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Biomedical subjects

Hiroshi Date

Publications and source records attributed to Hiroshi Date.

At least 19 recordsLinked to original sources
PubMed2007

The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer.

We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (-216G/T and -191C/A), using a PCR-based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation.

Aged↗
PubMed2007

Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers.

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined.

5' Flanking Region↗
PubMed2007

Anti-tumor effect of bisphosphonate (YM529) on non-small cell lung cancer cell lines.

BACKGROUND: YM529 is a newly developed nitrogen-containing bisphosphonate (BP) classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC). METHODS: Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157) were measured by MTS assay and calculated inhibition concentration 50 % (IC50) values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method). We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. RESULTS: We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 microM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819). CONCLUSION: Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.

Antineoplastic Agents↗
PubMed2006

Risk factors for local progression after percutaneous radiofrequency ablation of lung tumors: evaluation based on a preliminary review of 342 tumors.

BACKGROUND: The purpose of the study was to retrospectively evaluate the risk factors for local progression after percutaneous radiofrequency (RF) ablation of lung tumors. METHODS: The study included 128 patients (77 men, 51 women; mean age, 61.3 years) with 342 tumors (25 primary and 317 metastatic lung neoplasms; mean long-axis diameter, 1.7 cm) treated with RF ablation. The overall primary and secondary technique effectiveness rates were estimated using Kaplan-Meier analysis. Multiple variables were analyzed using the log-rank test, followed by multivariate multilevel analysis to determine independent risk factors for local progression. The primary and secondary technique effectiveness rates were again estimated when considering only tumors without independent risk factors. RESULTS: The median follow-up period was 12 months (range, 6-47 months). The overall primary and secondary technique effectiveness rates were 72% and 84% at 1 year, 60% and 71% at 2 years, and 58% and 66% at 3 years, respectively. Larger tumor size (hazard ratio [HR], 1.97; 95% confidence interval [95% CI], 1.47-2.65; P < .00001) and the use of an internally cooled electrode (HR, 2.32; 95% CI, 1.10-4.90; P = .027) were assessed as independent risk factors for local progression. The primary and secondary technique effectiveness rates when considering tumors smaller than 2 cm and treated with a multitined expandable electrode were 89% and 89% at 1 year and 66% and 78% at 2 years, respectively. CONCLUSIONS: Larger tumor size and the use of an internally cooled electrode were independent risk factors for local progression after RF ablation of lung tumors.

Adult↗
PubMed2006

Usefulness of EGFR mutation screening in pleural fluid to predict the clinical outcome of gefitinib treated patients with lung cancer.

The importance of epidermal growth factor receptor (EGFR) gene mutation has been recognized in nonsmall cell lung cancer (NSCLC), requiring the standardization of mutation screening system including the kind of samples. Here, we examined the EGFR mutation status in 61 pleural fluid samples from NSCLC cases using direct sequencing, nonenriched PCR, mutant-enriched PCR and peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp assay. The mutant-enriched PCR assay detected 16 mutant cases. Among them, the nonenriched PCR assay failed to detect 3 mutant cases. Regarding the discrepancy between mutant-enriched PCR and PNA-LNA PCR clamp assays, 3 cases of exon19-deletions were detected only by mutant-enriched PCR assay and no difference at the L858R mutation. There was no difference in results between direct sequencing and nonenriched PCR assay. We also correlated the EGFR mutation with clinical outcome of gefitinib-treated 29 cases. EGFR mutations were present in 10 cases, revealing 7 partial response and 3 no change (NC). In EGFR wild-type cases, 10 revealed NC and 9 progressive disease. The responders were significantly more frequent among the EGFR mutant cases than among the wild-type (p < 0.0001). Overall survival (p = 0.0092) and progression-free survival (p = 0.018) were significantly longer among the EGFR mutant cases than among the wild-type. In summary, we evaluated the utility of EGFR mutation screening in pleural fluid using 4 assays that showed some discrepancies arising from the designs of the assays. As clinical importance, the EGFR mutation status in pleural fluid can be a biomarker for the favorable outcome of gefitinib-treated NSCLC cases.

Aged↗
PubMed2006

Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer.

The threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non-small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib. Alternatively, the EGFR T790M mutation might be present in small fractions of tumor cells before drug treatment, and the tumor cells harboring the T790M mutation might be enriched during the proliferation after drug treatment. We developed a mutant-enriched PCR assay to detect small fractions of cells with T790M mutation and used this technique to detect mutations in 280 NSCLCs, including gefitinib-treated 95 cases. Although the direct sequencing detected only 1 T790M mutant case, the mutant-enriched PCR (confirmed to enrich one mutant out of 1 x 10(3) wild-type alleles) detected 9 additional cases among 280 cases. As linkage to clinicopathologic factors, the T790M mutation showed no bias for sex, smoking status, or histology but was significantly more frequent in advanced tumors (9 of 111 cases) than in early-stage tumors (1 of 169 cases; P = 0.0013). Among gefitinib-treated cases, gefitinib-sensitive mutations were found in 30 cases. The T790M mutation was present in 3 of 7 no-responders with the gefitinib-sensitive mutation and was not present in 19 responders (P = 0.014). Our results indicate that the T790M mutation is sometimes present in a minor population of tumor cells during the development of NSCLC and suggest that the detection of small fractions of T790M mutant alleles may be useful for predicting gefitinib resistance of NSCLCs with sensitive EGFR mutations.

Amino Acid Substitution↗
PubMed2006

Distance and oxygen desaturation in 6-min walk test predict prognosis in COPD patients.

The aim of the present study was to predict the prognosis of Chronic obstructive pulmonary disease (COPD) patients who underwent comprehensive pulmonary rehabilitation (PR). A total of 144 patients who performed PR between 1992 and 1999 was assessed. After PR, 67 patients underwent lung volume reduction surgery (LVRS). Baseline data before PR consisted of body mass index, serum albumin levels, use of supplement oxygen at home, pulmonary function, arterial blood gas analysis, and distance and fall of hemoglobin oxygen saturation (DeltaSpO(2)) in 6-min walk test. In addition to pre-PR factors, treatment with LVRS was taken into the analysis. The prognostic significance of variables influencing survival was determined by univariate analysis with Log rank test or multivariate analysis using Cox's proportional hazard model. By a median follow-up time of 8.4 years, the median survival time was 8.1 years (95% confidence interval: 6.9-9.4 years). Albumin level, PaCO(2), distance and DeltaSpO(2) were significant prognostic factors in univariate analysis. LVRS did not affect the prognosis. The multivariate analysis showed short distance and increase of DeltaSpO(2) as significant independent predictors of the risk of death. 6-min walk test was very useful for predicting the prognosis of the COPD patients.

Aged↗
PubMed2006

Comprehensive pulmonary rehabilitation according to severity of COPD.

A new classification for the severity of COPD was proposed at GOLD 2003: stage I: FEV(1) > or = 80% predicted; stage II: 50% < or = FEV(1)<80%; stage III: 30% < or = FEV(1)<50%; and stage IV: FEV(1) < 30%. To elucidate the acute effects of pulmonary rehabilitation (PR) on patients with different stages of COPD, data on pulmonary function, arterial blood gas analysis, the 6-min walk test, respiratory muscle strength, and activities of daily living were analyzed before and after our comprehensive 4- to 8-week inpatient PR program between 1992 and 2003. A total of 225 patients (201 men and 24 women; 21 with stage II, 79 with stage III, and 125 with stage IV COPD) was assessed. There were significant differences in FEV(1)% predicted and % residual volume in stages III and IV, in % vital capacity in stages II, III and IV, and in % total lung capacity in stage II when comparing the changes between pre- and post-PR. Significant differences of PaO(2) in stages III and IV and PaCO(2) in stage IV were found when comparing the changes between pre- and post-PR. The 6-min walk distance was significantly increased after PR by an average of approximately 50m for all staged patients. Respiratory muscle strength was also significantly increased in stages III and IV. Activities of daily living were significantly improved in all stages. These results showed that patients with COPD had benefited from PR regardless of disease severity. The effects included improvement in pulmonary function, arterial blood gas analysis, 6-min walk distance, respiratory muscle strength, and activities of daily living although there were some differences among the three stages.

Activities of Daily Living↗
PubMed2006

Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer.

Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-tyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib.

Aged↗
PubMed2006

Recovery of protein-losing enteropathy after living-donor lobar lung transplantation in primary pulmonary hypertension.

The patient investigated was a 43-year-old woman with primary pulmonary hypertension (PPH) and refractory protein-losing enteropathy (PLE). She underwent living-donor lobar lung transplantation (LDLLT), which led to remarkable improvement in both pulmonary hypertension and PLE. Although there have been no reports, to our knowledge, that have demonstrated PLE as a complication of PPH, the present case clearly shows how PLE could complicate PPH. In addition, and more importantly, hypo-proteinemia due to PLE should not necessarily be an exclusion criterion for lung transplantation when PPH is involved, because it could markedly improve after transplantation.

Adult↗
PubMed2006

Optimal time for post-mortem heparinization in canine lung transplantation with non-heart-beating donors.

BACKGROUND: We previously reported that post-mortem heparinization by closed-chest cardiac massage is beneficial in lung transplantation from non-heart-beating donors by preventing formation of microthrombi. In this study, we evaluated the optimal time for post-mortem heparinization in canine lung transplantation from non-heart-beating donors. METHODS: Left lung transplantation was performed in 25 weight-matched pairs of mongrel dogs. Donors were killed with an intravenous injection of potassium chloride and left at room temperature for 2 hours. The cadaver donors were assigned randomly to one of five study groups. In Group H0, heparin sodium (1,000 U/kg) was given intravenously before cardiac arrest. In Groups H10, H30, H45 and H60, heparin sodium (1,000 U/kg) was given intravenously 10, 30, 45 and 60 minutes after cardiac arrest, respectively, followed by closed-chest cardiac massage for 2 minutes. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran glucose solution and preserved for 60 minutes. After left lung allotransplantation, the right pulmonary artery was ligated, and recipient animals were followed up for 3 hours. Uni- and multivariate repeat analyses were utilized for statistical assessment. RESULTS: After transplantation, gas exchange was significantly worse in Groups H45 and H60 than in Groups H0, H10 and H30. Thrombin/anti-thrombin III complex concentration during warm ischemia was significantly higher in Groups H30, H45 and H60 than in Groups H0 and H10. CONCLUSIONS: The optimal time for post-mortem heparinization in lung transplantation from non-heart-beating donors is approximately 30 minutes after cardiac arrest.

Animals↗
PubMed2006

Relationship between epidermal growth factor receptor gene mutations and the severity of adverse events by gefitinib in patients with advanced non-small cell lung cancer.

PURPOSE: Recent reports have demonstrated that mutation of epidermal growth factor receptor (EGFR) gene is predictive factor for tumor responsiveness to gefitinib suggesting the importance of EGFR status for the treatment of the patients with non-small cell lung cancer (NSCLC). However, the relationship between EGFR mutation and adverse events of gefitinib is still unknown. The aim of this study was to evaluate its correlation. PATIENTS AND METHODS: Twenty-six tumor samples from Japanese NSCLC patients who received gefitinib in Okayama University Hospital between November 2000 and October 2004 were examined exons 18-21 of EGFR using direct sequence method. We retrospectively reviewed the clinical records and compared EGFR mutation status with adverse events during gefitinib treatment. RESULTS: Of all 26 patients, EGFR mutation (exon 19 in-frame deletion, 6; exon 21 L858R, 5), were detected in 11 patients (42.3%). The principal adverse event was skin rash (89%), diarrhea (39%), and liver injury (39%). Grade 3 or more adverse events were not common. EGFR mutation status was correlated with neither its frequency nor severity of adverse events during gefitinib treatment including skin rash, diarrhea, liver injury, and interstitial lung disease. As expected, objective response rate of those with EGFR mutations was significantly higher than those without EGFR mutations (78% versus 21%, P<0.001). CONCLUSION: Our study did not demonstrate the presence of close relationships between EGFR mutation status and adverse events during gefitinib treatment.

Adenocarcinoma↗
PubMed2006

Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers.

Genetic and epigenetic alterations are considered to play important roles in lung cancer. Recent studies showed that EGFR and K-RAS mutations exhibited a mutually exclusive pattern in adenocarcinoma of the lung, suggesting the presence of two independent oncogenic pathways. However, it is unknown how epigenetic alterations were involved in lung carcinogenesis mediated by EGFR or K-RAS mutation. In this study, we examined the relationship between genetic and epigenetic alterations in 164 cases of lung adenocarcinoma. Somatic mutations were determined by direct sequence of EGFR exons 18 to 21 and K-RAS codons 12 and 13. Methylation status of p16(INK4a), RASSF1A, APC, RARbeta, and CDH13, frequently methylated in lung cancer, was determined by methylation-specific PCR and the degree of methylation was defined as the methylation index. Multivariate analysis adjusted for age, sex, and smoking dose showed that the probability of having EGFR mutation was significantly lower among those with p16(INK4a) and CDH13 methylation than in those without [p16(INK4a): odds ratio (OR), 0.07; 95% confidence interval (95% CI), 0.02-0.33; CDH13: OR, 0.34; 95% CI, 0.15-0.77] and the methylation index was significantly lower in EGFR mutant cases than in wild type (OR, 0.70; 95% CI, 0.52-0.95). By contrast, K-RAS mutation was significantly higher in p16(INK4a) methylated cases than in unmethylated cases (OR, 4.93; 95% CI, 1.54-15.7) and the methylation index was higher in K-RAS mutant cases than in wild type with marginal significance (OR, 1.46; 95% CI, 0.95-2.25). Our results indicate the differences in the evolvement of epigenetic alterations between the EGFR- and K-RAS-mediated tumorigenesis and suggest the specific interaction of genetic and epigenetic changes in tumorigenesis of lung cancer.

Adenocarcinoma↗
PubMed2006

Detection of EGFR gene mutation in lung cancer by mutant-enriched polymerase chain reaction assay.

PURPOSE: Mutations in the epidermal growth factor receptor (EGFR) gene have been reported to be present in non-small cell lung cancer (NSCLC) and related to the responsiveness of tumors to EGFR tyrosine kinase inhibitors, suggesting its usefulness as a biomarker. Because clinical samples contain tumor and normal cells or genes, a highly sensitive assay for detecting mutation is critical for clinical applications. EXPERIMENTAL DESIGN: The mutant-enriched PCR is a rapid and sensitive assay with selective restriction enzyme digestion. We developed the mutant-enriched PCR assay targeting exons 19 and 21 of EGFR and applied the developed assay to detect mutations in 108 cases of surgically resected specimens of NSCLCs, 18 samples of computed tomography (CT)-guided needle lung biopsies, and 20 samples of pleural fluid. In addition, results were then compared with those from direct sequencing and a nonenriched PCR assay. RESULTS: The mutant-enriched PCR that was proved to enrich one mutant of 2 x 10(3) normal genes detected mutations in 37 cases of 108 resected tumors, seven samples of CT-guided lung biopsies, and seven samples of pleural fluid. Among mutant cases, four resected tumors, two CT-guided lung biopsies, and two pleural fluid were identified as additional mutant cases by the mutant-enriched PCR, which were considered normal based on nonenriched assays. CONCLUSIONS: Our results indicate that EGFR mutations are readily detectable by mutant-enriched PCR in various clinical samples. Thus, mutant-enriched PCR may provide a valuable method of potentially detecting a small fraction of mutant genes in heterogeneous specimens, indicating its possible use in clinical application for NSCLC.

Biopsy↗
PubMed2006

Post-mortem administration of urokinase in canine lung transplantation from non-heart-beating donors.

BACKGROUND: We previously reported that post-mortem heparinization by closed-chest cardiac massage within 30 minutes after cardiac arrest is beneficial in lung transplantation (LTx) from non-heart-beating donors (NHBDs) by preventing formation of microthrombi. In this study, we evaluated the effects of post-mortem administration of urokinase 60 minutes after cardiac arrest. METHODS: Left LTx was performed in 12 pairs of mongrel dogs. Donors were sacrificed and left at room temperature for 2 hours. In Group 1 (n = 6), heparin sodium (1,000 U/kg) was administered intravenously 60 minutes after cardiac arrest, then closed-chest cardiac massage was performed for 1 minute to distribute the heparin. In Group 2 (n = 6), the donors were treated as in Group 1, except, in addition to heparin sodium, urokinase (120,000 U) was administered intravenously before and at the end of cardiac massage. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran glucose solution. After left LTx, the right pulmonary artery was ligated, and recipients were followed up for 3 hours. Uni- and multivariate repeat analyses were performed to obtain statistical data. RESULTS: Group 2 had significantly better arterial oxygen tension, lower pulmonary vascular resistance and lower wet/dry weight ratio of the transplanted lung than Group 1. d-dimer level during the warm ischemia was significantly lower in Group 2 than in Group 1. CONCLUSIONS: Post-mortem administration of urokinase along with heparin is beneficial in LTx from NHBDs by fibrinolytic action on already formed pulmonary microthrombi in the cadaver donor lungs.

Animals↗