Faculty Profiles - Togashi Yosuke

Clinicopathologic Factors Affecting the Progression-Free Survival of Patients With Advanced Non-Small-Cell Lung Cancer After Gefitinib Therapy Reviewed

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

CLINICAL LUNG CANCER 12 ( 1 ) 56 - 61 2011.1

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

Background: The aim of this study was to analyze the factors independent of epidermal growth factor (EGFR) gene mutations that affect the progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) after gefitinib therapy. Patients and Methods: Eighty patients with advanced NSCLC between January 2003 and April 2010 at Kyoto University Hospital were analyzed for EGFR somatic mutations and treated with gefitinib. We adopted the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method for determination of EGFR mutation status. To evaluate risk factors associated with PFS, Cox proportional hazards regression model with a step-down procedure was used. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis. Results: The median PFS of patients with EGFR mutations were significantly longer than in patients with wild-type EGFR. The median PFS of patients after first-line gefitinib therapy was significantly longer than those who received treatment as a second-line therapy. The median PFS of patients over 75 years of age was significantly longer than in younger patients. Based on multivariate analysis, wild-type EGFR status and age < 75 years were significant and independent negative factors that affect PFS after gefitinib therapy. Conclusion: In this study, we showed the EGFR mutants and age > 75 years were good predictive factors for PFS after gefitinib therapy, suggesting that first-line gefitinib treatment for older patients is efficacious regardless of EGFR mutational status.

DOI： 10.3816/CLC.2011.n.008

Octreotide, a Somatostatin Analogue, in the Treatment of Chylothorax Associated with Idiopathic Fibrosing Mediastinitis Reviewed

Yosuke Togashi, Young Hak Kim, Ryo Miyahara, Kaoru Irisa, Yuichi Sakamori, Katsuhiro Masago, Tadashi Mio, Hiroshi Date, Michiaki Mishima

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 222 ( 1 ) 51 - 53 2010.9

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

Fibrosing mediastinitis (FM) is a rare benign disorder that is characterized by excessive fibrotic reactions in the mediastinum. FM is associated with various diseases, including Histoplasma capsulatum infection and IgG4-related disease, and may compromise the airways, great vessels, and other mediastinal structures. Chylothorax is not a common manifestation of FM, and there is no standard treatment for FM or chylothorax. Recently, however, somatostatin and octreotide, a somatostatin analogue, were successfully used for the treatment of chylothorax due to various causes, and they are considered as putative therapeutic interventions for chylothorax. Here, we present a 28-year-old Japanese man with chylothorax due to idiopathic FM, who was successfully treated with octreotide. The patient visited our hospital because of dyspnea on exertion. On admission, chest computed tomography revealed pericardial effusion, bilateral pleural effusion, and a mass in the mediastinum. The right pleural effusion appeared chylous, with the triglyceride level of 253 mg/dl. The biopsy specimen from the mediastinal mass showed collagenous fibers and fibroblasts with moderate infiltration of lymphocytes. Neither fungi nor bacteria were cultured from the biopsy specimen. Steroid therapy was not effective. The patient was then treated with subcutaneous octreotide (100 mu g three times daily). Five days after starting the treatment, the drained pleural fluid was decreased to similar to 150 ml/day from similar to 1,000 ml/day. The mediastinal mass decreased in size 2 weeks after the initiation of octreotide treatment. After discharge, the patient has received octreotide treatment for 6 months without serious adverse events. We suggest octreotide as a treatment option for FM.

DOI： 10.1620/tjem.222.51

Infectious background of febrile advanced lung cancer patients who received chemotherapy Reviewed

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

ONCOLOGY LETTERS 1 ( 5 ) 849 - 853 2010.9

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

The study aimed to determine the diagnostic utility of procalcitonin (PCT) in order to discriminate between infective fever and fever due to inflammation in febrile advanced lung cancer patients treated with cytotoxic chemotherapy. A total of 121 patients with advanced lung cancer, treated with a cytotoxic chemotherapy regimen between September 2007 and September 2008 at Kyoto University Hospital, were recruited. Blood samples were obtained on the first day of the fever. Serum c-reactive protein (CRP) and PCT levels were measured. At least two blood cultures were performed, and sputum was taken for Gram staining and culture. There were 71 episodes in 61 patients in the 12 months of the study, representing 50.4% of our study population. A total of 41 patients (57.7%) were diagnosed with, pneumonia using imaging modalities, 6 (8.5%) with bacteremia using blood culture and 4 (5.6%) with urinary tract infections using urine culture. Among the 41 pneumonia cases, culture from sputum revealed pathologic bacteria in 21 (51.2%) and fungal disease in 14 (34.1%) cases. Among the 71 febrile episodes, serum procalcitonin and CRP were measured in 50 episodes.. Serum procalcitonin-positive patients showed poor outcomes on antibiotics therapy (Fisher's exact test, p=0.042). Furthermore, serum procalcitonin positivity was able to discriminate infective fever from fever due to inflammation (Chi-square test, p=0.001). We showed the causative organisms of febrile advanced lung cancer patients who received cytotoxic chemotherapy, as well as the possibility of PCT to discriminate infective fever from fever due to inflammation.

DOI： 10.3892/ol_00000150

Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer Reviewed

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

JOURNAL OF THORACIC ONCOLOGY 5 ( 7 ) 950 - 955 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420.
Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8.
Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean +/- SD CSF concentrations of erlotinib and OSI-420 were 54 +/- 30 ng/ml and 10.8 +/- 8.2 ng/ml, respectively. The mean +/- SD CSF penetration rates of erlotinib and OSI-420 were 5.1% +/- 1.9% and 5.8% +/- 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC(50)) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene.
Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

DOI： 10.1097/JTO.0b013e3181e2138b

A Case of Radiation Recall Pneumonitis Induced by Erlotinib, Which Can be Related to High Plasma Concentration Reviewed

Yosuke Togashi, Katsuhiro Masago, Michiaki Mishima, Masahide Fukudo, Ken-ichi Inui

JOURNAL OF THORACIC ONCOLOGY 5 ( 6 ) 924 - 925 2010.6

Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420 in Patients with Non-small Cell Lung Cancer and Chronic Renal Failure Who Are Undergoing Hemodialysis Reviewed

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

JOURNAL OF THORACIC ONCOLOGY 5 ( 5 ) 601 - 605 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Introduction: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC).
Method: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8.
Results: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response.
Conclusion: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

DOI： 10.1097/JTO.0b013e3181d32287

Good Clinical Response to Erlotinib in a Non-Small Cell Lung Cancer Patient Harboring Multiple Brain Metastases and a Double Active Somatic Epidermal Growth Factor Gene Mutation. Reviewed International journal

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

Case reports in oncology 3 ( 2 ) 98 - 105 2010.4

Language：English

Recently, 2 small molecule kinase inhibitors (TKIs), targeting epidermal growth factor receptor (EGFR), have proven effective in the treatment of non-small cell lung cancer. However, it is unknown whether the EGFR double activating mutation of L858R in exon 21 and the in-frame deletion in exon 19 is a predictor of the effectiveness of EGFR-TKIs. We report for the first time a case of non-small cell lung cancer with central nervous system metastases harboring a rare EGFR double activating mutation who showed a good clinical response to erlotinib, regardless of his poor performance status, as swallowing is not possible. Therefore, we suggest that erlotinib may become a therapeutic choice in cases of central nervous system metastases even with poor performance status.

DOI： 10.1159/000310830

Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer. Reviewed International journal

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

Case reports in oncology 3 ( 1 ) 63 - 71 2010.3

Language：English

BACKGROUND: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. METHODS: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). RESULTS: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1-25 months). In particular, the group with a good postoperative performance status score (0-2) was shown to have a better median postoperative survival of 13 months. CONCLUSIONS: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor.

DOI： 10.1159/000299385

Clinical Significance of Pretreatment C-Reactive Protein in Patients with Advanced Nonsquamous, Non-Small Cell Lung Cancer Who Received Gefitinib Reviewed

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

ONCOLOGY 79 ( 5-6 ) 355 - 362 2010

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

Purpose: We examined patients with advanced nonsquamous, non-small cell lung cancer (NSCLC) to evaluate epidermal growth factor receptor (EGFR) mutation status and serum C-reactive protein (CRP) for their associations with response to gefitinib therapy and for prognostic impacts. Methods: Serum levels of CRP from 79 Japanese patients with advanced nonsquamous NSCLC were measured before the start of gefitinib. We used the peptic nucleic acid-locked nucleic acid clamp method to determine 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. Results: Having CRP-positive serum and having wild-type EGFR were both independent negative predictive factors for the response to gefitinib treatment by multivariate logistic regression model analysis. Having CRP-positive serum and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. Conclusions: Having CRP-positive serum predicted a lack of response to gefitinib therapy independent of EGFR mutational status. Both CRP-positive serum and wild-type EGFR were independent poor prognostic factors in patients with nonsquamous NSCLC who received gefitinib therapy. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000323486

大動脈瘤に起因する慢性播種性血管内凝固症候群を呈した家族性高コレステロール血症の1例

[Loeys-Dietz syndrome with acute myeloid leukemia]. Reviewed

Togashi Y, Sakoda H, Sugahara H, Asagoe K, Matsuzawa Y

[Rinsho ketsueki] The Japanese journal of clinical hematology 49 ( 8 ) 664 - 667 2008.8

冨樫庸介, 菅原浩之, 平岡久豊, 松澤佑次

住友病院医学雑誌 ( 35 ) 45 - 50 2008.7

A Japanese family of typical loeys-dietz syndrome with a TGFBR2 mutation Reviewed

Yosuke Togashi, Hiroto Sakoda, Akira Nishimura, Naomichi Matsumoto, Hisatoyo Hiraoka, Yuji Matsuzawa

INTERNAL MEDICINE 46 ( 24 ) 1995 - 2000 2007

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

This report describes a Japanese family with vessel and craniofacial abnormalities. Although the clinical findings of the patient's father fulfilled the diagnostic criteria for Marfan syndrome, arterial tortuosity, aneurysms, hypertelorism and a bifid uvula were noted in both the patient and his father. These findings were compatible with the clinical manifestations that were previously reported in Loeys-Dietz syndrome. A molecular genetic analysis demonstrated a heterozygous missense mutation of the transforming growth factor-beta receptor II gene in both the patient and his father, which thus caused Loeys- Dietz syndrome. This is the first Japanese family case report of typical Loeys- Dietz syndrome.

DOI： 10.2169/internalmedicine.46.0467