National Hospital Organization Yamaguchi Ube Medical Center

Ube, Japan

National Hospital Organization Yamaguchi Ube Medical Center

Ube, Japan
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PubMed | Saga University, Institute of Biomedical Research and Innovation, General Hospital, Kyoto University and 4 more.
Type: Journal Article | Journal: Cancer science | Year: 2016

Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re-biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment.


PubMed | Okayama University of Science, Red Cross, National Hospital Organization Shikoku Cancer Center, Chugoku Central Hospital and 7 more.
Type: | Journal: Clinical lung cancer | Year: 2016

Concurrent chemoradiotherapy (CRT) is the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, this intensive therapy often causes severe esophagitis, which could deteriorate a patients quality of life (QOL), leading to poor treatment compliance. Sodium alginate, approved in Japan for gastritis, is sufficiently highly viscous to remain in the esophageal mucosa, providing a protective effect in the esophagus. To investigate whether this compound has a preventive effect against severe esophagitis in patients receiving concurrent CRT, we plan a 3-arm randomized trial of sodium alginate with 2 different schedules versus water. The primary endpoint is set as the proportion of patients with grade 3 esophagitis using the Common Terminology Criteria for Adverse Events, version 4.0. With stratification by institute, performance status, and percentage of the esophageal volume receiving >35 Gy, the patients will be randomly assigned to 1 of the following groups: sodium alginate initiated concomitantly with CRT (group A), sodium alginate initiated soon after the development of extremely mild esophagitis during CRT (group B), or water administered throughout CRT (group C). Assuming that the proportion of grade 3 esophagitis would be 8% in groups A and B and 27% in group C, the required sample size would be 200 patients, with 70% power and 5% . The secondary endpoints include QOL, the frequency of additional prescriptions of analgesics, treatment response, and survival. The results of the present study will clarify whether sodium alginate can prevent esophagitis in patients with LA-NSCLC undergoing CRT.


Gemba K.,Okayama Rosai Hospital | Gemba K.,National Hospital Organization Fukuyama Medical Center | Fujimoto N.,Okayama Rosai Hospital | Aoe K.,National Hospital Organization Yamaguchi Ube Medical Center | And 4 more authors.
Acta Oncologica | Year: 2013

Background. There are few reports concerning treatment strategies and their contributions to survival of patients with malignant mesothelioma (MM) in Japan. Material and methods. We extracted all death cases due to MM between 2003 and 2008. The diagnosis of MM was confirmed in 929 cases. Histological subtypes was determined in 709 cases, including 396 (55.9%) epithelioid, 154 (21.7%) sarcomatoid, 126 (17.8%) biphasic, and 33 (4.7%) other types. Results and conclusion. Median overall survival (OS) of all MM cases was 7.7 months (95% confidence interval, 7.1-8.3). Median OS of patients with epithelioid MM was significantly longer than that of patients with biphasic (p = 0.030) or sarcomatoid (p < 0.001) MM. Surgical resection was performed in 172 patients (18.5%) and 449 (48.3%) received systemic chemotherapy. Survival of patients treated with both surgery and systemic chemotherapy was favorable. Median OS of patients in the late phase of the study period (2006-2008) was significantly longer than that in the early phase (2003-2005) (8.1 vs. 7.5 months, p = 0.008). Independent favorable prognostic factors included age younger than 70 years, female gender, epithelioid subtype, and clinical stage I-III. Multivariate analysis demonstrated that patients who had radical surgery and systemic chemotherapy showed a longer survival, though this could be due to selection bias of patients. © 2013 Informa Healthcare.


Aoe K.,National Hospital Organization Yamaguchi Ube Medical Center | Amatya V.J.,Hiroshima University | Fujimoto N.,Okayama Rosai Hospital | Ohnuma K.,Research Hospital | And 10 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive and therapy-resistant neoplasm arising from the pleural mesothelial cells, without established indicators to predict responsiveness to chemotherapy. Experimental Design: Our study involving 79 MPM patients showed that 73.4% of MPM expressed CD26 on cell membrane. Results: The majority of epithelioid and biphasic types of MPM expressed CD26 on the cell membrane, whereas the sarcomatoid type showed a lack of CD26 surface expression. Although the sarcomatoid type was associated with poor prognosis (P < 0.0001), no significant relationship between CD26 expression and survival was observed. On the contrary, there was a trend for an association between response rate to chemotherapy and CD26 expression (P = 0.053), with a higher level of CD26 expression more likely to be linked to better response to chemotherapy. Moreover, CD26 expression was a significant factor associated with improved survival in patients who received chemotherapy [median survival time (MST), 18.6 vs. 10.7 months, P = 0.0083]. Furthermore, CD26 expression was significantly associated with better prognosis in patients receiving non-pemetrexed-containing regimens (MST, 14.2 vs. 7.4 months, P = 0.0042), whereas there was no significant association between CD26 expression and survival time for patients receiving pemetrexed-containing regimens. Our in vitro and microarray studies showed that mesothelioma cells expressing high CD26 displayed high proliferative activity, and CD26 expression was closely linked to cell-cycle regulation, apoptosis, and chemotherapy resistance. Conclusions: Our results strongly suggest that CD26 is a clinically significant biomarker for predicting response to chemotherapy for MPM. ©2012 AACR.


Tanaka N.,Okayama University | Toyooka S.,Okayama University | Soh J.,Okayama University | Kubo T.,Okayama University | And 11 more authors.
Lung Cancer | Year: 2012

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p<. 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. © 2011 Elsevier Ireland Ltd.


Gemba K.,Okayama Rosai Hospital | Gemba K.,National Hospital Organization Fukuyama Medical Center | Fujimoto N.,Okayama Rosai Hospital | Kato K.,Okayama University | And 3 more authors.
Cancer Science | Year: 2012

In the present study, malignant mesothelioma (MM) cases in Japan were investigated retrospectively. We extracted records for 6030 cases of death due to MM between 2003 and 2008 to clarify the clinical features of MM, including its association with asbestos exposure (AE). Of all these cases, a clinical diagnosis of MM was confirmed for 929. The origin of MM included the pleura in 794 cases (85.5%), the peritoneum in 123 cases (13.2%), the pericardium in seven cases (0.8%), and the testicular tunica vaginalis in five cases (0.5%). The histological subtypes of MM included 396 epithelioid (55.9%), 154 sarcomatoid (21.7%), 126 biphasic (17.8%), and 33 cases (4.7%) classified as "other types". Of all the MM cases, AE was indicated in 76.8% and pleural plaques were detected in 34.2%. The number of asbestos particles was determined in 103 cases of MM. More than 1000 asbestos particles per gram dried lung tissue were detected in 74.8% of cases and more than 5000 particles were detected in 43.7% of cases. We compared patient characteristics and the diagnostic procedures for MM before and after the "Kubota shock". Compared with the early phase of this study (2003-2005), the median age at diagnosis of MM was higher, the number of cases without definite diagnosis of MM was lower, the proportion of cases diagnosed by thoracoscopy was higher, and the percentage of cases in which the occupational history was described in the medical records was significantly higher in the later phase (2006-2008). Our study confirmed that more than 70% of MM cases in Japan are associated with AE. The "Kubota shock" may affect some features pertaining to MM. © 2011 Japanese Cancer Association.


Nojiri S.,University of Tokyo | Gemba K.,Japan Labor Health and Welfare Organization Okayama Rosai Hospital | Aoe K.,National Hospital Organization Yamaguchi Ube Medical Center | Kato K.,Okayama University | And 4 more authors.
Japanese Journal of Clinical Oncology | Year: 2011

Objective: The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan. Methods: Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan-Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors. Results: Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio = 2.17; 95% confidence interval, 1.36-3.46), non-epithelioid type (hazard ratio = 1.58; 95% confidence interval, 1.15-2.18), poor performance status (hazard ratio = 3.22; 95% confidence interval, 1.19-8.74), high white blood cell count (hazard ratio = 1.49; 95% confidence interval, 0.99-2.26) and high C-reactive protein level (hazard ratio = 1.80; 95% confidence interval, 1.06-3.06) were negatively associated with survival, after adjustment for other factors. Conclusions: Some baseline conditions including old age, poor performance status, non-epithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma. © The Author (2010). Published by Oxford University Press. All rights reserved.


PubMed | Miyagi Cancer Center, Chugai Pharmaceutical Co Ltd, Tokyo Electron, National Cancer Center Hospital East and 4 more.
Type: Journal Article | Journal: Clinical lung cancer | Year: 2016

Obtaining tumor samples for epidermal growth factor receptor (EGFR) mutation analysis during treatment can be difficult; therefore, serum samples may be a convenient alternative. We analyzed serum EGFR mutations in the Japanese phase 2 JO22903 study in chemotherapy-naive non-small-cell lung cancer patients with tumor EGFR mutations.Serum samples were analyzed by Scorpion-ARMS to detect EGFR mutations before and after erlotinib administration. Agreement between serum and tumor EGFR mutations and time course changes of EGFR mutations were evaluated.A total of 95 of 103 patients consented to examination of serum samples; baseline serum EGFR mutations (exon 19 deletions or L858R) were detected in 25 patients (26.3%). The agreement rate between tumor and serum samples was 96.2%. Among 65 serum samples taken at 190 days after treatment initiation, EGFR mutations were detected in 5 patients (7.7%). Of the serum samples taken at progression (n= 71), EGFR mutations were detected in 16 patients (22.5%). Patients with baseline serum EGFR mutations had a median progression-free survival of 9.7 months; those without baseline serum mutations had a median progression-free survival of 15.2 months.The sensitivity of these analyses was not enough to draw firm conclusions; however, the results suggest that serum EGFR mutations correlate with disease activity.


PubMed | Hiroshima University, Okayama Rosai Hospital, National Hospital Organization Yamaguchi Ube Medical Center and Okayama University
Type: Journal Article | Journal: Japanese journal of radiology | Year: 2016

The purpose of this study was to clarify the characteristic findings of mesothelioma at the time of diagnosis, and determine precautions and guidelines for diagnosing mesothelioma early in imaging studies.Overall, 327 patients with pleural mesothelioma were selected from 6030 patients who died of mesothelioma between 2003 and 2008 in Japan. Their imaging findings were examined retrospectively.Plaques were found in 35% of computed tomography (CT) scans. Asbestosis, diffuse pleural thickening, and rounded atelectasis were found in only seven (2%), five (2%), and two cases (1%), respectively. Pleural thickening findings on CT scans were classified into four stages: no irregularity, mild irregularity, high irregularity, and mass formation. Overall, 18% of cases did not show a clear irregularity. Localized thickening was observed in the mediastinal (77%) and basal (76%) pleura and in the interlobar fissure (49%). Eight percent of cases did not have any thickening in these three areas.Upon examination of the CT scans at diagnosis, 18% of mesothelioma cases did not show a clear irregularity. When diagnosing pleural effusion of unknown etiology, it is necessary to consider the possibility of mesothelioma even when no plaque and pleural irregularity are observed.


PubMed | Hiroshima University, Okayama Rosai Hospital, National Hospital Organization Yamaguchi Ube Medical Center and Okayama University
Type: Journal Article | Journal: European journal of radiology | Year: 2016

To elucidate differences in the level and localization of pleural irregularities in early malignant pleural mesothelioma (eMPM) and benign asbestos pleural effusion (BAPE) using CT.Retrospective assessment of CT findings of consecutive patients with BAPE at a single centre and patients with eMPM reported in Japanese vital statistics.Thirty-six patients with confirmed diagnoses of BAPE and sixty-six patients with confirmed diagnoses of eMPM (mesothelioma stages T1 or T2) were included. Informed consent, CT scans, and clinical and pathologic details were obtained for all patients and were reviewed by one radiologist, two pathologists, and two pulmonologists. Asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening were assessed in all patients.Prevalence of asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening was significantly higher in the BAPE group. Low-level irregularity was more common in the BAPE group (p<0.001), whereas high-level irregularity, mediastinal localization, and interlobar fissure were more prevalent in the eMPM group (p<0.001). Interlobar pleural irregularity was not observed in any patients in the BAPE group, although 55% of patients in the eMPM group showed interlobar pleural irregularity. Mediastinal pleural involvement was observed in 74% of patients in the eMPM group and had a positive predictive value of 89%.This study demonstrates that the level and localization of plural irregularities significantly differed between patients with BAPE and eMPM. Large-scale prospective studies are needed to fully establish the diagnostic utility of such differences.

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