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Biomedical subjects

Takeshi Isobe

Publications and source records attributed to Takeshi Isobe.

34 records · Page 2Linked to original sources
PubMed2004

Investigating the relationship between serum thrombopoietin kinetics and the platelet-sparing effect: A clinical pharmacological evaluation of combined paclitaxel and carboplatin in patients with non-small cell lung cancer.

We conducted a clinical pharmacological evaluation of paclitaxel/carboplatin combination in Japanese patients with non-small cell lung cancer. The purpose of this study was to identify the optimal dose of this combination and to investigate the relationships between the pharmacokinetic profiles of these 2 drugs, serum thrombopoietin (TPO) kinetics and the platelet-sparing effect. Patients received paclitaxel at 180-225 mg/m(2) by intravenous infusion over 3 h, followed by carboplatin at a target area under the concentration-time curve (AUC) of 6 mg/ml x min as a 1-h infusion. Serum paclitaxel, free platinum and TPO concentrations were measured using high-performance liquid chromatography, atomic absorption spectrometry and a double-sandwich enzyme-linked immunosorbent assay, respectively. Thirteen patients were enrolled. Neutropenia was the most frequent hematological toxicity and was significantly related to the time for which paclitaxel concentrations remained above 0.05 micro mol/ml. The prominent non-hematological toxicities were myalgia and sensory-dominant neuropathy. In this study, platelet and serum TPO kinetics were clearly different from those in our previous study of single-agent carboplatin (21). The platelet counts at the nadir were significantly higher (p<0.0001) in patients treated with paclitaxel/carboplatin combination (161,000+/-38,000/ micro l) compared with single-agent carboplatin (92,000+/-28,000/ micro l). The early increase in TPO (the percentage increase in TPO at day 4) was significantly greater (p=0.0345) in patients treated with paclitaxel/carboplatin combination (57.8+/-44.5%) compared with single-agent carboplatin (21.3+/-34.1%). The recommended doses are paclitaxel 210 mg/m(2) and carboplatin at an AUC of 6 mg/ml x min every 3 weeks. The observed platelet-sparing effect of the paclitaxel/carboplatin might be related to the early increase in circulating TPO levels, although the precise mechanism remains to be elucidated.

Adenocarcinoma↗
PubMed2003

Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice.

PURPOSE: This study was conducted to develop biologically relevant animal models of human lung cancer that are reproducible, inexpensive, and easy to perform. EXPERIMENTAL DESIGN: Human lung adenocarcinoma (PC14PE6), bronchioloalveolar carcinoma (NCI-H358), squamous cell carcinoma (NCI-H226), poorly differentiated non-small cell lung cancer (NCI-H1299 and A549), or small cell lung cancer (NCI-H69) cells in Matrigel were injected percutaneously into the left lungs of nude mice. The growth pattern of the different lung cancer tumors was studied. For PC14PE6 and NCI-H358, the growth pattern in the subcutis and the response to paclitaxel were also studied. RESULTS: As is observed for human primary lung cancer, tumors formed from a single focus of disease and progressed to a widespread and fatal thoracic process characterized by diffuse dissemination of lung cancer in both lungs and metastasis to intra- and extrathoracic lymph nodes. When the lung cancer cell lines were implanted s.c., systemic therapy with paclitaxel induced tumor regression. However, only a limited therapeutic response to paclitaxel was observed when the same cells were implanted orthotopically into the lung. Immunohistochemical analysis of tumor tissue revealed increased expression of the proangiogenic factors interleukin 8, basic fibroblast growth factor, and vascular endothelial growth factor/vascular permeability factor. CONCLUSIONS: Our orthotopic models of human lung cancer confirm the "seed and soil" concept and likely provide more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies.

Animals↗
PubMed2003

Soluble P-selectin and thrombomodulin-protein C-Protein S pathway in cyanotic congenital heart disease with secondary erythrocytosis.

INTRODUCTION: The aim of the study was to elucidate the roles of soluble P-selectin and thrombomodulin (TM)-protein C-protein S pathway in the pathogenesis of coagulopathy or thrombosis in cyanotic congenital heart disease (CCHD) with secondary erythrocytosis, and their correlations with hematocrit (Hct) value. MATERIALS AND METHODS: We studied 27 patients (age: 4.8 to 34.9, median 15) with cyanotic congenital heart disease complicated by secondary erythrocytosis (hematocrit >45%) and 26 patients with acyanotic congenital heart disease (ACHD). Plasma levels of P-selectin, beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), thrombomodulin, protein S and activity of protein C were compared between the two groups, and the relationships between these indices and hematocrit value were evaluated. RESULTS: Plasma levels of P-selectin, beta-thromboglobulin and platelet factor 4 [mean (S.D.)] were significantly high in cyanotic patients comparing with acyanotic patients [138 (70.1) vs. 82.5 (28.7), p<0.001; 94.4 (74.0) vs. 54.9 (19.7), p<0.01; 45.4 (48.7) vs. 22.7 (11.9), p=0.020, respectively]. Those of thrombomodulin and protein S and activity of protein C were significantly low in cyanotic patients comparing with acyanotic patients [22.1 (9.69) vs. 34.3 (27.4), p=0.029; 90.7 (15.1) vs. 112 (21.4D), p<0.0001; 88.8 (19.7) vs. 106 (27.7), p<0.01, respectively]. P-selectin (r=0.445, p=0.001) and beta-thromboglobulin (r=0.311, p=0.025) correlated positively, and platelet count (r=-0.418, p=0.0015), protein C (r=-0.322, p=0.018) and protein S (r=-0.368, p=0.007) correlated negatively with hematocrit. CONCLUSIONS: Chronic platelet activation and suppression of the thrombomodulin-protein C-protein S pathway might play an important role in coagulopathies identified in patients with erythrocytosis. Hematocrit is an important determinant of such abnormalities.

Adolescent↗
PubMed2003

Ventricular fibrillation during anesthesia in association with J waves in the left precordial leads in a child with coarctation of the aorta.

A 14-year-old boy with coarctation of the aorta who showed repeat ventricular fibrillation during anesthesia, and ultimately sudden cardiac death in school, is presented. Electrocardiography showed J waves in the left precordial leads, which became prominent after an episode of ventricular fibrillation. While some of the clinical features and electrophysiological findings were similar to those seen in Brugada syndrome, others were inconsistent. J waves in the left precordial leads should be recognized as a possible waveform change inducing ventricular fibrillation predominantly at rest.

Adolescent↗
PubMed2003

Pulse wave velocity as an indicator of atherosclerosis in impaired fasting glucose: the Tanno and Sobetsu study.

OBJECTIVE: Brachial-ankle pulse wave velocity (baPWV), as an indicator of atherosclerosis in impaired fasting glucose (IFG), was studied in 232 subjects randomly selected from inhabitants of two rural communities in Japan. RESEARCH DESIGN AND METHODS: BMI, systolic blood pressure (SBP), fasting blood glucose (FBS), lipid parameters, ankle brachial pressure index (ABI), and baPWV were measured in each subject. ABI and baPWV were measured using the recently developed device, form ABI/PWV. The subjects were divided into three groups according FBS level: a normal group consisting of subjects with FBS <110 mg/dl, an IFG group consisting of subjects with FBS 110-125 mg/dl, and a diabetic group consisting of subjects with FBS > or =126 mg/dl and subjects taking hypoglycemic agents. The parameters in the three groups were compared. RESULTS-It was found that the baPWV value increased with increasing plasma glucose level. Significant differences were found between the baPWV values in the normal and IFG groups (1,518 vs. 1,673 cm/s, P = 0.01) and in the normal and diabetic groups (1,518 vs. 1,771 cm/s, P < 0.0001). The results of multiple regression analysis showed that FBS was closely related to baPWV as well as to age and SBP. CONCLUSIONS: The relationship between IFG and atherosclerosis remains controversial. Further studies are needed to evaluate whether strict control of blood glucose level in patients with IFG will result in the prevention of atherosclerosis progression.

Aged↗
PubMed2003

[Relation of hypertension and glucose tolerance impairment in elderly people to the development of arteriosclerosis--investigation using pulse wave velocity].

Hypertension and diabetes are risk factors for arteriosclerosis and have a synergistic effect on the progression of arteriosclerosis. The aim of this study was to determine the correlation between complications of hypertension and diabetes and arteriosclerosis as assessed by pulse wave velocity (PWV) in elderly subjects. The subjects of this study were 186 people aged 60 years or older (mean age: 68.8 +/- 5.8 years) who were scheduled to undergo health examinations. PWV, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), fasting blood sugar (FBS), total cholesterol (TC), triglyceride (TG) and HDL cholesterol (HDL) were measured in each subject. The patients were divided according to the American Diabetes Association (ADA) diagnostic criteria for diabetes based on fasting blood sugar level into the following three groups: a normal (NGT) group (FBS < 110 mg/dl), an impaired fasting glucose (IFG) group (110 < or = FBS < 126 mg/dl) and a diabetes mellitus (DM) group (FBS > or = 126 mg/dl or receiving treatment for diabetes). Based on the JNC-VI and WHO/ISH diagnostic criteria, subjects who had a SBP of 140 mmHg or higher or a DBP of 90 mmHg or higher or who had been taking hypotensive drugs were assigned to the hypertension (HT) group, and the other subjects were assigned to the normotension (NT) group. PWV showed significant positive correlations with SBP and FBS (r = 0.499 and r = 0.300, respectively). The effects of hypertension on PWV were significantly higher in subjects with HT than in subjects with NT in all of the glucose tolerance groups (all p < 0.01). Moreover, in the subjects with HT, PWV started to increase from the IFG stage, and PWV was significantly higher in the DM groups than in the NGT group (p < 0.01). In multiple regression analysis using PWV as an objective variable, SBP and FBS were selected as significant explanatory variables. The results of this study indicate the need for stricter management of elderly people with slight glucose tolerance impairment and hypertension in order to prevent the occurrence of arteriosclerosis.

Aged↗
PubMed2003

A phase II study of topotecan in patients with relapsed small-cell lung cancer.

An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.

Journal Article↗
PubMed2003

Increased plasma ghrelin level in lung cancer cachexia.

PURPOSE: Ghrelin, a novel growth hormone-releasing peptide,has been shown to cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in cachexia associated with lung cancer. EXPERIMENTAL DESIGN: Plasma ghrelin level was measured in 43 patients with lung cancer and 21 control subjects. Patients with lung cancer were divided into two groups: patients with cachexia (n = 21) and those without cachexia (n = 22). RESULTS: Plasma ghrelin level did not significantly differ between all patients with lung cancer and controls (157 +/- 10 versus 132 +/- 8 fmol/ml, P = 0.1). However, plasma ghrelin level was significantly higher in patients with cachexia than in those without cachexia (180 +/- 17 versus 135 +/- 10 fmol/ml, P = 0.011). Furthermore, plasma ghrelin level increased significantly in patients with decreased food intake after chemotherapy (from 136 +/- 11 fmol/ml to 170 +/- 16 fmol/ml on day 8, 179 +/- 20 fmol/ml on day 21 after start of chemotherapy), although plasma ghrelin level did not significantly change in those without decreased food intake. CONCLUSIONS: Baseline plasma ghrelin level was elevated in cachectic patients with lung cancer, and follow-up plasma ghrelin level increased in patients with anorexia after chemotherapy. Considering the positive energy effects induced by ghrelin, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with lung cancer.

Aged↗
PubMed2003

Genetic susceptibility for emphysematous changes of the lung in Japanese.

Risk of chronic pulmonary emphysema from exposure to tobacco smoke varies widely from person to person, depending in part on the status of particular genes and acquired susceptibilities. Certain genes determine how cells activate and/or detoxify tobacco smoke products. We aimed to determine whether any genetic susceptibility exists in the development of emphysematous changes confirmed by chest computed tomography (CT). Genotypes of various enzymes involved in the activation or detoxification of tobacco smoke, epoxide hydrolase (EPHX1), cytochrome P450s (CYP1A1 and CYP2E1), glutathione S-transferases (GSTM1/P1/T1), and hemoxygenase-1 (HMOX1), were determined by PCR-based assays in a total of 235 heavy smokers (Brinkman index >/=400). They were divided into two groups according to the CT findings: 63 and 172 subjects with and without emphysematous changes, respectively. Although the allele frequency of any genetic polymorphism was not statistically different between the two groups, the frequency of the individuals having combination of the genotype representing very slow activity for epoxide hydrolase and at least one allele with large size of (GT)n repeats in the HMOX1 gene promoter region was higher in the subjects with emphysematous changes (p=0.03; odds ratio 2.8; 95% CI = 1.07-7.5) among the stratified individuals (age >/=51 years). These findings suggest that combination of several polymorphisms in the enzymes that activate or detoxify the tobacco smoke, such as EPHX1 and HMOX1, might be associated with its affects on the development of emphysematous changes of the lung.

Age of Onset↗
PubMed2002

Anastomosis between the left atrial appendage and left superior vena cava in a patient with mitral atresia.

A 5-day-old boy with mitral atresia and restrictive interatrial communication underwent an anastomosis between the left atrial appendage and left superior vena cava draining to the right atrium after unsuccessful balloon atrial septostomy. Consequent reduction of left atrial pressure improved the child's clinical condition, enabling palliative surgery. This procedure may be done safely without cardiopulmonary bypass in a seriously ill patient with combined elevated left atrial pressure and persistent left superior vena cava.

Anastomosis, Surgical↗
PubMed2002

Relationship between insulin-resistance and remnant-like particle cholesterol.

We investigated the relationship between insulin-resistance (IR) and remnant-like particle cholesterol (RLP-C) using 472 subjects (174 men and 298 women) randomly selected from inhabitants of two rural communities in Japan, Tanno and Sobetsu. The level of fasting immunoreactive insulin (FIRI), fasting blood glucose (FBS), total cholesterol (TC), triglyceride (TG), HDL cholesterol, LDL cholesterol, and RLP-C were measured in each subject. Homeostasis model assessment (HOMA-R) was used as an indicator of IR. The subjects were divided into two groups according to the value of HOMA-R: an IR group of subjects with HOMA-R > approximately equal to 1.73 and a normal (NR) group of subjects with HOMA-R <1.73. There was a significant positive correlation between HOMA-R and RLP-C. The value of RLP-C was higher in the IR group than in the NR group (7.1 vs. 3.9 mg/dl in men and 5.3 vs. 3.6 mg/dl in women). The frequency of hyper RLP cholesterolemia (RLP-C > approximately equal to 7.5 mg/dl) was higher in the IR than in the NR group (23.7 vs. 6.6% in men and 20.3 vs. 6.6% in women). The results of multiple regression analysis showed that HOMA-R was closely related to RLP-C. The results of this study suggest that RLP-C is closely associated with IR syndrome.

Aged↗
PubMed2002

A case of micronodular pneumocyte hyperplasia diagnosed through lung biopsy using thoracoscopy.

We present a case of a 39-year-old woman with sporadic tuberous sclerosis (TSC), whose chest radiograph demonstrated bilateral diffuse nodular shadowing. A transbronchial lung biopsy specimen revealed the possibility of multiple atypical adenomatous hyperplasia (AAH), which had not been reported in TSC. Thoracoscopic lung biopsy was, therefore, performed. The specimens revealed the characteristic histological and immunohistochemical features of micronodular pneumocyte hyperplasia, which has been reported as an extremely rare pulmonary manifestation of TSC. In addition, no evidence of AAH or any other pulmonary involvements of TSC including lymphangioleiomyomatosis were detected in biopsy specimens obtained at thoracoscopy.

Adult↗
PubMed2002

Usefulness of the modified lavage technique of Bingisser and KL-6 monitoring in a patient with pulmonary alveolar proteinosis.

A 48-year-old man diagnosed as pulmonary alveolar proteinosis (PAP) received a whole-lung lavage by the conventional lavage technique, but he failed to show any clinical or functional improvement. Therefore, we applied a modified lavage technique of Bingisser resulting in the impressive clinical and functional improvement. We measured the levels of KL-6 in bronchoalveolar lavage fluid (BALF) at selected time intervals. KL-6 levels in BALF were higher during the lavage by the modified lavage technique of Bingisser than the conventional lavage technique. We were able to verify the usefulness of the modified lavage technique of Bingisser by monitoring the levels of KL-6 in BALF. The modified lavage technique of Bingisser may be useful for PAP treatment.

Antigens↗
PubMedDate not supplied

Validation of the limited-sampling models for carboplatin AUC in combination chemotherapy with taxanes.

We previously developed limited-sampling models (LSM) for estimation of the area under the concentration curve (AUC) of free carboplatin (Anticancer Res 17: 4571-4576, 1997). The one-point model was: AUC (mg/ml x min) = 0.93 x C3h + 0.47 and the two-point model was: AUC (mg/ml x min) = 0.16 x C1h + 2.26 x C8h + 0.75, in which C3h, C1h and C8h represented the plasma concentration, sampled at 3 h, 1 h and 8 h after the start of a 1-h carboplatin infusion, respectively. In this study, we tried to confirm the utility of our LSMs in combination chemotherapy with taxanes. We obtained 29 data series from 29 patients who received carboplatin in combination with docetaxel (n = 16) or paclitaxel (n = 13). The actual AUC was strongly correlated with the AUC calculated from both one- and two-point models (one-point model; the mean prediction error (MPE) = -4.44 +/- 2.15%, the root mean squared error (RMSE) = 12.22 +/- 0.84%, two-point model; MPE = -1.89 +/- 1.66%, RMSE = 8.99 +/- 0.81%). Our LSMs proved to be unbiased and precise and are also useful for calculating carboplatin AUC in combination with taxanes.

Aged↗
PubMedDate not supplied

UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers.

BACKGROUND: We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance. In order to extend this result to the clinical setting, it is important to elucidate the role of SN-38 glucuronidation by UGT1A isoforms in CPT-11/SN-38 resistance in vivo. MATERIALS AND METHODS: We examined SN-38 glucuronidation activity in COS-7 cells transfected with full-length cDNAs for human UGT isoforms (UGT1A1, UGT1A3, UGT1A6 and UGT1A10). The gene expression levels of UGT isoforms were examined in lung cancer cell lines and 14 lung cancer samples by semi, quantitative RT-PCR. RESULTS: Our HPLC assay results showed that both UGT1A1 and UGT1A10 are responsible for SN-38 glucuronidation. The levels of UGT1A1 and UGT1A10 expression in a CPT-11/SN-38-resistant cell line were increased compared to levels in the parent cell line. Furthermore, there was considerable intersubject variability in 14 lung cancer samples, but UGT1A1 and UGT1A10 expression levels were significantly correlated (r=0. 70, p=0.004). Our results suggest that not only UGT 1A1, but also UGT 1A10, plays an important role in detoxifying CPT-11/SN-38, leading to resistance to CPT-11/SN-38 in lung cancer.

Aged↗