Osaka Prefectural Medical Center for Respiratory and Allergic Disease

Ōsaka, Japan

Osaka Prefectural Medical Center for Respiratory and Allergic Disease

Ōsaka, Japan

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Niho S.,National Cancer Center Hospital East | Kunitoh H.,National Cancer Center Hospital | Nokihara H.,National Cancer Center Hospital | Horai T.,Cancer Institute Hospital | And 18 more authors.
Lung Cancer | Year: 2012

Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Chemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p= 0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p= 0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p= 0.9526). No new safety signals were detected. Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). © 2011 Elsevier Ireland Ltd.


Hida T.,Fukuoka University | Hida T.,Kyushu University | Matsumoto S.,Fukuoka University | Hamasaki M.,Fukuoka University | And 9 more authors.
Cancer Science | Year: 2015

Differentiating malignant pleural mesothelioma (MPM) cells morphologically from reactive mesothelial hyperplasia cells is problematic. Homozygous deletion (HD) of p16 (CDKN2A), detected by FISH, is a good marker of malignancy and is useful to differentiate between these cells. However, the correlation between the p16 status of effusion smears and that of the underlying MPM tissues has not been investigated. We used p16-specific FISH to investigate 20 cases of MPM from which both effusion cytologic smears and histologic specimens were available. In five cases, histologic specimens included both an invasive component and surface mesothelial proliferation. In 14 cases (70%), MPM cells in both tissue sections and effusion smears were p16 HD-positive. Conversely, MPM cells in the remaining six tumors (30%) were p16 HD-negative in both tissue sections and effusion smears. For all five MPM cases with surface mesothelial proliferations and invasive components, the effusion smears, surface mesothelial proliferations, and invasive MPM components all displayed p16 deletion. Moreover, the extent to which p16 was deleted in smears highly correlated with the extent of p16 deletion in tissues. The p16 deletion percentages were also similar among smears, tissue surface proliferations, and invasive components. In cases with clinical and radiologic evidence of a diffuse pleural tumor, detection of p16 deletion in cytologic smear samples may permit MPM diagnosis without additional tissue examination. However, the absence of p16 deletion in cytologic smear samples does not preclude MPM. This study demonstrated the correlation between the p16 deletion status of effusion cytology and that of underlying malignant pleural mesothelioma (MPM) tissues by fluorescence in situ hybridization (FISH) analysis for MPM cases in which both materials were available. To the best of our knowledge, this is the first study to evaluate the correlation of p16 FISH status in MPM between cytologic and histologic specimens. If p16 FISH status of cytologic preparations can predict that of the underlying MPM, it may be possible to diagnose MPM in cytologic preparations in cases with clinical and radiological evidence of a diffuse pleural tumor. © 2015 Japanese Cancer Association.


PubMed | Red Cross, Kansai University of Welfare Sciences, Osaka Saiseikai Nakatsu Hospital, National Hospital Organization Kinki Chuo Chest Medical Hospital and 8 more.
Type: Journal Article | Journal: The American journal of hospice & palliative care | Year: 2016

To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an APs pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer.


PubMed | Fukuoka University, Tokyo Women's Medical University, Pathology Cytology Center, Osaka Prefectural Medical Center for Respiratory and Allergic Disease and Hyogo College of Medicine
Type: Journal Article | Journal: Diagnostic cytopathology | Year: 2016

Because most of malignant pleural mesothelioma (MPM) patients first present with pleural effusion, detection of mesothelioma cells on effusion smears is critical for early diagnosis. Recently, accumulating evidence indicating that the cytological diagnosis of MPM supported by ancillary techniques is as reliable as that based on histopathology has led to new guidelines for the cytopathologic diagnosis of MPM. Based on the guidelines, a combination of cytomorphological criteria and verification by ancillary techniques is required for the cytologic diagnosis of MPM. Detection of p16 homozygous deletion by fluorescence in situ hybridization (FISH) is the most reliable ancillary technique for differentiating MPM from reactive mesothelial cells (RMC) because of its relatively high sensitivity and extremely high specificity. We showed that the p16 deletion status of MPM cells in pleural effusions reflected that of the underlying invasive MPM tissues, indicating the usefulness of p16 FISH in effusion smear cytology for MPM diagnosis. Thus, for differentiating MPM from RMC, we propose to perform p16 FISH as often as possible. A positive p16 homozygous deletion supports the diagnosis of MPM. However, a negative result does not rule out the possibility of MPM. In such cases, a morphological assessment is critical. Therefore, we analyzed the morphological characteristics of p16 deletion-positive mesothelioma cells using a combination of virtual microscopy and p16 FISH, and identified three morphological characteristics useful for the differentiation, including cell-in-cell engulfment with or without hump formation, multinucleate cells, and larger berry-like cell aggregates. Diagn. Cytopathol. 2016;44:774-780. 2016 Wiley Periodicals, Inc.


PubMed | Fukuoka University, Tokyo Women's Medical University, National Hospital Organization, Hyogo College of Medicine and 3 more.
Type: Journal Article | Journal: Cancer science | Year: 2016

Differentiating malignant pleural mesothelioma (MPM) cells morphologically from reactive mesothelial hyperplasia cells is problematic. Homozygous deletion (HD) of p16 (CDKN2A), detected by FISH, is a good marker of malignancy and is useful to differentiate between these cells. However, the correlation between the p16 status of effusion smears and that of the underlying MPM tissues has not been investigated. We used p16-specific FISH to investigate 20 cases of MPM from which both effusion cytologic smears and histologic specimens were available. In five cases, histologic specimens included both an invasive component and surface mesothelial proliferation. In 14 cases (70%), MPM cells in both tissue sections and effusion smears were p16 HD-positive. Conversely, MPM cells in the remaining six tumors (30%) were p16 HD-negative in both tissue sections and effusion smears. For all five MPM cases with surface mesothelial proliferations and invasive components, the effusion smears, surface mesothelial proliferations, and invasive MPM components all displayed p16 deletion. Moreover, the extent to which p16 was deleted in smears highly correlated with the extent of p16 deletion in tissues. The p16 deletion percentages were also similar among smears, tissue surface proliferations, and invasive components. In cases with clinical and radiologic evidence of a diffuse pleural tumor, detection of p16 deletion in cytologic smear samples may permit MPM diagnosis without additional tissue examination. However, the absence of p16 deletion in cytologic smear samples does not preclude MPM.


Shintani Y.,Osaka University | Shintani Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Disease | Okimura A.,Osaka Prefectural Medical Center for Respiratory and Allergic Disease | Sato K.,Osaka University | And 11 more authors.
Annals of Thoracic Surgery | Year: 2011

Background: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype; it has a profound impact on cancer progression. The purpose of this study was to clarify the role of EMT in the sensitivity of non-small cell lung cancer (NSCLC) to chemoradiotherapy (CRT). Methods: We evaluated the correlation between EMT and sensitivity to chemotherapy or radiotherapy using NSCLC cells induced to undergo EMT with epidermal growth factor or transforming growth factor-β1. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, cytokeratin, N-cadherin, and vimentin in 50 tumor specimens obtained from patients with NSCLC both before and after CRT. Results: The EMT resulted in increased malignant potential and reduced sensitivity to cisplatin and paclitaxel in NSCLC cells. Furthermore, chronic exposure to cisplatin, paclitaxel, or radiation altered the cells into therapy-resistant sub-lines that showed phenotypic changes such as a spindle-cell shape and increased EMT marker expression. Also, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after CRT compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors. Conclusions: The EMT marker expression was detected in NSCLC tumors after CRT, indicating that EMT changes are associated with insensitivity to CRT. New therapeutic combinations using EMT-signaling inhibitors may be needed to circumvent the resistance of some types of cancer to CRT. © 2011 The Society of Thoracic Surgeons.


Shintani Y.,Osaka University | Funaki S.,Osaka University | Nakagiri T.,Osaka University | Inoue M.,Osaka University | And 4 more authors.
Interactive Cardiovascular and Thoracic Surgery | Year: 2013

OBJECTIVES: Although video-assisted thoracoscopic surgery (VATS) is widely used for the resection of a mediastinal mass, it is converted to an open resection in some patients with a mature teratoma because of dense adhesions. We reviewed cases with a mature teratoma removed by VATS and investigated the indications for that procedure for this tumour. METHODS: We retrospectively investigated 15 patients with a benign mediastinal mature teratoma who underwent a thoracoscopic procedure. RESULTS: The mean tumour diameter was 5.3 cm (range 3.2-8.5). The mean operative time was 188 min (78-430), and intraoperative blood loss was 138 ml (10-450). Thoracoscopic resection was completed in all except 3 patients with larger tumours, which presented the most difficult problems with dissection. Each of those 3 had severe preoperative chest pain and a tumour larger than 5.5 cm. No mortality or postoperative complications were recorded, except for postoperative chylothorax. Tumour recurrence did not develop in any patient during the mean follow-up period of 4.6 years. CONCLUSIONS: For selected patients with a mediastinal teratoma, VATS may be considered standard care, as most are benign. In contrast, an open approach may be more appropriate for patients with a large tumour or preoperative symptoms. © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.


Shintani Y.,Osaka University | Inoue M.,Osaka University | Funakoshi Y.,National Hospital Organization Toneyama Hospital | Matsumura A.,National Hospital Organization Kinki Chuo Chest Medical Center | And 3 more authors.
Anticancer Research | Year: 2011

Background: The enzyme dihydropyrimidine dehydrogenase (DPD) is involved in the metabolism of 5-fluorouracil (5-FU). The aim of this study was to clarify the correlation between the expression of DPD and the efficacy of 5-FU therapy in patients with lung adenocarcinoma (AD). Patients and Methods: We examined surgically resected specimens from 90 stage I to IIIA patients with lung ADs to determine the level of intra-tumoral DPD mRNA. Results: Administration of 5-FU improved the prognosis of patients with low DPD-expressing tumors, whereas it did not do so for patients with high DPD expressing tumors. Patients with low DPD-expressing tumors administered with 5-FU had a significantly better prognosis than those who underwent surgery alone. A Cox proportional hazards regression model revealed that administration of 5-FU was an independent variable to predict prognosis in patients with low DPD-expressing tumors. Conclusion: Quantification of DPD mRNA levels is useful for determining the subgroup of lung AD patients who would benefit most from 5-FU after surgery.


Shintani Y.,Osaka University | Shintani Y.,Osaka Prefectural Medical Center for Respiratory and Allergic Disease | Funakoshi Y.,National Hospital Organization Toneyama Hospital | Inoue M.,Osaka University | And 4 more authors.
Annals of Thoracic and Cardiovascular Surgery | Year: 2012

Objectives: The benefits of preoperative chemoradiotherapy for advanced nonsmall cell lung cancer (NSCLC) remain controversial. To evaluate prognostic indicators of clinical N2 NSCLC patients treated with concurrent chemotherapy followed by pulmonary resection, we performed a retrospective study. Methods: We retrospectively investigated 52 patients with pathologically proven N2 NSCLC who underwent concurrent chemoradiotherapy before pulmonary resection. Each received 2 cycles of cisplatin-vinca alkaloid-based chemotherapy every 4 weeks. Radiotherapy, directed at the tumor and mediastinal nodes, was started on day 2 at a median dose of 44 Gy. A thoracotomy was performed 6 to 8 weeks after completion of chemoradiotherapy. Results: The overall 5-year survival rate for the 52 patients was 38%. Complete pathological response by the tumor was found in 11 (21%). Down-staging of nodal stage occurred in 29 patients, (56%) and overall survival was better in those with lower pathological N status. The 5-year survival rate was 58% for pathological N0-N1 disease and 0% for N2 disease. While the response to induction therapy by the primary tumor was correlated with postoperative nodal stage, multivariate analysis revealed postoperative nodal stage as an independent prognostic factor. Conclusion: Pathological status of mediastinal lymph nodes in response to preoperative concurrent chemoradiotherapy determined prognosis in our patients. © 2012 The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery. All rights reserved.


PubMed | Fukuoka University, Hyogo College of Medicine, Kyushu University and Osaka Prefectural Medical Center for Respiratory and Allergic Disease
Type: Journal Article | Journal: Pathology international | Year: 2016

Differentiation of malignant pleural mesothelioma (MPM) from benign mesothelial proliferation remains problematic. Loss of nuclear staining of BRCA1-associated protein 1 (BAP1; detected using immunohistochemistry (IHC)) and homozygous deletion (HD) of p16 (detected using fluorescence in situ hybridization (FISH)) are useful for differentiation of MPM from reactive mesothelial hyperplasia (RMH), but the correlation between BAP1 expression loss and p16 HD has not been fully described. We performed BAP1 IHC and p16-specific FISH for 40 MPM and 20 RMH cases, and measured proportions of cells showing BAP1 expression and p16 HD for each case. The diagnostic accuracy for MPM and the cut-off values of the two methods were assessed using receiver operating characteristic (ROC) analysis. BAP1 expression loss, p16 HD and coexistence of both were present in 27 (67.5 %), 27 (67.5 %) and 17 (42.5 %) MPM cases, respectively. Three MPM cases (7.5 %) and all 20 RMH cases had neither BAP1 loss nor p16 HD. There was no correlation between the results of the two methods. Their combination showed higher sensitivity (92.5 %, 37/40) and estimated probability than BAP1 IHC and p16-specific FISH used alone. BAP1 IHC and p16-specific FISH have independent diagnostic value, and have increased reliability when used in combination, for MPM diagnosis.

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