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Biomedical subjects

Keisuke Aoe

Publications and source records attributed to Keisuke Aoe.

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↗
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

Heterogeneous nuclear ribonucleoprotein B1 expression in malignant mesothelioma.

Heterogeneous nuclear ribonucleoprotein B1, an RNA-binding protein required for mRNA maturation, reportedly is overexpressed in early lung cancer and in several other tumors, including precancerous lesions. Expression of the protein was assessed immunohistochemically in 39 specimens of malignant mesothelioma and five of non-neoplastic pleura, and by flow cytometry in a human epithelioid mesothelioma cell line. No tumor showed overexpression, but 29 of 39 cases showed modest expression. Patients whose tumors showed expression had significantly better survival rates than others. Epithelioid tumors and reactive mesothelial cells were more likely to express the protein than sarcomatoid tumors and resting mesothelial cells. Flow cytometric analysis of an epithelioid mesothelioma cell line demonstrated stronger expression in exponentially growing than growth-restricted cells. Heterogeneous nuclear ribonucleoprotein B1 is expressed widely in malignant mesotheliomas and in reactive mesothelial cells, but is not overexpressed. This protein may regulate proliferation linked with differentiation toward epithelioid morphology in mesothelial cells. Expression of the protein may be a prognostic indicator for patents with malignant mesothelioma.

Adult↗
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

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

Infrequent existence of simian virus 40 large T antigen DNA in malignant mesothelioma in Japan.

Malignant mesothelioma is the most common primary pleural neoplasm. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. However, significant geographic variation is present as to how often this association occurs. As no study concerning SV40 in malignant mesothelioma has been reported from Japan, we examined the frequency of SV40 infection in Japanese malignant mesothelioma cases. In pleural malignant mesothelioma tissue from 35 patients in Japan, we sought the presence of SV40 large T antigen DNA using real-time polymerase chain reaction (PCR), as well as expression of the viral protein using immunohistological methods. Real-time PCR demonstrated that two of 35 mesotheliomas contained DNA sequences encoding portions of SV40 large T antigen. None of the 35 malignant mesothelioma specimens showed immunoreactivity for SV40 large T antigen. SV40 infection does not appear to have a major role in the development of malignant mesothelioma in Japan.

Adult↗
PubMed2006

Recurrent superior mediastinal primary hemangiopericytoma 23 years after the complete initial excision: a case report.

We describe here a patient with a recurrent hemangiopericytoma of the superior mediastinum 23 years after an initial complete resection. In the current biopsy specimen, the tumor cells were much more anaplastic than those seen 23 years ago. Although the patient was treated with chemotherapy, which consisted of ifosfamide and epirubicin, the tumor was unresponsive and he died 6 months later from disease progression. Careful long-term follow-up is mandatory for patients with hemangiopericytomas because recurrence with greater malignancy can develop following an extended disease-free interval.

Aged↗
PubMed2006

The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells.

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Anthracyclines↗
PubMed2006

Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: concurrent measurement of ten cytokines and their respective ratios using cytometric bead array.

Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.

Acute Disease↗
PubMed2006

Elevated pleural fluid RCAS1 is a diagnostic marker and outcome predictor in lung cancer patients.

RCAS1, a type II membrane protein also secreted in soluble form, may be important in tumor cell evasion of immune surveillance and contribute to the aggressiveness of human tumors. We examined the implications of elevated pleural fluid RCAS1 at the onset of effusion in lung cancer patients. Of 102 patients presenting with pleural effusion, 59 proved to have a malignant effusion and 43, nonmalignant. Malignant effusions exhibited higher RCAS1 concentrations than nonmalignant effusions (mean +/- SD; 36.3 +/- 114 vs. 2.7 +/- 1.8 U/ml; p=0.014). Lung cancer patients with pleural fluid RCAS1 concentrations below 15 U/ml had a longer mean survival than those with higher concentrations (4.7 vs. 1.7 months; p<0.05). By multivariate analysis, pleural fluid RCAS1 was an independent prognostic factor in lung cancer patients with effusion. In conclusion, RCAS1 determination at onset of pleural effusion is informative for both diagnosis and outcome prediction in lung cancer patients.

Adult↗
PubMed2005

Chronic lung abscess with Pasteurella multocida infection.

We report a patient with chronic lung abscess due to Pasteurella multocida infection that may be caused by the contact with cows in his workplace. Despite its apparent rarity, chronic abscess due to P. multocida should be considered in the differential diagnosis of solitary pulmonary masses. This case report suggests that P. multocida infection can be potentially caused from saliva of cows as well as dogs or cats.

Bronchoscopy↗
PubMed2005

Serum hemoglobin level determined at the first presentation is a poor prognostic indicator in patients with lung cancer.

OBJECTIVES: Anemia is observed in various malignancies including lung cancer and is recently considered to be a poor prognostic indicator. We investigated whether there is a correlation between anemia, other clinicopathologic factors, and survival. METHODS: We retrospectively examined the clinical records of 611 patients with lung cancer. RESULTS: Of those, 298 (48.8%) patients had anemia at the time of their first visit to our hospital. There was a significant correlation between anemia and age (p=0.0006) or ECOG performance status (p=0.0002), however, there was no correlation of anemia with gender, histological type, clinical stage, or serum level of lactate dehydrogenase. Survival was significantly shorter in 298 patients with anemia (median survival time (MST): 7.5 months) compared with 313 patients without anemia (MST: 11.8 months, p<0.0001). Multivariate analysis of prognostic factors using the Cox proportional hazards model revealed that anemia appeared to be an independent prognostic indicator. CONCLUSION: Anemia observed at the first presentation is an independent poor prognostic indicator in patients with lung cancer.

Adult↗
PubMed2005

Clinical significance of the expression of tumor-associated antigen, RCAS1, and its soluble protein in pleural fluid in malignant mesothelioma.

RCAS1 is a type II membrane protein which is also secreted as a soluble protein. RCAS1 may play a role in evading immune surveillance by tumor cells and be responsible for the aggressive behavior of tumors. We examined the usefulness of RCAS1 in the follow-up of malignant mesothelioma. In addition, we examined the usefulness of its soluble protein (sRCAS1) in pleural effusion for the diagnosis of malignant mesothelioma. We studied 38 patients with pleural malignant mesothelioma and examined the correlation between RCAS1 expression, clinicopathologic variables and overall survival. We also determined the pleural fluid sRCAS1 concentration with an enzyme-linked immunosorbent assay (ELISA). We found that 34 out of 38 (89.5%) malignant mesothelioma cells stained for RCAS1. The positive rate was 90.9% in biphasic type, 78.6% in epithelioid type, and 100% in sarcomatoid type. No statistically significant correlation was observed between RCAS1 expression and gender, age, histology or clinical stage. Interestingly, survival of the malignant mesothelioma patients with RCAS1 expression was significantly increased compared with those without (median survival time: 13.0 vs. 4.3 months, p=0.011). Multivariate analysis of prognostic factors, using the Cox proportional hazards model, revealed that RCAS1 expression had a significantly positive effect on survival. sRCAS1 concentrations in pleural fluid in malignant mesothelioma were lower than those in lung cancer (2.18+/-2.20 vs. 46.3+/-129 U/ml; p=0.019). RCAS1 expression is informative for the follow-up of malignant mesothelioma patients. In addition, sRCAS1 in pleural fluid may be useful for the diagnosis of malignant mesothelioma.

Adult↗
PubMed2004

Comparison of six biological markers for the diagnosis of tuberculous pleuritis.

STUDY OBJECTIVE: We sought a marker to differentiate tuberculous pleural effusions from nontuberculous pleural effusions, which otherwise can be difficult. PATIENTS: We studied 55 patients with pleural effusions, 20 (36%) with tuberculous pleuritis and 35 (64%) with a nontuberculous etiology. MEASUREMENTS AND RESULTS: Pleural fluid levels of adenosine deaminase, interferon (INF)-gamma, interleukin (IL)-12p40, IL-18, immunosuppressive acidic protein, and soluble IL-2 receptors were measured and were subjected to receiver operating characteristic analysis. INF-gamma had the greatest sensitivity and specificity for tuberculous pleuritis among the six biological markers studied. CONCLUSION: The determination of INF-gamma levels in pleural fluid is the most informative in the diagnosis of tuberculous effusion.

Adenosine Deaminase↗
PubMed2004

Soluble receptor-binding cancer antigen expressed on SiSo cells in pleural fluid: a potential diagnostic marker for malignant pleural effusion.

BACKGROUND: We sought a marker to differentiate malignant from nonmalignant pleural effusions. METHODS: We studied 41 patients presenting with pleural effusions to the National Sanyo Hospital between April 2000 and January 2002 (33 men and 8 women; mean age, 68 years). Twenty patients (49%) were proven to have malignant pleural effusions, while 21 patients (51%) had nonmalignant pleural effusions. Thoracentesis was performed. RESULTS: The mean (+/- SD) concentration of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) in malignant pleural effusions, measured by enzyme-linked immunosorbent assay, was significantly higher than that in nonmalignant pleural effusions (15.1 +/- 33.6 vs 1.4 +/- 0.81 U/mL, respectively; p < 0.05). CONCLUSION: The determination of the RCAS1 concentration in pleural fluid is informative in the diagnosis of malignant pleural effusions.

Adult↗
PubMed2004

[Diagnosis and treatment of tuberculous pleurisy--with special reference to the significance of measurement of pleural fluid cytokines].

Tuberculous pleurisy as well as malignant pleuritis is a representative disease presenting pleural effusion. The diagnosis of tuberculous pleurisy is made from examination of pleural effusion, but the sensitivity of smear or culture of Mycobacterium tuberculosis from pleural fluid is generally low. Although the pleural fluid concentration of adenosine deaminase (ADA) is useful in terms of sensitivity or specificity, the value could be high in empyema or rheumatoid pleuritis. Thoracoscopic biopsy of pleura is more sensitive rather than conventional percutaneous needle biopsy, but is more invasive. Tuberculous pleural effusion is caused by delayed allergy which macrophage and T-helper 1 cells mainly relate and the stimuli of bacterial body consecutively induces T-helper 1 cytokines. Pleural fluid interferon-gamma (INF-gamma) is important not only in pathogenesis but also in diagnosis. We demonstrated that INF-gamma is a more sensitive and specific indicator for tuberculous pleurisy than ADA using receiver operating characteristics (ROC) analysis. Cytometric bead array (CBA) is a tool to simultaneously measure abundance of various cytokines and is expected to be a very useful method to provide informations for understanding a feedback mechanism of cytokine network. It is needed to clear the immunity in pleural fluid and to establish the less invasive and more useful method to diagnose tuberculous pleurisy.

Adenosine Deaminase↗
PubMed2003

Effect of nebulized furosemide in terminally ill cancer patients with dyspnea.

We evaluated the effect of ultrasonically nebulized furosemide (20 mg) on dyspnea uncontrollable by standard therapy in patients with terminal cancer. Dyspnea was evaluated using the Cancer Dyspnea Scale (CDS) before and 60 min after inhalation. Changes in arterial blood gases, hemoglobin oxygen saturation (SpO2), heart rate (HR), and respiratory rate (RR) also were evaluated. In 12 of 15 patients (80%), total dyspnea scores by CDS improved significantly after inhalation of furosemide (P = 0.007), especially concerning a reduced sense of effort (P = 0.013) and reduced anxiety (P = 0.04). No significant changes were observed in the partial pressure of oxygen in arterial blood (PaO2), the partial pressure of carbon dioxide in arterial blood (PaCO2), SpO2, HR, or RR. Inhalation of nebulized furosemide appears to be effective against dyspnea in terminally ill cancer patients.

Chloride Channels↗