Publications by authors named "Yosuke Miura"

27 Publications

  • Page 1 of 1

Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel as Second- or Third-Line Therapy in Patients with Advanced Non-Small Cell Lung Cancer.

Chemotherapy 2020 16;65(1-2):21-28. Epub 2020 Jul 16.

Department of Respiratory Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.

Introduction: Treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) are poor due to limited treatment options.

Objective: We conducted a multicenter, single-arm phase II study to prospectively assess the efficacy and safety of weekly nab-PTX in patients with advanced NSCLC with failed cytotoxic chemotherapy.

Methods: Patients with advanced NSCLC having adequate organ functions with a performance status of 0-1 were enrolled. A 100 mg/m2 dose of nab-paclitaxel was administered on days 1, 8, and 15 of a 28-day cycle. Primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), toxicity profile, progression-free survival (PFS), and overall survival (OS).

Results: Between September 2013 and May 2016, 35 patients were enrolled. The ORR was 31.4%, and the DCR was 74.3%. The median PFS was 3.6 months, and the median OS was 11.4 months. The most common grade 3 or 4 toxicities included neutropenia (54.3%), leukopenia (42.9%), and anemia (11.4%). Two patients discontinued chemotherapy due to pneumonitis.

Conclusions: Nab-PTX may be a later-line chemotherapeutic option for previously treated advanced NSCLC.
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http://dx.doi.org/10.1159/000508715DOI Listing
May 2021

Phase I/II study of carboplatin plus weekly nab-paclitaxel in patients aged ≥75 years with squamous-cell lung cancer: TORG1322.

Lung Cancer 2020 08 19;146:182-188. Epub 2020 May 19.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Objectives: This phase I/II study assessed the efficacy and safety of combination therapy with carboplatin (CBDCA) and nab-paclitaxel (nab-PTX) in advanced elderly patients (aged ≥75 years) with advanced squamous cell lung cancer (SqCLC).

Materials And Methods: In this phase I study, the doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL/min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m) on days 1, 8, and 15 every 4 weeks for up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6 m PFS) rate.

Results: A total of 46 patients were enrolled in this study. Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia; at dose level 2, 1/3 patient exhibited grade 3 anorexia as a DLT. The recommended dose was determined to be level 2. Efficacy was then evaluated in 39 patients enrolled in a phase II study. The median number of cycles was 4 (range, 1-6), and the median follow-up time was 17.5 months (range, 5.6-28.9 months). The 6 m PFS rate was 59.4% (90% confidence interval [CI], 44.8%-71.4%), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54%, and the disease control rate was 92%. Sixteen patients (41%) received immune checkpoint inhibitors post-study. Common grade 3 or 4 toxicities were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%).

Conclusion: Combination chemotherapy consisting of CBDCA with weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly patients (aged ≥75 years) with advanced SqCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.005DOI Listing
August 2020

Clinical significance of topoisomerase-II expression in patients with advanced non-small cell lung cancer treated with amrubicin.

Thorac Cancer 2020 02 3;11(2):426-435. Epub 2020 Jan 3.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.

Background: Amrubicin chemotherapy is a treatment option for patients with non-small cell lung cancer (NSCLC) after third-line treatment in Japan. Although topoisomerase-II (Topo-II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown.

Methods: Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo-II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection.

Results: The majority of enrolled patients were men (68%) with a median age of 67 (range, 43-78) years. The most common histological type was adenocarcinoma (70%). High Topo-II expression was observed in 13 (30%) of the 44 patients. The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. Good performance status and low expression of Topo-II were all significantly associated with a favorable OS.

Conclusion: Low expression of Topo-II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo-II inhibitor.

Key Points: Significant findings of the study The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. Good performance status and low expression of Topo-II were all significantly associated with a favorable OS. What this study adds This study is the first to assess the effects of topoisomerase-II (Topo-II), a target of amrubicin, as a prognostic or predictive marker for chemosensitivity and clinical outcomes in the Japanese population.
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http://dx.doi.org/10.1111/1759-7714.13289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997014PMC
February 2020

Successful Treatment of Gastrosplenic Fistula Arising from Diffuse Large B-Cell Lymphoma with Chemotherapy: Two Case Reports.

Case Rep Oncol 2019 May-Aug;12(2):376-383. Epub 2019 May 23.

Department of Internal Medicine and Hematology/Blood Disorders Center, Aiiku Hospital, Sapporo, Japan.

Gastrosplenic fistula (GSF) is a rare condition arising from gastric or splenic lymphomas. Surgical resection is the most common treatment, as described in previous reports. We report two cases of GSF in diffuse large B-cell lymphoma (DLBCL) patients that were successfully treated with chemotherapy and irradiation without surgical resection. Case 1 was of a 63-year-old man who had primary gastric DLBCL with a large lesion outside the stomach wall, leading to a spontaneous fistula in the spleen. Case 2 was of a 59-year-old man who had primary splenic DLBCL, which proliferated and infiltrated directly into the stomach. In both cases, chemotherapy comprising rituximab + dose-adjusted EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) was administered. Case 1 had significant bleeding from the lesion of the stomach during the treatment cycle; however, endoscopic hemostasis was achieved. Case 2 developed a fistula between the stomach and the spleen following therapeutic chemotherapy; however, no complications related to the fistula were observed thereafter. In both cases, irradiation was administered, and complete remission was achieved.
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http://dx.doi.org/10.1159/000500505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547279PMC
May 2019

An Exploratory Randomized Phase II Trial Comparing CDDP Plus S-1 With Bevacizumab and CDDP Plus Pemetrexed With Bevacizumab Against Patients With Advanced Non-squamous Non-small Cell Lung Cancer.

Anticancer Res 2019 May;39(5):2483-2491

Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Background/aim: It remains unclear which chemotherapeutic regimens are better for the addition of bevacizumab. We conducted an exploratory randomized phase II trial comparing first-line S-1 plus cisplatin with bevacizumab and pemetrexed plus cisplatin with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

Patients And Methods: Chemotherapy-naïve patients received S-1 (80 mg/m) from day 1 to day 14 plus cisplatin (80 mg/m) on day 1 with bevacizumab (15 mg/kg) on day 1, followed by maintenance with bevacizumab plus S-1 (SCB) on day 1 every 3 weeks and pemetrexed (500 mg/m) on day 1 plus cisplatin (75 mg/m) on day 1 with bevacizumab (15 mg/kg) on day 1 followed by maintenance bevacizumab plus pemetrexed (PCB) on day 1 every 3 weeks. The expression of thymidylate synthase (TS) was analyzed using immunohistochemistry.

Results: Forty-eight patients were enrolled in this study, and eligible patients were randomly assigned at 1:1 ratio to receive SCB (n=24) or PCB (n=24). The median number of chemotherapy and maintenance therapy for SCB and PCB was 4 (range, 1-6 cycles) and 4 (range, 2-6 cycles), and 5 (range, 0-39 cycles) and 5 (range, 0-28 cycles), respectively. The overall response rate (ORR) for PCB and SCB were 54.2% and 83.3%, respectively (p=0.06). The median progression-free survival (PFS) and overall survival (OS) for PCB and SCB were 406 and 351 days, (p=0.96), and 678 and 1190 days, respectively (p=0.23). The mild adverse events were observed in both regimens. TS expression was more predictive of the chemotherapeutic response in SCB compared to PCB, but not for PFS.

Conclusion: The combination regimen of SCB was identified as having a similar activity and tolerability to that of PCB in patients with advanced non-squamous NSCLC.
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http://dx.doi.org/10.21873/anticanres.13368DOI Listing
May 2019

Dual inhibition of MEK and p38 impairs tumor growth in -mutated non-small cell lung cancer.

Oncol Lett 2019 Mar 4;17(3):3569-3575. Epub 2019 Feb 4.

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

Despite the high frequency of mutations in non-small cell lung cancer (NSCLC), therapeutic modalities targeting -mutated NSCLC have not been established. Based on our previous findings that mutant knockdown sensitized NSCLC cells to a p38 inhibitor, the growth-inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring mutations was investigated. In -mutated NSCLC cells, the MEK inhibitor, selumetinib, inhibited cell growth in a dose-dependent manner, and its growth-inhibitory effect was enhanced by combined treatment with the p38 inhibitor LY2228820. Similarly, another pair of MEK and p38 inhibitors also exhibited antitumor activity. Small interfering RNAs (siRNAs) against , which encodes p38α MAPK, enhanced the growth-inhibitory effect of the MEK inhibitors in NSCLC cells with mutations. Notably, MEK inhibitors reduced p38 expression levels but increased p38 phosphorylation levels, resulting in sensitization to p38 inhibitors in -mutated NSCLC cells. These results provide evidence that dual MEK and p38 inhibition could be a potent therapeutic strategy against oncogenic -driven NSCLC.
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http://dx.doi.org/10.3892/ol.2019.10009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396226PMC
March 2019

Post-treatment Glasgow Prognostic Score Predicts Efficacy in Advanced Non-small-cell Lung Cancer Treated With Anti-PD1.

Anticancer Res 2019 Mar;39(3):1455-1461

Gunma University, Graduate School of Health Sciences, Maebashi, Japan.

Background/aim: No definitive biomarker exists for predicting treatment efficacy or response to therapy with antibody to programmed cell death-1 (PD1) for patients with advanced non-small cell lung cancer (NSCLC). Hence, we investigated whether the Glasgow prognostic score (GPS) predicted anti-PD1 treatment response for advanced NSCLC.

Patients And Methods: This study retrospectively identified 47 patients with NSCLC treated with anti-PD1 and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations 1 month after starting anti-PD1 treatment. Kaplan-Meier method and Cox proportional hazard models were used to examine differences in progression-free (PFS) and overall (OS) survival, and clinical response.

Results: The post-treatment GPS independently predicted anti-PD1 treatment efficacy, as a good post-treatment GPS (GPS 0-1) was significantly associated with improved PFS. Intra-treatment GPS change was associated with clinical response.

Conclusion: The post-treatment GPS independently predicted efficacy of anti-PD1 treatment for NSCLC.
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http://dx.doi.org/10.21873/anticanres.13262DOI Listing
March 2019

Coexistence of primary colorectal follicular lymphoma and multiple myeloma: a case report.

Int J Gen Med 2018 12;11:363-367. Epub 2018 Sep 12.

Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Colorectal follicular lymphoma (FL) occurs less frequently than duodenal-type FL, which is an established entity, and primary multiple FL only involving the colon is rare. Furthermore, the coexistence of lymphoma and multiple myeloma (MM) within the same patient is rare and the current study reports such a case. The patient was an asymptomatic 62-year-old man. He underwent colonoscopy screening, which revealed at least five polypoid tumors from the cecum to the rectum. Biopsy samples stained positive for CD20 and B-cell lymphoma 2 (BCL2) but stained negative for CD10, and fluorescence in situ hybridization analysis identified in 95.2% of the tumor cells. Based on these findings, the patient was diagnosed with FL. On the bone marrow aspirate, the plasma cell count was 30% of all nucleated cells. Bence-Jones κ-type protein was detected by protein electrophoresis in serum and urine. The serum-free light chain κ/λ level was significantly elevated (484.3). Thus, the patient was also diagnosed with MM. Both FL and MM were targeted therapeutically; rituximab and bendamustine were effective for FL, and lenalidomide and low-dose dexamethasone were effective for MM. The patient was treated for 3 years and 7 months and, until now, was off-treatment for 4 years without rapid progression of the two malignancies. Although both diseases are still present, the patient has maintained stable disease. Our findings suggest that lymphoma and MM should be targeted separately as independent hematological malignancies when they occur concurrently.
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http://dx.doi.org/10.2147/IJGM.S171387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140731PMC
September 2018

Role of Immunotherapy for Oncogene-Driven Non-Small Cell Lung Cancer.

Cancers (Basel) 2018 Jul 27;10(8). Epub 2018 Jul 27.

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi 371-8511, Japan.

The clinical application of immune checkpoint inhibitors (ICIs) has led to dramatic changes in the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Despite the observation of improved overall survival in NSCLC patients treated with ICIs, their efficacy varies greatly among different immune and molecular profiles in tumors. Particularly, the clinical significance of ICIs for oncogene-driven NSCLC has been controversial. In this review, we provide recent clinical and preclinical data focused on the relationship between oncogenic drivers and immunological characteristics and discuss the future direction of immunotherapy in NSCLC patients harboring such genetic alterations.
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http://dx.doi.org/10.3390/cancers10080245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115923PMC
July 2018

Borrelia miyamotoi Disease Rash.

Intern Med 2018 09 30;57(17):2601-2602. Epub 2018 Mar 30.

Disease Control and Prevention Center, National Center for Global Health and Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.0432-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172547PMC
September 2018

The effect of post-progression survival on overall survival among patients with sensitive relapse of small cell lung cancer.

Med Oncol 2018 Mar 5;35(4):45. Epub 2018 Mar 5.

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Recent studies have suggested that, among patients with advanced lung cancer, subsequent treatment after failure of first-line or second-line chemotherapy has a greater effect on overall survival (OS) than tumor shrinkage or progression-free survival (PFS). However, no studies have examined this issue among patients with sensitive relapse of small cell lung cancer (SCLC). We retrospectively evaluate 77 patients with sensitive relapse of SCLC who received second-line chemotherapy after first-line platinum doublet chemotherapy between January 1999 and November 2013. The analyses included patient characteristics, treatment parameters, tumor shrinkage, PFS, post-progression survival (PPS), and OS. Spearman rank correlation analysis and linear regression analysis revealed that PPS was strongly correlated with OS (r = 0.91, p < 0.01, R = 0.96), PFS was moderately correlated with OS (r = 0.58, p < 0.01, R = 0.28), and tumor shrinkage was weakly correlated with OS (r = 0.34, p < 0.01, R = 0.12). A multivariate Cox proportional hazards model with a stepwise regression procedure revealed that PPS was significantly associated with age at the start of second-line chemotherapy, best response to second-line and third-line chemotherapy, and the number of regimens after progression beyond second-line chemotherapy (p < 0.05). These findings suggest that PPS has a stronger effect than PFS on OS among patients with sensitive relapse of SCLC. Thus, response to second-line chemotherapy and subsequent treatment for disease progression after second-line chemotherapy may be important factors that influence OS.
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http://dx.doi.org/10.1007/s12032-018-1107-6DOI Listing
March 2018

High expression of topoisomerase-II predicts favorable clinical outcomes in patients with relapsed small cell lung cancers receiving amrubicin.

Lung Cancer 2018 01 13;115:42-48. Epub 2017 Nov 13.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-8511, Japan.

Objectives: Amrubicin monotherapy is a treatment option for patients with relapsed small cell lung cancers (SCLCs). Topoisomerase-II (Topo-II) - a target of amrubicin - has been reported as a predictive or prognostic marker for chemosensitivity or outcomes in patients with various malignancies. Here, we investigated the prognostic role of Topo-II expression in patients with relapsed SCLCs who underwent amrubicin monotherapy.

Materials And Methods: Eighty-three patients with relapsed SCLCs who received amrubicin monotherapy between 2004 and 2015, after progression beyond first-line chemotherapy, were enrolled in the study. We retrospectively collected clinical data from their medical records, and evaluated the expression levels of Topo-II, by immunohistochemical staining of archival tumor specimens obtained through surgical resections or biopsies.

Results: Most of the enrolled patients were elderly men (89%), with a median age of 70 years (range, 49-83); 16% of these patients showed Topo-II overexpression. Compared to patients with sensitive relapses, those with refractory relapses showed significantly higher Topo-II expression levels (P=0.03). The overall response rates in patients with high and low Topo-II expression were 38.5% and 25.7%, respectively (P=0.34). Multivariate analysis confirmed that patients with a higher Topo-II expression level had significantly longer progression-free survival (hazard ratio (HR), 0.39; P<0.01) and overall survival (HR, 0.48; P=0.04), compared to patients with a lower Topo-II expression level.

Conclusion: Our study identified Topo-II expression as a significant biomarker for the prediction of favorable outcomes in patients with relapsed SCLCs who underwent treatment with amrubicin, a Topo-II inhibitor. Thus, Topo-II expression may be a promising predictor of the efficacy of amrubicin.
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http://dx.doi.org/10.1016/j.lungcan.2017.11.010DOI Listing
January 2018

A phase II study of biweekly gemcitabine and carboplatin in completely resected stage IB-IIIA non-small cell lung cancer.

Cancer Chemother Pharmacol 2018 01 9;81(1):103-109. Epub 2017 Nov 9.

Department of Respiratory Medicine, Shibukawa Medical Center, Shibukawa, Gunma, Japan.

Purpose: We conducted a prospective study to evaluate the efficacy and safety of biweekly gemcitabine and carboplatin combination treatment in patients with resected non-small cell lung cancer (NSCLC).

Methods: Patients with completely resected stage IB to IIIA NSCLC were treated with four cycles of gemcitabine (1000 mg/m, days 1 and 15) plus carboplatin [area under the time-concentration curve (AUC) 5 mg/mL/min, day 1] every 4 weeks as adjuvant chemotherapy.

Results: Forty-three patients were enrolled in this study. The median number of treatment cycles was four. The completion rate of chemotherapy was 79.1%. Major grade 3/4 hematological adverse events included leukocytopenia (27.9%) and neutropenia (53.5%), whereas non-hematological toxicities were generally mild. Ten patients (23.3%) required chemotherapy treatment schedule delay, and one patient required one dose level reduction because of drug fever. Median disease-free survival was 78.6 months [95% confidence interval (CI) 39.5-not reached (NA)] and median overall survival was not reached (95% CI 83.7-NA).

Conclusions: Biweekly administration of gemcitabine and carboplatin is effective and well tolerated for patients with completely resected NSCLC as an adjuvant chemotherapy.
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http://dx.doi.org/10.1007/s00280-017-3439-xDOI Listing
January 2018

Prognostic effect of class III β-tubulin and Topoisomerase-II in patients with advanced thymic carcinoma who received combination chemotherapy, including taxanes or topoisomerase-II inhibitors.

Oncol Lett 2017 Aug 19;14(2):2369-2378. Epub 2017 Jun 19.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

Class III β-tubulin (TUBB3) and Topoisomerase-II (topo-II) are considered to be the predictors of therapeutic efficacy and outcome in several types of human neoplasm. However, whether TUBB3 or topo-II may predict the response to combination chemotherapy and prognosis in patients with advanced thymic carcinoma (ATC) remains unclear. The aim of the present study was to investigate the prognostic significance of TUBB3 and topo-II expression levels in ATC. A total of 34 patients with ATC who received combination chemotherapy were enrolled in the present study. Immunohistochemical analysis was used to examine the expression of TUBB3, topo-II and Ki-67 in tumor specimens obtained by surgical resection or biopsy. TUBB3 and topo-II were highly expressed in 38 and 53% of the tumors, respectively. Progression-free survival (PFS) was significantly shorter in patients with high levels of TUBB3 compared with those with low levels of TUBB3 (P<0.01), whereas no significant difference in PFS between patients with high and low topo-II expression levels was observed (P=0.31). Patients with overexpression of TUBB3 or topo-II exhibited significantly shorter overall survival rates (OS) compared with those patients with low levels of expression of these proteins (TUBB3; P=0.01, topo-II; P=0.01). Multivariate analysis demonstrated that a high level of TUBB3 expression was an independent unfavorable prognostic factor for OS, and a high level of topo-II expression tended to correlate with poor prognosis without statistical significance. Additionally, a subset analysis demonstrated that the treatment with taxanes, but not topo-II inhibitors, tended to prolong OS in patients with TUBB3 overexpression and there was significant survival advantage of chemoradiotherapy over chemotherapy in patients with topo-II overexpression. It was revealed that an enhanced expression of TUBB3 or topo-II was clearly associated with clinical outcomes in patients with ATC who received combination chemotherapy, including taxanes or topo-II inhibitors, suggesting the prognostic significance of these markers.
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http://dx.doi.org/10.3892/ol.2017.6419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530002PMC
August 2017

High expression of GRP78/BiP as a novel predictor of favorable outcomes in patients with advanced thymic carcinoma.

Int J Clin Oncol 2017 Oct 26;22(5):872-879. Epub 2017 May 26.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Background: Glucose-regulated protein (GRP) 78/immunoglobulin heavy chain binding protein (BiP) is a member of the endoplasmic reticulum chaperone family, and its role in various types of human malignancies has recently been investigated. However, the clinicopathological characteristics of GRP78/BiP in advanced thymic carcinoma (ATC) remain unknown. We aimed to examine the relationship between GRP78/BiP expression and the clinical outcomes of ATC patients.

Methods: Thirty-four patients with ATC receiving combination chemotherapy at three institutions between April 1998 and April 2014 were enrolled in this study. We retrospectively collected patient characteristics such as therapeutic efficacy, pathological findings, and survival data from their medical records. We performed immunohistochemical analysis to evaluate the expression of GRP78/BiP in tumor specimens obtained from surgical resection or biopsy.

Results: This study included 21 men (68%) and 13 women (32%) with a median age of 62 years (range 36-75 years). GRP78/BiP overexpression was observed in 65% of the patients (22 of 34 patients). There was no correlation between GRP78/BiP expression and any patient characteristic. Patients with a high level of GRP78/BiP expression had significantly longer overall survival (OS) compared to those with a low level (46.2 vs. 16.8 months, p = 0.04). Multivariate analysis demonstrated that a high level of GRP78/BiP expression was an independent prognostic factor for prolonged OS.

Conclusions: Our findings indicate that the overexpression of GRP78/BiP is a novel predictor of favorable outcomes in patients with ATC who receive combination chemotherapy.
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http://dx.doi.org/10.1007/s10147-017-1142-xDOI Listing
October 2017

Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-disease small-cell lung cancer (LD-SCLC): TORG 0604.

BMC Cancer 2017 05 26;17(1):377. Epub 2017 May 26.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, Japan.

Background: The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated.

Methods: Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0-2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m). Primary objective of the phase II study was overall responce rate.

Results: Forty-three patients were enrolled and forty-one were finally analyzed (median age: 75 years [range 70-86 years); males 31; PS 0/1/2, n = 22/18/1]. Two patients were excluded because of protocol violation (ascertained to be extensive disease). Twelve patients were accrued at phase I and the number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and -2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose, total of 35 patients. The median number of chemotherapy cycles was 4 (range 1-4), and the median radiation dose was 54Gy (range 36-60). Toxicities were generally mild. There were 4 complete and 27 partial responses (response rate 88.6%). With a median follow-up of 52 months, the median progression-free and overall survival times of phase II were 11.2 and 27.1 months, respectively.

Conclusions: Induction chemotherapy of carboplatin plus irinotecan and sequential TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional confirmatory studies are warranted.

Trial Registration: Trial registration number: UMIN000007352 Name of registry: UMIN. Date of registration: 1/Dec/2006. Date of enrolment of the first participant to the trial: 6/Feb/2007. Clinical trial registration date: 1/Feb/2006 (prospective).
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http://dx.doi.org/10.1186/s12885-017-3353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446686PMC
May 2017

Post-Progression Survival Associated with Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Docetaxel Monotherapy as Second-Line Chemotherapy.

Chemotherapy 2017 6;62(4):205-213. Epub 2017 Apr 6.

Department of Respiratory Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.

Background: In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy.

Methods: Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level.

Results: Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R2 = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R2 = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05).

Conclusions: In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS.
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http://dx.doi.org/10.1159/000456534DOI Listing
September 2017

Evaluation of gefitinib efficacy according to body mass index, body surface area, and body weight in patients with EGFR-mutated advanced non-small cell lung cancer.

Cancer Chemother Pharmacol 2017 03 6;79(3):497-505. Epub 2017 Feb 6.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Purpose: In patients with epidermal growth factor receptor (EGFR)-mutated, advanced, non-small cell lung cancer (NSCLC), common gefitinib-sensitive EGFR mutations that predict a greater response to therapy include the exon 19 deletion and L858R point mutation. The objective of this study was to evaluate whether body surface area (BSA), body weight (BW), and body mass index (BMI) affect gefitinib efficacy in such patients.

Methods: The medical charts of 138 consecutive patients with advanced NSCLC harboring sensitive EGFR mutations, who underwent gefitinib treatment, were reviewed. The median BSA and BW were used as cutoff values to evaluate their impact on gefitinib efficacy. BMI was categorized as underweight (<18.5 kg/m), normal (18.5-25 kg/m), and overweight (≥25 kg/m).

Results: The median BSA and BW were 1.48 m and 53 kg, respectively. The overall response rate, progression-free survival (PFS), and overall survival (OS) were 65.2%, 12.2, and 24.2 months, respectively. There were no significant differences in clinical outcomes according to BSA, BW, or BMI alone. Subgroup analysis based on the mutation type and BSA revealed no significant differences in PFS between the groups; however, the median OS in those with exon 19 deletion combined with low BSA was significantly favorable compared with the other groups.

Conclusions: Gefitinib efficacy in patients with NSCLC harboring sensitive EGFR mutations did not differ according to BSA, BW, and BMI. However, OS was superior in patients with both the exon 19 deletion and low BSA.
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http://dx.doi.org/10.1007/s00280-016-3232-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344961PMC
March 2017

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BMC Cancer 2015 Oct 19;15:740. Epub 2015 Oct 19.

Yokohama Municipal Citizen's Hospital, 56 Kazawa-cho, Hodogaya-ku, Yokohama, 240-8555, Japan.

Background: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients.

Methods: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy.

Results: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts.

Conclusions: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted.

Trial Registration: UMIN Clinical Trial Registry; UMIN000004240 .
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http://dx.doi.org/10.1186/s12885-015-1756-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612532PMC
October 2015

First-line gefitinib treatment in elderly patients (aged ≥75 years) with non-small cell lung cancer harboring EGFR mutations.

Cancer Chemother Pharmacol 2015 Oct 8;76(4):761-9. Epub 2015 Aug 8.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Purpose: The efficacy of gefitinib [an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor] in elderly patients with non-small cell lung cancer (NSCLC) and EGFR mutation has not been elucidated. Therefore, the objective of this study was to investigate the efficacy and feasibility of gefitinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.

Methods: We retrospectively evaluated the clinical effects of gefitinib as a first-line treatment for elderly (≥75 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially treated with gefitinib (250 mg/day) at seven institutions.

Results: Between January 2006 and December 2012, 62 patients (17 men, 45 women) with a median age of 80 years (range, 75-89 years) were included in our analysis. The overall response and disease control rates were 61.2 and 83.8 %, respectively, and the median progression-free survival and overall survival were 13.2 and 19.0 months, respectively. Common adverse events included rash, diarrhea, and liver dysfunction. Major grade 3 or 4 toxicities included skin rash (3.2 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (21.0 %). Gefitinib treatment was discontinued owing to adverse events of liver dysfunction in 3 patients, drug-induced pneumonitis in 2, and diarrhea in 1.

Conclusion: First-line gefitinib could be a preferable standard treatment in elderly patients with advanced NSCLC harboring sensitive EGFR mutations.
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http://dx.doi.org/10.1007/s00280-015-2841-5DOI Listing
October 2015

[A case of clinically diagnosed eosinophilic bronchiolitis].

Arerugi 2014 Nov;63(9):1265-70

Gunma University Graduate School of Medicine, Department of Medicine and Molecular Science, Allergy and Respiratory Medicine.

A 71-year-old man was referred to our hospital because of an intractable productive cough. Although he was treated for bronchial asthma, the symptom did not improve. Furthermore, since he developed progressive dyspnea and hypoxemia, he was admitted to our hospital. Marked eosinophilia in a blood test and sputum, poorly defined centrilobular nodules throughout the bilateral lung fields in a chest CT scan, and mixed ventilatory impairment in a spirometric test were revealed. Thoracoscopic lung biopsy and bronchoalveolar lavage were not conducted because of progressive respiratory failure. Therefore, we clinically diagnosed eosinophilic bronchiolitis, and immediately administered oral prednisolone (30 mg daily). His symptoms and examination findings rapidly improved. This case suggests that eosinophilic bronchiolitis should be taken into consideration for differential diagnoses of eosinophilic lung disease and obstructive lung disease, and marked eosinophilia in sputum may be one of the useful tools for diagnosis of this disease when invasive examinations are inadequate.
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November 2014

Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer.

Int J Clin Oncol 2015 Aug 11;20(4):659-67. Epub 2014 Oct 11.

Department of Medical Oncology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan,

Purpose: To evaluate a 3-drug combination of carboplatin, docetaxel and bevacizumab as a front-line chemotherapy for patients with advanced non-squamous non-small cell carcinoma (NSCLC), a single arm phase II study was conducted.

Methods: Patients with stage IIIB/IV or postoperative recurrent non-squamous NSCLC were treated with carboplatin (targeted area under the curve of 6 mg h/L), docetaxel (60 mg/m(2)), and bevacizumab (15 mg/kg) on day 1, repeated every 3 weeks for 4 to 6 cycles, followed by maintenance with bevacizumab every 3 weeks until disease progression or occurrence of predefined toxicity. The planned patient number was 40, and the primary endpoint was progression free survival (PFS) as assessed by independent reviewers.

Results: One patient refused the treatment after enrollment; thus, 39 patients were treated and analyzed. The 3-drug therapy was delivered for a median of 4 cycles, and 54 % of the patients proceeded to the maintenance therapy for a median of 4 cycles. The overall response rate was 74.4 % (29/39), with a 95 % confidence interval (CI) of 60.0 to 88.7 %. The median PFS and overall survival (OS) were 6.2 months (95 % CI, 4.8-8.5 months) and 22.4 months (95 % CI, 11.3-26.2 months), respectively. Toxicities of grade 3 or higher included neutropenia in 71.8 %, febrile neutropenia in 23.1 %, and hypertension in 38.5 % of the patients, but they were transient and manageable.

Conclusion: The primary endpoint was met. The regimen yielded promising results with an excellent overall response rate, PFS, and OS for chemotherapy-naïve patients with advanced non-squamous NSCLC. Further studies are warranted.
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http://dx.doi.org/10.1007/s10147-014-0755-6DOI Listing
August 2015

Phase II study of oral S-1 plus cisplatin with bevacizumab for advanced non-squamous non-small cell lung cancer.

Lung Cancer 2013 Oct 5;82(1):103-8. Epub 2013 Aug 5.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan. Electronic address:

Background: We conducted a phase II study to evaluate the efficacy and safety of S-1 plus cisplatin with bevacizumab followed by maintenance bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

Patients And Methods: Chemotherapy-naïve patients received S-1 plus cisplatin with bevacizumab. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, cisplatin (60 mg/m(2)) on day 1, and bevacizumab (15 mg/kg) on day 1 and every 3 weeks for 4-6 cycles. Patients with an objective response or stable disease received maintenance bevacizumab every 3 weeks until disease progression.

Results: Thirty patients were enrolled in this study. The median number of chemotherapy was four (range, 1-6 cycles), and the median number of bevacizumab alone was three (range, 1-31 cycles). The grade 3/4 toxicities were neutropaenia (23%), thrombocytopaenia (10%), febrile neutropaenia (3%), hypertension (17%), pneumonia (7%), and bowel perforation (3%). The objective response rate was 71% (95% CI, 55-88%) for a disease control rate of 100%. The median progression-free and overall survival times were 7.0 months and 20.0 months, respectively.

Conclusions: S-1 plus cisplatin with bevacizumab is an active and well-tolerated regimen in patients with chemotherapy-naïve non-squamous NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2013.07.008DOI Listing
October 2013

Hepatic sinusoidal obstruction associated with S-1 plus cisplatin chemotherapy for highly advanced gastric cancer with paraaortic lymph node metastases: report of a case.

Clin J Gastroenterol 2012 Oct 18;5(5):341-6. Epub 2012 Sep 18.

Department of Surgery, Hokushinkai Megumino Hospital, 2-3-5 Megumino-Nishi, Eniwa, Hokkaido, 061-1395, Japan.

A 56-year-old man who was diagnosed with gastric cancer with multiple paraaortic lymph node metastases was treated with S-1 plus cisplatin. The spleen gradually enlarged during the therapeutic courses. After the 6th course of therapy, the primary gastric lesion and paraaortic lymphadenopathies disappeared. He underwent a curative resection, including a distal gastrectomy with regional and paraaortic lymph node dissections. Irregularly distributed congestion of the liver was noted during the surgery. Histological examinations revealed residual cancer cells in 3 regional lymph nodes and no cancer cells in the primary site and paraaortic lymph nodes. Hepatic sinusoidal obstruction syndrome (SOS) was also confirmed histologically. This is the first report of a case with SOS after S-1 plus cisplatin therapy. S-1 plus cisplatin therapy can cause SOS, although it is a promising preoperative chemotherapy for highly advanced gastric cancer.
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http://dx.doi.org/10.1007/s12328-012-0333-2DOI Listing
October 2012

Isothiocyanates from Wasabia japonica activate transient receptor potential ankyrin 1 channel.

Chem Senses 2012 Nov 6;37(9):809-18. Epub 2012 Aug 6.

Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) and 6-(methylthio)hexyl isothiocyanate (6-MTITC) have low pungency and are responsible for the fresh flavor of wasabi (Wasabia japonica [Miq] Matsumura). In this study, we found that these two isothiocyanates activate transient receptor potential ankyrin 1 (TRPA1), and 6-MSITC activates transient receptor potential vanilloid 1 (TRPV1), but not other transient receptor potential channels expressed in sensory neurons. Both 6-MSITC and 6-MTITCinduced intracellular Ca(2+) increases in human embryonic kidney-derived 293 cells expressing mouse TRPA1 (mTRPA1) as measured by Ca(2+) imaging. In whole-cell patch-clamp recordings, 6-MSITC and 6-MTITC dose-dependently activated both mTRPA1 (EC(50) = 147±26 µM for 6-MSITC and 30±3 µM for 6-MTITC) and human TRPA1 (hTRPA1; EC(50) = 39±4 µM for 6-MSITC and 34±3 µM for 6-MTITC). In addition, TRPA1 N-terminal cysteines, which are reported to be important for channel activation by electrophilic ligands, were involved in 6-MSITC- and 6-MTITC-evoked TRPA1 activation. These isothiocyanates also activated endogenous TRPA1 expressed in mouse dorsal root ganglion neurons and intraplantar injection of 10-30 mM 6-MSITC-evoked pain-related behaviors in mice. These results indicate the following: 1) 6-MSITC and 6-MTITC activate both mTRPA1 and hTRPA1; 2) 6-MSITC activates mTRPV1; and 3) the pharmacological functions of these isothiocyanates could be derived from TRPA1 activation.
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http://dx.doi.org/10.1093/chemse/bjs065DOI Listing
November 2012

[Clinical study on expression of Smad5 mRNA in human gastric mucosa infected with Helicobacter pylori].

Authors:
Yosuke Miura

Hokkaido Igaku Zasshi 2005 Sep;80(5):487-93

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September 2005

Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection.

J Biol Chem 2003 Feb 6;278(7):4821-5. Epub 2002 Dec 6.

Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.

The gastric pathogen Helicobacter pylori activates epithelial cell signaling pathways, and its infection induces changes in the expression of several genes in infected human gastric tissues. Recent studies have indicated that the ability of H. pylori to regulate epithelial cell responses depends on the presence of an intact cag pathogenicity island (cagPAI). We investigated altered mRNA expression of gastric epithelial cells after infection with H. pylori, both cagPAI-positive and cagPAI-negative strains, by cDNA microarray, reverse transcription PCR, and Northern blot analysis. Our results indicated that cagPAI-positive H. pylori strains (ATCC 43504 and clinical isolated strains) significantly activated Smad5 mRNA expression of human gastric epithelial cells (AGS, KATOIII, MKN28, and MKN45). We further examined whether the up-regulated Smad5 was related to apoptosis of gastric epithelial cells induced by H. pylori. Smad5 RNA interference completely inhibited H. pylori-induced apoptosis. These results suggest that Smad5 is up-regulated in gastric epithelial cells through the presence of cagPAI of H. pylori and that Smad5 mediates apoptosis of gastric epithelial cells induced by H. pylori infection.
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http://dx.doi.org/10.1074/jbc.M211143200DOI Listing
February 2003