Faculty Profiles - Togashi Yosuke

Papers - Togashi Yosuke

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Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: A case report and review of the literature Reviewed

Yosuke Togashi, Katsuhiro Masago, Yasuhiro Hamatani, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

LUNG CANCER 77 ( 2 ) 464 - 468 2012.8

Language：English Publisher：ELSEVIER IRELAND LTD

The most serious adverse reaction associated with treatment with epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) is drug-induced interstitial lung disease (ILD). Because EGFR-TKIs are key drugs for patients with non-small cell lung cancer who have somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations), several cases of retreatment with EGFR-TKIs after ILD induced by these drugs have been reported. Here, we present a 68-year-old man with lung adenocarcinoma and leptomeningeal metastases having an EGFR mutation who was retreated with erlotinib after erlotinib-induced ILD. He suffered no ILD recurrence and his leptomeningeal metastases dramatically improved. In addition to the present case, reports of nine patients who were retreated with EGFR-TKIs after ILD were found in the literature. Only one patient had recurrence of ILD (although seven were retreated at a reduced dose of EGFR-TKIs, including the patient with recurrence). In contrast, three patients had no recurrence of ILD even without dose-reduction. These reports suggest that dose-reduction plays a limited role in preventing recurrence. Many patients received corticosteroids during retreatment, but not the one with recurrence of ILD. This may suggest that corticosteroids can prevent recurrence due to their antiinflammatory properties. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2012.04.013

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902 Reviewed

Young Hak Kim, Masataka Hirabayashi, Yosuke Togashi, Katsuya Hirano, Keisuke Tomii, Katsuhiro Masago, Toshihiko Kaneda, Harukazu Yoshimatsu, Koujirou Otsuka, Tadashi Mio, Hiromi Tomioka, Yujiro Suzuki, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 70 ( 2 ) 271 - 276 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population.
This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500 mg/m(2)) combined with carboplatin (area under the curve: AUC 6) every 3 weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival.
Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90 %) patients completed four cycles, and 33 (67 %) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51 %) and stable disease in 18 patients (37 %). Median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 24.3 months, respectively. The median PFS and OS were 7.9 months and 24.3 months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3 months and 21.0 months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p = 0.09) and OS (p = 0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33 %) and 9 (18 %) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.
The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).

DOI： 10.1007/s00280-012-1910-2

Prognostic Significance of Preexisting Interstitial Lung Disease in Japanese Patients With Small-Cell Lung Cancer Reviewed

Yosuke Togashi, Katsuhiro Masago, Tomohiro Handa, Kiminobu Tanizawa, Chiyuki Okuda, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

CLINICAL LUNG CANCER 13 ( 4 ) 304 - 311 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

We retrospectively investigated patients with small-cell lung cancer with or without interstitial lung disease (ILD). Response rates and median progression-free survival of first-line chemotherapy in patients with or without preexisting ILD was not significantly different. However, pneumonitis associated with chemotherapy was significantly increased in patients with preexisting ILD, and preexisting ILD is an independent prognostic factor for poorer survival.
Background: In Japan, iatrogenic acute exacerbation of interstitial lung disease (ILD) is a serious complication in patients with lung cancer and simultaneous ILD. Results of some reports suggest that patients with ILD and small-cell lung cancer (SCLC) might benefit from chemotherapy, but the influence of ILD on prognosis is unclear. Patients and Methods: Retrospective study of patients with SCLC with or without ILD. Between April 2006 and March 2011, 122 patients with SCLC who were receiving platinum-based combination chemotherapy participated. Results: Twenty-eight patients (23.0%) had ILD at diagnosis. Pneumonitis associated with chemotherapy, including acute exacerbation-ILD was significantly increased in patients with preexisting ILD (8/28 vs. 2/94; P = .0001). In patients receiving chemotherapy alone, response rates and median progression-free survival of first-line chemotherapy in patients with or without preexisting ILD was not significantly different (P = .26; 20/26 vs. 52/60 and P = .089; 4.4 months vs. 5.4 months, respectively). The median overall survival of all patients was 15.5 months, but those without preexisting ILD survived significantly longer (P = .0010; 17.8 months vs. 10.7 months). Multivariate analysis revealed that performance status of 0 or 1 (hazard ratio [HR] 0.19 [95% confidence interval {CI}, 0.10-0.37]; P < .0001) limited disease (HR 0.42 [95% CI, 0.23-0.73]; P = .0017), and no preexisting ILD (HR 0.36 [95% CI, 0.19-0.69]; P = .0027) were significantly associated with longer overall survival. Conclusion: Patients with SCLC and ILD might benefit from chemotherapy, but preexisting ILD is an independent prognostic factor for poorer survival.

DOI： 10.1016/j.cllc.2011.11.001

Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO-cGMP signaling in lung adenocarcinoma cells in vitro and in vivo Reviewed

Hiroki Nagai, Hiroyasu Yasuda, Yukimasa Hatachi, Deng Xue, Takahiko Sasaki, Mutsuo Yamaya, Yuichi Sakamori, Yousuke Togashi, Katsuhiro Masago, Isao Ito, Young Hak Kim, Tadashi Mio, Michiaki Mishima

INTERNATIONAL JOURNAL OF ONCOLOGY 41 ( 1 ) 24 - 30 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Pemetrexed (PEM) is a novel, multitargeted, antifolate, antineoplastic agent for the treatment of non-small cell lung cancer and malignant pleural mesothelioma. Additional effects of nitric oxide (NO) donors on the chemosensitivity of cancers have been reported. However, the effects of an NO donor on PEM-induced cytotoxicity remain unknown. In this study, we investigated the effects of the NO donors, NOC-18 on the cytotoxicity in A549 cells in vitro and of nitroglycerin (GTN), on the tumor growth of Lewis lung carcinoma cells in a murine syngraft model treated with PEM. The effects of NO donors on the expression of proteins associated with PEM metabolism, including thymidylate synthase (TS), reduced folate carrier 1 (RFC1), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH) and multidrug resistance-related protein (MRP)5, and the effects of cyclic guanosine monophosphate (cGMP) signaling on these proteins were examined in A549 cells. Treatment with 100 nM NOC-18 for 3 days significantly enhanced PEM-induced cytotoxicity and increased the expression of RFC1 and FPGS in A549 cells. Treatment with 10 nM 8-bromo-cGMP (8-Br-cGMP) for 3 days also increased the expression of RFC1 and FPGS in A549 cells. 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 mu m) significantly reversed the increase in RFC1 and FPGS expression induced by 100 nM NOC-18 in A549 cells. Combination therapy with GTN and PEM significantly reduced tumor growth compared with PEM alone in the syngraft model. The enhanced antitumor effect of GTN plus PEM was significantly reversed by the concomitant addition of ODQ. These findings suggest that NO donors, such as NOC-18 and GTN, enhance the anticancer effects of PEM by increasing the RFC1 and FPGS expression and stimulating cGMP signaling pathways in cancer cells.

DOI： 10.3892/ijo.2012.1461

Increase in circulating endothelial progenitor cells predicts response in patients with advanced non-small-cell lung cancer Reviewed

Yuichi Sakamori, Katsuhiro Masago, Katsuyuki Ohmori, Yosuke Togashi, Hiroki Nagai, Chiyuki Okuda, Young Hak Kim, Satoshi Ichiyama, Michiaki Mishima

CANCER SCIENCE 103 ( 6 ) 1065 - 1070 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets. (Cancer Sci 2012; 103: 10651070)

DOI： 10.1111/j.1349-7006.2012.02249.x

Significance of pretreatment comorbidities in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitor Reviewed

Kaoru Irisa, Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Yuichi Sakamori, Yung Hak Kim, Tadashi Mio, Michiaki Mishima

MEDICAL ONCOLOGY 29 ( 1 ) 185 - 192 2012.3

Language：English Publishing type：Research paper (scientific journal) Publisher：HUMANA PRESS INC

A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.

DOI： 10.1007/s12032-010-9764-0

Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer Reviewed

Yosuke Togashi, Katsuhiro Masago, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Michiaki Mishima

LUNG CANCER 74 ( 1 ) 98 - 102 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Purpose: The maximum tolerated dose (MTD) of erlotinib (150 mg) is the approved daily dose. In contrast, the approved daily dose of gefitinib (250 mg) is only one-third of its MID. Significantly different adverse events have been associated with gefitinib and erlotinib.
Experimental design: A retrospective investigation examining the adverse events and tolerances of 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer (NSCLC) was performed. Adverse events were assessed according to Common Terminology Criteria for Adverse Events version 3.0. To determine tolerance for each agent, failure was defined as dose reduction or discontinuation of the drug due to adverse events, and early failure as dose reduction or discontinuation due to adverse events before the first evaluation of response.
Results: More adverse events including skin disorders, diarrhea, oral mucositis, asthenic conditions, anorexia, nausea, vomiting, and gastrointestinal bleeding were observed in the erlotinib group. Liver function test abnormalities and pneumonitis did not differ between the two groups. Based on multivariate analysis, failure, early failure, and discontinuation due to adverse events were independently associated with erlotinib use.
Conclusion: Our data show that 150 mg daily erlotinib was associated with more toxicity and less tolerability than 250 mg daily gefitinib. (C) 2011 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.lungcan.2011.01.022

Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation Reviewed

Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Yasuhiro Tsuchido, Chiyuki Okuda, Young Hak Kim, Yasuaki Ikemi, Yuichi Sakamori, Tadashi Mio, Toshiya Katsura, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 68 ( 4 ) 1089 - 1092 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. Wedescribe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib.
Methods Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection.
Results The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean +/- standard deviation of CSF concentrations and penetration rates were 106 +/- 59 nM and 4.5 +/- 1.5%, respectively. There was a good correlation (R(2) = 0.84) between plasma and CSF concentrations (P = 0.0005).
Conclusions This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients.

DOI： 10.1007/s00280-011-1691-z

Clinical significance of epidermal growth factor receptor mutations and insulin-like growth factor 1 and its binding protein 3 in advanced non-squamous non-small cell lung cancer Reviewed

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Kaoru Irisa, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

ONCOLOGY REPORTS 26 ( 4 ) 795 - 803 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

This study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and two serum markers, serum insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3), for their associations to response to gefitinib therapy and for their prognostic impact. An immunoradiometric assay determined levels of IGF1 and IGFBP3 in serum from 68 patients with advanced non-squamous NSCLC. The peptic nucleic acid locked nucleic acid clamp method determined their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. Having IGF1-positive serum as determined by the 75th percentile and having wild-type EGFR were both independent negative predictive factors for geftinib treatment by multivariate logistic regression model analysis. Both having serum positive for IGF1 as determined by the 25th percentile and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. We demonstrated that having IGF1-positive serum predicts a negative response to gefitinib therapy independent of EGFR mutational status. We also demonstrated that both IGF1-positive serum and wild-type EGFR were independent poor prognostic factors in patients with non-squamous NSCLC who received gefitinib therapy.

DOI： 10.3892/or.2011.1354

Plasma and Pleural Fluid Pharmacokinetics of Erlotinib and its Active Metabolite OSI-420 in Patients With Non-Small-Cell Lung Cancer With Pleural Effusion Reviewed

Katsuhiro Masago, Yosuke Togashi, Masahide Fukudo, Tomohiro Terada, Kaoru Irisa, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

CLINICAL LUNG CANCER 12 ( 5 ) 307 - 312 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

Background: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). Patients and Methods: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. Results: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. Conclusions: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.

DOI： 10.1016/j.cllc.2011.06.004

Pulmonary embolism due to internal jugular vein thrombosis in a patient with non-small cell lung cancer receiving bevacizumab Reviewed

Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Koji Tamai, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 ( 4 ) 444 - 446 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Internal jugular vein thrombosis is much less common than deep venous thrombosis of lower limbs and is generally caused by an indwelling venous catheter or otological infection. Several cases of internal jugular vein thrombosis associated with malignancy have been also reported. Bevacizumab, a monoclonal neutralizing antibody against vascular endothelial growth factor, has shown benefits in the treatment of many types of malignancy and its use is increasing. Serious adverse effects, however, are associated with the use of bevacizumab, including venous thromboembolism. In this article, we present a rare case of non-small cell lung cancer complicated by pulmonary embolism due to internal jugular vein thrombosis associated with bevacizumab.

DOI： 10.1007/s10147-010-0148-4

Good Clinical Response to Erlotinib in a Patient With Anaplastic Thyroid Carcinoma Harboring an Epidermal Growth Factor Somatic Mutation, L858R, in Exon 21 Reviewed

Katsuhiro Masago, Masako Miura, Yoshiro Toyama, Yosuke Togashi, Michiaki Mishima

JOURNAL OF CLINICAL ONCOLOGY 29 ( 16 ) E465 - E467 2011.6

Two Cases of Cancer-associated Retinopathy Combined with Small-cell Lung Cancer Reviewed

Yuichi Sakamori, Young Hak Kim, Chiyuki Okuda, Yosuke Togashi, Daisuke Kinose, Katsuhiro Masago, Tadashi Mio, Akihito Uji, Michiaki Mishima

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 5 ) 669 - 673 2011.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Cancer-associated retinopathy is a rare paraneoplastic syndrome that is often associated with small-cell lung cancer. It is caused by an autoantibody to the 23 kDa photoreceptor protein, recoverin. A small number of reports have described effective treatment for the disease. We report two cases of cancer-associated retinopathy with small-cell lung cancer whose visual symptom preceded the diagnosis of cancer. Their visual acuity and visual field were slightly improved after steroid and anticancer therapy. Steroid therapy was effective, although the period from visual symptom onset to therapy was comparative longer. When cancer-associated retinopathy is suspected, a comparatively large quantity of steroids and anticancer treatment should be combined immediately.

DOI： 10.1093/jjco/hyr025

Long-term Survival in a Patient with Small-cell Lung Cancer Undergoing Hemodialysis Who Received Multiple Courses of Chemotherapy Reviewed

Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 4 ) 582 - 585 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The prognosis of small-cell lung cancer remains poor and it is speculated that small-cell lung cancer patients with end-stage renal failure undergoing hemodialysis have a poorer prognosis. In this article, we present a Japanese woman with extensive small-cell lung cancer with end-stage renal failure undergoing hemodialysis who received multiple courses of chemotherapy. Although she achieved long-term survival of more than 2 years, the last-line chemotherapy, consisting of irinotecan, induced grade 4 febrile neutropenia and her performance status deteriorated even with a reduced dose according to the analysis of UDP-glucuronosyltransferase 1A1. We also conducted a pharmacokinetic analysis of irinotecan, the resulting values of which were much higher than in previous reports. Although further studies are needed, chemotherapy for small-cell lung cancer patients should not be withheld just because they are undergoing hemodialysis; however, chemotherapy should be performed more carefully because more severe toxicities can occur than expected.

DOI： 10.1093/jjco/hyq244

EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy Reviewed

Young Hak Kim, Katsuhiro Masago, Yosuke Togashi, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

ONCOLOGY LETTERS 2 ( 2 ) 383 - 387 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p < 0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.

DOI： 10.3892/ol.2011.240

Association between brain natriuretic peptide and distant metastases in advanced non-small cell lung cancer patients Reviewed

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Kaoru Irisa, Yuichi Sakamori, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Young Hak Kim, Tadashi Mio, Michiaki Mishima

ONCOLOGY LETTERS 2 ( 2 ) 253 - 256 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

This study aimed to investigate the relationship between clinicopathological factors and plasma brain natriuretic peptide (BNP) levels in non-small cell lung cancer (NSCLC) patients. A total of 133 patients with advanced NSCLC were included in this study. The level of BNP was determined at the time of diagnosis. The BNP plasma concentration was measured using a chemiluminescent enzyme immunoassay kit. The univariate relationship between each independent clinicopathological variable and plasma BNP was examined using the Chi-square test. The survival curves were determined using the Kaplan-Meier method. According to the cut-off value of plasma BNP levels (11.5 and 22.4 pg/ml), plasma BNP negatively correlated with the presence of metastases (Chi-square test, p=0.0374 and p=0.0098, respectively). However, no significant association between patient survival time and plasma BNP levels was found. Reduced plasma BNP levels in advanced NSCLC patients with metastases were noted and the possibility was raised that BNP decreases distant metastases of advanced NSCLC patients.

DOI： 10.3892/ol.2011.247

Successful Treatment with Pemetrexed in a Patient with Mucinous Bronchioloalveolar Carcinoma Long-Term Response Duration with Mild Toxicity Reviewed

Chiyuki Okuda, Young Hak Kim, Kengo Takeuchi, Yosuke Togashi, Katsuhiro Masago, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

JOURNAL OF THORACIC ONCOLOGY 6 ( 3 ) 641 - 642 2011.3

Clinical significance of the ratio between the alpha 2 plasmin inhibitor-plasmin complex and the thrombin-antithrombin complex in advanced non-small cell lung cancer Reviewed

Katsuhiro Masago, Shiro Fujita, Tadashi Mio, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Yuichi Sakamori, Michiaki Mishima

MEDICAL ONCOLOGY 28 ( 1 ) 351 - 356 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：HUMANA PRESS INC

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-alpha 2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.

DOI： 10.1007/s12032-010-9454-y

Phase I study of the combination of nedaplatin and gemcitabine in previously untreated advanced squamous cell lung cancer Reviewed

Katsuhiro Masago, Shiro Fujita, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Hiroki Nagai, Yuichi Sakamori, Yosuke Togashi, Tadashi Mio, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 67 ( 2 ) 325 - 330 2011.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The objectives of this phase I trial were to evaluate the toxicity of the nedaplatin/gemcitabine regimen, determine the maximum tolerated doses (MTDs) of these agents, and observe the anti-tumor effects of this regimen on advanced squamous cell lung cancer.
Patients with previously untreated advanced squamous cell lung cancer were eligible if they had a performance status of 0 or 1 with adequate organ function. The doses of gemcitabine (days 1 and 8) and nedaplatin (day 8) studied were 800/70, 1,000/80, 1,000/90, and 1,000/100 (mg/m(2)), repeated every 3 weeks.
Toxicity and response could be assessed in all 13 patients enrolled. The patients included 12 men and one woman with a median age of 69 years (range 57-81 years). Three patients had stage IIIB disease and 10 patients had stage IV disease. The MTDs were reached at 1,000 mg/m(2) gemcitabine and 80 mg/m(2) nedaplatin. The most frequent toxic effects were thrombocytopenia and neutropenia; grade 3 or 4 thrombocytopenia was observed in 23% of patients, and grade 3 or 4 neutropenia was seen in 46% of patients. Non-hematologic toxicities were mild. Grade 3 fatigue, nausea/vomiting, and appetite loss occurred in two patients. The overall response rate was 62%.
We recommend doses of 800 mg/m(2) gemcitabine and 70 mg/m(2) nedaplatin for phase II study. This combination chemotherapeutic regimen is active and well tolerated.

DOI： 10.1007/s00280-010-1321-1

Association of the transforming growth factor beta 1 promoter polymorphism, C-509T, with smoking status and survival in advanced non-small cell lung cancer Reviewed

Yosuke Togashi, Katsuhiro Masago, Shiro Fujita, Young Hak Kim, Yuichi Sakamori, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Tadashi Mio, Michiaki Mishima

ONCOLOGY REPORTS 25 ( 2 ) 377 - 382 2011.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Transforming growth factor beta (TGF-beta) signaling can inhibit tumor growth in developing tumors. However, it promotes tumor invasiveness and metastasis in late-stage tumors. A number of TGF-beta gene polymorphisms have been identified that can affect the survival of patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated the association of the TGF-beta 1 polymorphism, C-509T, with survival in patients with advanced NSCLC. Japanese patients who were treated for unresectable advanced NSCLC between April 2003 and March 2008 at Kyoto University Hospital, were enrolled in this study. Analyses of genotype associations with survival outcomes were performed using statistical tests. The median survival of patients with the TT genotype was shorter, although not significantly, than that of patients with either the CT or CC genotype. Based on both univariable and multivariable analyses, the TGF-B1 polymorphism, C-509T, was not associated with prognosis. In patients with a smoking status of <40 pack-years, the median survival was significantly shorter with the TT genotype than with the CT or CC genotype. Based on univariable analysis, stage IV cancer and the TT genotype had a significant prognostic effect on survival. Based on multivariable analysis, the TT genotype was a significantly independent prognostic factor for survival. There was no association between the TGF-beta 1 polymorphism, C-509T, and survival in patients with advanced NSCLC. In patients with a smoking status of <40 pack-years, however, the TGF-beta 1 polymorphism, C-509T, was significantly associated with the prognosis of advanced NSCLC, and the TT genotype was an independent prognostic factor for poor survival.

DOI： 10.3892/or.2010.1098

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