS: Collagenase activity in patients with primary lung cancer (5.54 (0.65)) or non-small cell lung cancer (NSCLC) (5.62 (0.71)) was significantly higher than in those with non-malignant disease (3.63 (0.78), p=0.006 and p=0.008, respectively). Only three of 18 patients in the low activity group were diagnosed as having cancer compared with 18 of 27 in the high activity group (p=0.001). This significance was not seen in non-smokers but it was apparent in smokers/ex-smokers. Excluding non-smokers improved the specificity of collagenase activity in differentiating cancer and non-malignant disease from 62.5% to 80.0%. The sensitivity of the test was 85.7% in all patients and 88.2% in smokers/ex-smokers. CONCLUSIONS: Measurement of intracellular collagenase activity in macrophages in bronchial lavage fluid is a useful diagnostic tool for distinguishing between cancer and non-malignant diseases, especially in smokers and ex-smokers.

Adult↗
PubMed2002

Elevated plasma level of differentiation inhibitory factor nm23-H1 protein correlates with risk factors for myelodysplastic syndrome.

We measured plasma nm23-H1 level (nm23-H1), a differentiation inhibitory factor, by an enzyme-linked immunosorbent assay (ELISA) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). The nm23-H1 in AA was not significantly elevated when compared to normal subjects (6.66 +/- 1.20 ng/ml vs 5.13 +/- 0.81 ng/ml; P = 0.274). In contrast, MDS patients had significantly high levels of nm23-H1 compared not only to normal subjects (11.16 +/- 1.42 vs 5.13 +/- 0.81 ng/ml; P = 0.0004) but also to those of the AA group (11.16 +/- 1.42 ng/ml vs 6.66 +/- 1.20 ng/ml; P = 0.018). In the MDS group of patients, no significant difference was observed in the nm23-H1 levels between patients with refractory anemia (RA) and RA with excess blasts (RAEB)/RAEB in transformation (10.71 +/- 1.61 ng/ml vs 9.24 +/- 2.66 ng/ml; P = 0.672). Of the patients with RA, patients with low risk according to the International Prognostic Scoring System (IPSS) had significantly low levels of nm23-H1 compared to those of IPSS INT-1 level cases (6.40 +/- 1.36 ng/ml vs 13.05 +/- 2.50 ng/ml; P = 0.0028), suggesting that nm23-H1 may be useful as a prognostic marker for MDS, especially in low risk patients.

Acute Disease↗
PubMed2002

Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells.

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.

Acute Disease↗
PubMed2001

Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma.

BACKGROUND: Tumor-related leukocytosis is a paraneoplastic syndrome that is encountered occasionally in the clinical course of patients with lung carcinoma. Recently, autonomous production of hematopoietic cytokines (granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage-colony stimulating factor [GM-CSF], and interleukin-6 [IL-6]) were identified in some of these patients. However, the incidence and clinical characterization of this phenomenon have not been clarified. METHODS: During a 7-year period, 227 patients with carcinoma of the lung were investigated, and 33 patients were diagnosed with tumor-related leukocytosis. Except for one patient with small cell lung carcinoma, the other 32 patients had nonsmall cell lung carcinoma, and the highest incidence is recognized in large cell carcinoma. These 33 patients were examined for serum G-CSF, GM-CSF, and IL-6 levels using enzyme immunoassays and enzyme-linked immunosorbent assays. Tumor specimens were stained for antihuman cytokine (G-CSF, GM-CSF, and IL-6) monoclonal antibodies. RESULTS: Sixteen patients showed high serum G-CSF levels, 4 patients showed high serum GM-CSF levels, and 18 patients showed high serum IL-6 levels. Twelve specimens stained positively against anti-G-CSF antibody. Two specimens stained positively against anti-GM-CSF antibody, and three specimens were stained positively against anti-IL-6 antibody, including one double positive specimen for both G-CSF and IL-6. All specimens that were positive for monoclonal antibodies were from patients with nonsmall cell lung carcinoma. These patients had a poor outcome compared with the other patients. CONCLUSIONS: Tumor-related leukocytosis and cytokine production frequently occur in the clinical course of lung carcinoma, and this phenomenon is related mainly to nonsmall cell lung carcinoma. Its occurrence appears to be an ominous prognostic sign in patients with lung carcinoma.

Adult↗
PubMed2001

An improved method for the rapid preparation of 2-amino-4,4a-dihydro-4a,7-dimethyl-3H-phenoxazine-3-one, a novel antitumor agent.

A simple and rapid preparation method for a novel antitumor agent, 2-amino-4,4a-dihydro-4a,7-dimethyl-3H-phenoxazine-3-one (Phx) was described. The procedure included (1) the reaction of bovine hemolysates with 2-amino-5-methylphenol, (2) one-shot denaturation of hemoglobin and proteins by methanol, and removal of the denatured hemoglobin and proteins, (3) concentration of the reaction products, and (4) purification by a Sephadex column. These procedures yielded Phx in 34% yield.

Animals↗
PubMed2001

Anaplastic large-cell lymphoma which showed severe inflammatory status and myelodysplasia with increased VEGF and IL-6 serum levels after long-term immunosuppressive therapy.

We report a patient with anaplastic large-cell lymphoma (ALCL) who has been given immunosuppressive therapy for Evans syndrome for 10 years. He was admitted with spike fever, intra-abdominal lymphadenopathy, and multiple liver masses. Examination of biopsy specimens obtained by para-aortic lymph nodes and liver masses resulted in a diagnosis of ALCL. Immunohistochemically, these cells were reactive to anti-CD30 antibody but were not of B- or T-lineage. Bone marrow aspiration demonstrated the invasion of giant neoplastic cells and trilineage myelodysplasia. Because the patient showed severe inflammatory symptoms, we examined serum levels of various cytokines. Pretreatment levels of IL-6 and VEGF in this patient were significantly elevated compared to those of normal controls. He was treated with combination chemotherapy (ABVD regimen), achieving complete remission. Myelodysplasia and serum IL-6 and VEGF also normalized after treatment. We assumed that ALCL resulted from long-term immunosuppressive therapy and that the up-regulation of IL-6 and VEGF played a role in pathogenesis of this type of lymphoma.

Abdominal Pain↗
PubMed2001

In situ telomerase activity in pleural effusions: a promising marker for malignancy.

Telomerase activity in 16 pleural effusions was studied using an in situ telomerase repeat amplification protocol (TRAP) assay on cytospin preparations. Six of nine cytologically malignant specimens contained telomerase-positive cells (67%), and in two further specimens, suspicious positive cells were seen. Two of four atypical specimens contained telomerase-positive cells, whereas two benign cases were telomerase-negative. No mesothelial cells showed telomerase reactivity. Thus, telomerase activity was specific for malignancy and it was always found only in malignant cells. The results suggest that telomerase activity measured with this in situ method can be a valuable complement in the assessment of malignancy in pleural effusions.

Biomarkers, Tumor↗
PubMed2001

Disparity between the macroglobulin-producing components of 2 cases of follicular lymphoma with Waldenström's macroglobulinemia.

We report 2 patients with follicular lymphoma (FL) which was accompanied by Waldenström's macroglobulinemia (WM). One patient was a 65-year-old woman and the other a 60-year-old man. Both patients showed a high level of circulating macroglobulin (4.6 g/dL and 3.6 g/dL, respectively) and bone marrow involvement of small lymphoid cells. Moreover, in each case, the macroglobulin-producing component and the follicular component were determined to be of the same clone based on their identical light-chain restriction pattern and other factors. However, there was a difference in the histopathological characteristics of the macroglobulin-producing components of the 2 patients, especially the cytoplasmic immunoglobulin (Ig)M+ cell distribution in the biopsied lymph nodes. Test results for the female patient showed intrafollicular proliferation of those cells. The male patient's test results showed that IgM+ cells were located in the narrow extrafollicular areas of the lymph nodes. Our observations suggest that at least 2 different subtypes of FL may also be causative of a WM presentation.

Aged↗
PubMed2001

Re-evaluation of refractory anemia with excess blasts in transformation.

The category 'refractory anemia with excess blasts in transformation (RAEBt)' consists of two sub-sets; one group is categorized based on the percentage of blasts in the marrow (> or =20%) and other is based on the percentage of blasts in the peripheral blood (> or =5%). We separated RAEBt patients based on these two criteria and compared hematologic and clinical relevance to assess the reasonable basis for the new classification. All RAEBt patients showing peripheral blood (PB) blasts of > or =5% were re-classified as RAEB by the WHO classification. This subset of RAEBt patients had lower percentages of bone marrow (BM) blasts, and notably they showed frequent complex cytogenetic abnormalities, including -5/5q- and/or -7/7q-. Moreover, the RAEBt patients of this group had shorter survivals compared to RAEBt patients with BM blasts between 20 and 30%. We next assessed hematologic and clinical relevance between refractory anemia with excess blasts (RAEB) and RAEBt patients with PB blasts of > or =5%. Except for the percentage of blasts in the PB (P=0.0037) and BM (P=0.0073), there was no significant difference in hematologic or clinical features between RAEB patients with BM blasts of > or =11% and RAEBt patients with PB blasts of > or =5%. When MDS patients with PB blasts of > or =5% (RAEBt by the FAB classification) were included as RAEB-II based on the "MDS 2000 classification', there was a high frequency of patients with complex chromosome changes, involving 5q and 7q, with significant poorer outcome compared to those with RAEB-I. Although it is still controversial whether MDS patients with BM blasts 20% or more should be considered as acute leukemia, the utilization of the 'MDS 2000 classification' might be useful to designate MDS patients diagnosed based on the percentage of blasts in the peripheral blood.

Adult↗