Higashi Hiroshima Medical Center

Higashi Hiroshima, Japan

Higashi Hiroshima Medical Center

Higashi Hiroshima, Japan
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Yamasaki M.,Red Cross | Murakami I.,Higashi Hiroshima Medical Center | Nakano K.,National Hospital Organization Kure Medical Center | Doi M.,Hiroshima Prefectural Hospital | And 5 more authors.
Anticancer Research | Year: 2017

Aim: We aimed to evaluate the efficacy and safety of carboplatin plus weekly paclitaxel with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Patients and Methods: Patients with stage IIIB/IV or postoperative recurrent NSCLC (n=33) were treated with carboplatin (area under the curve of 6) on day 1; paclitaxel (80 mg/m2) on days 1, 8, and 15; and bevacizumab (15 mg/kg) on day 1 repeated every 4 weeks, for four to six cycles; followed by maintenance bevacizumab (15 mg/kg) every 3 weeks. Results: The overall response rate was 76%. The median progression-free survival and overall survival were 8.4 months and 22.2 months, respectively. Grade 3-4 toxicities included neutropenia in 55% of patients, anemia in 18%, febrile neutropenia in 12%, and anorexia in 9%. No treatmentrelated deaths were observed. Conclusion: Carboplatin plus weekly paclitaxel with bevacizumab was effective and well tolerated by patients with advanced NSCLC.


Suda K.,Aurora University | Suda K.,Osaka University | Murakami I.,Higashi Hiroshima Medical Center | Yu H.,Aurora University | And 5 more authors.
Journal of Thoracic Oncology | Year: 2017

Introduction Expression of immune markers is of scientific interest because of their potential roles as predictive biomarkers for immunotherapy. Although the microenvironment of metastatic tumors and/or therapy-inducible histological transformation may affect the expression of these immune markers, there are few data regarding this context. Methods A 76-year-old never-smoking female with EGFR-mutated lung adenocarcinoma (AC) acquired resistance to gefitinib. After her death, an autopsy revealed SCLC transformation and EGFR T790M secondary mutation (T790M) as mutually exclusive resistance mechanisms occurring differently in different metastases; two liver metastases (SCLC versus AC with T790M) and two lymph node metastases (SCLC versus AC with T790M) were analyzed to compare the expression status of immune markers by immunohistochemistry and by an immune oncology gene expression panel. Results Programmed death ligand 1 (PD-L1) protein was partially expressed in tumor cells with AC lesions (T790M) but not in tumor cells with SCLC transformation. The liver metastasis with SCLC transformation showed no stromal PD-L1 expression and scant tumor-infiltrating lymphocytes, whereas the other lesions demonstrated stromal PD-L1 staining and infiltration of CD8-positive T cells. Data generated using an immuno-oncology gene expression panel indicated a higher level of T-cell costimulatory molecules and lower expression of type I interferon–regulated genes in lesions with SCLC transformation. Conclusion These data highlight the heterogeneity of expression of immune markers depending on the metastatic sites and histological transformation and indicate that the biopsy specimen from one lesion may not be representative of immune marker status for all lesions. © 2017 International Association for the Study of Lung Cancer


Kawahara T.,Hiroshima University | Miyata Y.,Hiroshima University | Akayama K.,Higashi Hiroshima Medical Center | Okajima M.,Hiroshima University | Kaneko M.,Osaka University
IEEE/ASME Transactions on Mechatronics | Year: 2010

In video-assisted thoracic surgery (VATS), a surgeon cannot easily detect a lung tumor during surgical operation. This paper discusses a noncontact tumor imager capable of detecting a tumor position for application during VATS; this sensor is based on the phase differential technique. The developed sensor comprises an air supply system and an optical-fiber-based displacement sensor adjacent to the air nozzle. For a periodic air pressure, a displacement sensor provides sinusoidal outputs with individual phases. The phase difference varies according to the change in the mechanical impedance parameters of tissues between two points. We confirmed the validity of the sensor for the removed human lung through basic experiments. With regard to clinical applications, both the tumor detection capability and the safety to lung tissues of the developed sensor were confirmed through in vivo animal experiments using pig lungs. Finally, the sensor system was developed for clinical tests and the results of the clinical experiments are shown. © 2010 IEEE.


Haga Y.,National Hospital Organization Kumamoto Medical Center | Haga Y.,Kumamoto University | Miyanari N.,National Hospital Organization Kumamoto Medical Center | Takahashi T.,Higashi Hiroshima Medical Center | And 5 more authors.
Scandinavian Journal of Infectious Diseases | Year: 2013

Background: Risk factors for catheter-related bloodstream infections (CRBSIs) may change over time with progress in infection control. This study was undertaken to explore the current risk factors for CRBSIs in hospitalized patients. Methods: Adult patients with non-tunneled central venous catheters (CVCs) in 12 Japanese referral hospitals were prospectively enrolled between December 2009 and January 2012. Patients were monitored for CRBSIs for up to 8 weeks from CVC insertion; data were collected regarding patient characteristics, the purpose of CVC insertion, insertion methods, mechanical complications during insertion, and post-insertion catheter care. Results: A total of 892 patients were enrolled in this study. The overall incidence of CRBSIs was 0.40 infections per 1000 catheter-days. Univariate analysis using the Fisher's exact test identified one of the participating hospitals (hospital A; p < 0.001), internal jugular vein catheterization (IJVC) (p = 0.0013), not using maximal sterile barrier precautions (p = 0.030), and the Seldinger technique for catheter insertion (p = 0.025) as significant risk factors for CRBSI. After excluding data from hospital A, only IJVC remained a significant risk factor for CRBSI (p = 0.025). The cumulative probability of remaining without CRBSI was significantly lower in patients with IJVCs than in patients with other catheter routes (p < 0.001; log-rank test). Similarly, the cumulative probability of remaining without catheter removal due to a suspected infection was significantly lower in patients with IJVCs (p = 0.034; log-rank test). Conclusions: The current study suggests that IJVC might be a risk factor for CRBSI under current infection control conditions. © 2013 Informa Healthcare.


PubMed | Hyogo College of Medicine, Higashi Hiroshima Medical Center, Aichi Cancer Center Hospital and Kinki University
Type: | Journal: Scientific reports | Year: 2015

Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.


Suda K.,Kinki University | Murakami I.,Higashi Hiroshima Medical Center | Sakai K.,Kinki University | Tomizawa K.,Kinki University | And 4 more authors.
Lung Cancer | Year: 2016

Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients. Materials and methods: We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed. Results and conclusion: We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M. +. MET gene copy number gain, and mutant EGFR loss + unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p = 0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p = 0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations. © 2015 Elsevier Ireland Ltd.


Suda K.,Kinki University | Mizuuchi H.,Kinki University | Murakami I.,Higashi Hiroshima Medical Center | Uramoto H.,University of Occupational and Environmental Health Japan | And 7 more authors.
Lung Cancer | Year: 2014

Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. Materials and methods: We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined. Results and conclusion: In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations. © 2014 Elsevier Ireland Ltd.


PubMed | Higashi Hiroshima Medical Center and Kinki University
Type: | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2015

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients.We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed.We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M+MET gene copy number gain, and mutant EGFR loss+unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p=0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations.


PubMed | Higashi Hiroshima Medical Center, Aichi Cancer Center Research Institute and Kinki University
Type: Journal Article | Journal: Cancer science | Year: 2016

Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an oncogene swap. Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an oncogene swap from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene.


PubMed | Higashi Hiroshima Medical Center, Aichi Cancer Center Hospital, Aichi Cancer Center Research Institute, Kinki University and University of Occupational and Environmental Health Japan
Type: Journal Article | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2014

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs.We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined.In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations.

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