Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Junji Kishimoto Last modified date:2022.06.14

Associate Professor / Center for Clinical and Translational Research(CCTR) / Kyushu University Hospital

1. Ikeda, S; Shinohara, K; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H, Serial measurement of B-type natriuretic peptide and future cardiovascular events in patients with type 2 diabetes mellitus without known cardiovascular disease, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2022.03.049, 356, 98-104, 2022.06, Background: In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients. Methods: We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study. Results: Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/ mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5-29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P < 0.001]). The analysis of 12-month BNP showed similar associations. In serial BNP measurement, compared with low-low BNP group (baseline <35 pg/mL and 12-month <35 pg/mL), low-high BNP group as well as high-high BNP group was associated with cardiovascular events (HR: low-high, 2.05 [P = 0.004]; high-high, 2.07 [P = 0.001]) and non-renal cardiovascular events. High-low BNP group tended to be associated with non-renal cardiovascular events (HR vs low-low: 2.05 [P = 0.056]). Conclusions: BNP levels were associated with first cardiovascular events except for heart failure in T2DM patients with retinopathy and hyperlipidemia. Serial BNP measurement may be useful in further stratifying high-risk patients among this T2DM population..
2. Kimura, Kiminori; Kanto, Tatsuya; Shimoda, Shinji; Harada, Kenichi; Kimura, Masamichi; Nishikawa, Koji; Imamura, Jun; Ogawa, Eiichi; Saio, Masanao; Ikura, Yoshihiro; Okusaka, Takuji; Inoue, Kazuaki; Ishikawa, Tetsuya; Ieiri, Ichiro; Kishimoto, Junji; Todaka, Koji; Kamisawa, Terumi., Safety, tolerability, and anti-fibrotic efficacy of the CBP/beta-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study., EBioMedicine, 10.1016/j.ebiom.2022.104069, 80, 104069, 2022.03, BACKGROUND: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/beta-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis.

METHODS: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at (no. NCT03620474).

FINDINGS: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level.

INTERPRETATION: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted.

FUNDING: AMED, Ohara Pharmaceutical..
3. Otsubo, Kohei; Kishimoto, Junji; Ando, Masahiko; Kenmotsu, Hirotsugu; Minegishi, Yuji; Horinouchi, Hidehito; Kato, Terufumi; Ichihara, Eiki; Kondo, Masashi; Atagi, Shinji; Tamiya, Motohiro; Ikeda, Satoshi; Harada, Toshiyuki; Takemoto, Shinnosuke; Hayashi, Hidetoshi; Nakatomi, Keita; Kimura, Yuichiro; Kondoh, Yasuhiro; Kusumoto, Masahiko; Ichikado, Kazuya; Yamamoto, Nobuyuki; Nakagawa, Kazuhiko; Nakanishi, Yoichi; Okamoto, Isamu, Nintedanib plus chemotherapy for non-small cell lung cancer with IPF: a randomized phase 3 trial., The European respiratory journal, 10.1183/13993003.00380-2022, 2022.03, BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced non-small cell lung cancer (NSCLC) with IPF.

METHODS: Chemotherapy-naive advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nab-paclitaxel (100 mg m-2 on days 1, 8, and 15) every 3 weeks with or without nintedanib (150 mg b.i.d., daily). The primary end point was exacerbation-free survival (EFS).

RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (HR, 0.89; 90% CI, 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR, 0.68; 95% CI, 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR, 0.61; 95% CI, 0.40-0.93) and in those at GAP stage I (HR, 0.61; 95% CI, 0.38-0.98). Seven (2.9%) of 240 patients experienced acute exacerbation during study treatment.

CONCLUSIONS: The primary end point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology..
4. Iwama, E; Zenke, Y; Sugawara, S; Daga, H; Morise, M; Yanagitani, N; Sakamoto, T; Murakami, H; Kishimoto, J; Matsumoto, S; Nakanishi, Y ; Goto, K; Okamoto, I, Trastuzumab emtansine for patients with non-small cell lung cancer positive for human epidermal growth factor receptor 2 exon-20 insertion mutations, EUROPEAN JOURNAL OF CANCER, 10.1016/j.ejca.2021.11.021, 162, 99-106, 2022.02, Background: Human epidermal growth factor receptor 2 (HER2) mutations are present in-3% of patients with non-small cell lung cancer (NSCLC), with exon-20 insertions accounting for-90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody-cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations.Patients and methods: Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR). Results: Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0-55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade >3 being low.Conclusion: T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations. Clinical trial number: JapicCTI-194620 (c) 2021 Elsevier Ltd. All rights reserved..
5. Shinohara, K; Ikeda, S; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H, Efficacy of intensive lipid-lowering therapy with statins stratified by blood pressure levels in patients with type 2 diabetes mellitus and retinopathy: Insight from the EMPATHY study, HYPERTENSION RESEARCH, 10.1038/s41440-021-00734-x, 44, 12, 1606-1616, 2021.12, Intensive lipid-lowering therapy is recommended in individuals exhibiting type 2 diabetes mellitus (T2DM) with microvascular complications (as high-risk patients), even without known cardiovascular disease (CVD). However, evidence is insufficient to stratify the patients who would benefit from intensive therapy among them. Hypertension is a major risk factor, and uncontrolled blood pressure (BP) is associated with increased CVD risk. We evaluated the efficacy of intensive vs. standard statin therapy for primary CVD prevention among T2DM patients with retinopathy stratified by BP levels. We used the dataset from the EMPATHY study, which compared intensive statin therapy targeting low-density lipoprotein cholesterol (LDL-C) levels of <70 mg/dL and standard therapy targeting LDL-C levels ranging from >= 100 to <120 mg/dL in T2DM patients with retinopathy without known CVD. A total of 4980 patients were divided into BP >= 130/80 mmHg (systolic BP >= 130 mmHg and/or diastolic BP >= 80 mmHg, n = 3335) and BP < 130/80 mmHg (n = 1645) subgroups by baseline BP levels. During the median follow-up of 36.8 months, 281 CVD events were observed. Consistent with previous studies, CVD events occurred more frequently in the BP >= 130/80 mmHg subgroup than in the BP < 130/80 mmHg subgroup (P < 0.001). In the BP >= 130/80 mmHg subgroup, intensive statin therapy was associated with lower CVD risk (HR 0.70, P = 0.015) than standard therapy after adjustment. No such association was observed in the BP < 130/80 mmHg subgroup. The interaction between BP subgroup and statin therapy was significant. In conclusion, intensive statin therapy targeting LDL-C < 70 mg/dL provided benefits in primary CVD prevention when compared with standard therapy among T2DM patients with retinopathy and BP >= 130/80 mmHg..
6. Tohyama, T; Ide, T; Ikeda, M; Kaku, H; Enzan, N; Matsushima, S; Funakoshi, K; Kishimoto, J; Todaka, K; Tsutsui, H, Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure, ESC HEART FAILURE, 10.1002/ehf2.13556, 8, 5, 4077-4085, 2021.10, Aims Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy-to-use prediction model with high accuracy using the top predictors identified by the ML algorithm.

Methods and results Machine learning-based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow-up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy-to-use prediction model was developed based on these predictors. The c-statistics and Brier scores of the developed ML-based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD-VC) achieved the highest c-statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non-loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART-HF) was established as an easy-to-use prediction model. Compared with the conventional models, SMART-HF achieved a higher c-statistic {ACD-VC: 0.777 [95% confidence interval (CI) 0.751-0.803], SMART-HF: 0.765 [95% CI 0.739-0.791], SHFM: 0.713 [95% CI 0.684-0.742], MAGGIC: 0.726 [95% CI 0.698-0.753]} and better Brier scores (ACD-VC: 0.121, SMART-HF: 0.124, SHFM: 0.139, MAGGIC: 0.130).

Conclusions The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART-HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART-HF model has the clear merit of easy operability even by non-healthcare providers with a user-friendly online interface ( Risk models developed using SMART-HF may provide a novel modality for risk stratification of patients with HF..
7. Oda, S; Ashida, K; Uchiyama, M; Sakamoto, S; Hasuzawa, N; Nagayama, A; Wang, LX; Nagata, H; Sakamoto, R; Kishimoto, J; Todaka, K; Ogawa, Y; Nakanishi, Y; Nomura, M, An Open-label Phase I/IIa Clinical Trial of 11 beta-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 10.1210/clinem/dgab450, 106, 10, E3865-E3880, 2021.10, Context: 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients.

Objective: To confirm the efficacy and safety of S-707106 (11 beta-HSD1 inhibitor) administered to CS and ACS patients.

Design: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database.

Setting: Kyushu University Hospital, Kurume University Hospital, and related facilities.

Patients: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance.

Intervention: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks.

Main Outcome Measures: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks.

Results: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P=0.033] and -2.7% [14.5 (-10.2 to 3.4), P=0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P<0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P<0.001].

Conclusions: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients..
8. Yoneshima, Y; Morita, S; Ando, M; Nakamura, A; Iwasawa, S; Yoshioka, H; Goto, Y; Takeshita, M; Harada, T; Hirano, K; Oguri, T; Kondo, M; Miura, S; Hosomi, Y; Kato, T; Kubo, T; Kishimoto, J; Yamamoto, N; Nakanishi, Y; Okamoto, I, Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC, JOURNAL OF THORACIC ONCOLOGY, 10.1016/j.jtho.2021.03.027, 16, 9, 1523-1532, 2021.09, Introduction: We aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC.

Methods: In this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m(2)) on day 1 or nab-paclitaxel (100 mg/m(2)) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis.

Results: Between May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment Median OS was 16.2 months (95% confidence interval [CI]: 14.4-19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9-16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68-1.07). Median progression-free survival was 4.2 months (95% CI: 3.9-5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9-4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63-0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0-36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9-20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nabpaclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively).

Conclusions: Nab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc..
9. Arima, Mitsuru Inoue, Hirosuke Nakao, Shintaro Misumi, Akiko Suzuki, Maya Matsushita, Itsuka Araki, Shunsuke Yamashiro, Chiemi Takahashi, Kazumasa Ochiai, Masayuki Yoshida, Noriko Hirose, Masayuki Kishimoto, Junji Todaka, Koji Hasegawa, Shunji Kimura, Kazuhiro Kusuhara, Koichi Kondo, Hiroyuki Ohga, Shouichi Sonoda, Koh-Hei, Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity, BMJ OPEN, 10.1136/bmjopen-2020-047003, 11, 7, 2021.09, Introduction Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP.

Methods and analysis This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints.

Ethics and dissemination This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals..
10. Murata, K; Onoyama, S; Yamamura, K; Mizuno, Y; Furuno, K; Matsubara, K; Hatae, K; Masuda, K; Nomura, Y; Ohno, T; Kinumaki, A; Miura, M; Sakai, Y ; Ohga, S; Fukushima, W; Kishimoto, J; Nakamura, Y; Hara, T, Kawasaki Disease and Vaccination: Prospective Case-Control and Case-Crossover Studies among Infants in Japan, VACCINES, 10.3390/vaccines9080839, 9, 8, 2021.08, The causal effects of vaccines on Kawasaki disease (KD) remain elusive. We aimed to examine the association between vaccines administered during infancy and the development of KD in Japan. We conducted a multicenter prospective case-control study using questionnaires and compared the vaccination status of infants (age: 6 weeks to 9 months) who developed KD (KD group; n = 102) and those who did not develop KD (non-KD group; n = 139). Next, we performed a case-crossover study of 98 cases in the KD group and compared the status of vaccinations between the case and control periods. We also compared the incidence of KD in children for each 5-year period before and after the addition of new vaccines (2012-2013) using data from the Nationwide Survey of KD. In the case-control study, the vaccination status of the KD and control groups did not differ to a statistically significant extent. Multivariable analysis of the vaccination status and patient backgrounds showed no significant association between vaccination and KD development. In the case-crossover study, the status of vaccinations during the case and control periods did not differ to a statistically significant extent. In the analysis of data from the Nationwide Survey of KD, the incidence of KD in children of ages subject to frequent vaccination showed no significant increases in the latter five years, 2014-2018. Based on these prospective analyses, we confirmed that vaccination in early infancy did not affect the risk of KD..
11. Kawaguchi, M; Miyagi, Y; Kishimoto, J; Samura, K; Tokunaga, Y; Watari, M; Eguchi, H; Ueda, S; Iihara, K, Development of Quality of Life Questionnaire for Patients with Parkinson's Disease Undergoing STN-DBS, NEUROLOGIA MEDICO-CHIRURGICA, 10.2176/nmc.oa.2020-0388, 61, 8, 475-483, 2021.08, In device-aided therapy (DAT) for Parkinson's disease (PD), factors such as device-related adverse effects, psychological and lifestyle changes, and specific disease progression can affect the quality of life (QoL) of patients with advanced PD. However, there is no existing QoL scale that includes the effects of therapeutic devices. From a semi-structured interview with patients with PD undergoing deep brain stimulation (DBS), we extracted the content of utterances that were thought to affect the QoL and created a draft questionnaire consisting of 113 items. This questionnaire was administered to 54 other patients undergoing DBS, whose data were examined for reliability and validity by factor analysis, and finally, a 24-item PD QoL questionnaire for patients on DAT (PDQ-DAT) was developed. Presently, the PDQ-DAT is the only scale that can assess the QoL of patients on DAT, including the influence treatment devices have on them. In the future, it might be used to help in shared decision-making in medicine by incorporating the patient's sense of burden and values in the selection of treatment methods.

12. Hotta, K; Saeki, S; Yamaguchi, M; Harada, D; Bessho, A; Tanaka, K; Inoue, K; Gemba, K; Shiojiri, M; Kato, Y; Ninomiya, T; Kubo, T; Kishimoto, J; Shioyama, Y; Katsui, K; Sasaki, J; Kiura, K; Sugio, K, Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study, ESMO OPEN, 10.1016/j.esmoop.2021.100191, 6, 4, 2021.08, Background: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) induction coupled with standard concurrent chemoradiotherapy (CRT) is unclear in unresectable, stage III, EGFR-mutant non-small-cell lung cancer (NSCLC). Therefore, a phase II trial was conducted to evaluate the efficacy and safety of gefitinib induction followed by CRT in this disease setting.

Patients and methods: Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy (250 mg/day) for 8 weeks. Subsequently, patients without disease progression during induction therapy were administered cisplatin and docetaxel (40 mg/m(2) each) on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy. The primary endpoint was the 2-year overall survival (OS) rate, which was hypothesized to reach 85%, with a threshold of the lower limit of 60%.

Results: Twenty patients (median age: 66 years; male/female: 9/11; histology: 20 adenocarcinoma; stage IIIA/IIIB: 9/11; and exon 19/21: 10/10) were enrolled. The 2-year OS rate was 90% (90% confidence interval: 71.4% to 96.8%), indicating that this trial met the primary objective. The overall response rate and 1- and 2-year progression-free survival rates were 85.0%, 58.1%, and 36.9%, respectively. Grade >= 3 adverse events (>10%) included hepatic toxicity during the induction phase and neutropenia and febrile neutropenia in the CRT phase. Radiation pneumonitis grade >= 3 or treatment-related death did not occur.

Conclusions: This is the first prospective study to demonstrate the favorable efficacy and safety of EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III NSCLC. Further confirmatory studies are needed..
13. Ikeda, S Shinohara, K Enzan, N Matsushima, S Tohyama, T Funakoshi, K Kishimoto, J Itoh, H Komuro, I Tsutsui, H, Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability, JOURNAL OF HYPERTENSION, 10.1097/HJH.0000000000002823, 39, 7, 1435-1443, 2021.07.
14. Kubo, H Urata, H Sakai, M Nonaka, S Kishimoto, J Saito, K Tateno, M Kobara, K Fujisawa, D Hashimoto, N Suzuki, Y Honda, Y Otsuka, K Kanba, S Kuroki, T Kato, TA, Development of a 3-Day Intervention Program for Family Members of Hikikomori Sufferers, JAPANESE PSYCHOLOGICAL RESEARCH, 10.1111/jpr.12368, 2021.06.
15. Tanaka, K Asahina, H Kishimoto, J Miyata, Y Uchida, T Watanabe, K Hamai, K Harada, T Tsubata, Y Sugawara, S Kobayashi, K Sugio, K Oizumi, S Okamoto, I, Original Research Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: An open-label, randomised phase 2 clinical trial, EUROPEAN JOURNAL OF CANCER, 10.1016/j.ejca.2021.02.019, 149, 14-22, 2021.05.
16. Urasaki, E Miyagi, Y Kishimoto, J, Effects of Medications and Subthalamic Nucleus-Deep Brain Stimulation on the Cutaneous Silent Period in Patients With Parkinson's Disease, NEUROMODULATION, 10.1111/ner.13454, 2021.05.
17. Hara, T Furuno, K Yamamura, K Kishimoto, J Mizuno, Y Murata, K Onoyama, S Hatae, K Takemoto, M Ishizaki, Y Kanno, S Sato, K Motomura, Y Sakai, Y Ohga, S Yashiro, M Nakamura, Y Hara, T, Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan, JAMA NETWORK OPEN, 10.1001/jamanetworkopen.2021.4475, 4, 4, 2021.04.
18. Murahashi, M Tsuruta, T Yamada, K Hijikata, Y Ogata, H Kishimoto, J Yoshimura, S Hikichi, T Nakanishi, Y Tani, K, Clinical Trial of a Cancer Vaccine Targeting VEGF and KIF20A in Advanced Biliary Tract Cancer, ANTICANCER RESEARCH, 10.21873/anticanres.14907, 41, 3, 1485-1496, 2021.03.
19. Yamaguchi, M Osoegawa, A Nakamura, T Morinaga, R Tanaka, K Kashiwabara, K Miura, T Suetsugu, T Taguchi, K Nabeshima, K Kishimoto, J Sakai, K Nishio, K Sugio, K, Mechanisms of acquired resistance to osimertinib in advanced NSCLC with EGFR T790M mutation (LOGIK1607), CANCER SCIENCE, 112, 567-567, 2021.02.
20. Bouchi, R Sonoda, N Itoh, J Ono, Y Fukuda, T Takeuchi, T Kishimoto, J Yamada, T Ogawa, Y, Effects of intensive exercise, combined with dapagliflozin on body composition in type 2 diabetes: a randomised controlled trial, DIABETOLOGIA, 63, SUPPL 1, S275-S275, 2020.09.
21. Ikeda, S Shinohara, K Enzan, N Matsushima, S Tohyama, T Funakoshi, K Kishimoto, J Itoh, H Komuro, I Tsutsui, H, Plasma B-type Natriuretic Peptide Levels Are Associated With Future Cardiovascular Events in Patients With Type 2 Diabetes Mellitus Without Known Cardiovascular Disease, CIRCULATION, 142, 2020.11.
22. Hanamoto, H Morita, Y Ichikawa, M Nannya, Y Shibayama, H Maeda, Y Hata, T Miyamoto, T Kawabata, H Takeuchi, K Tanaka, H Kishimoto, J Miyano, S Matsumura, I Ogawa, S Akashi, K Kanakura, Y Mitani, K, ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-Risk MDS: A Multicenter, Phase II Study, BLOOD, 10.1182/blood-2020-134483, 136, 2020.11.
23. Ikeda, S Shinohara, K Enzan, N Matsushima, S Tohyama, T Funakoshi, K Kishimoto, J Itoh, H Komuro, I Tsutsui, H, Effectiveness Of Intensive Lipid-lowering Therapy With Statins In Type 2 Diabetes Mellitus Patients With Poorly Controlled Blood Pressure, HYPERTENSION, 10.1161/hyp.76.suppl_1.P199, 76, 2020.09.
24. Shiraishi, Y Kishimoto, J Tanaka, K Sugawara, S Daga, H Hirano, K Azuma, K Hataji, O Hayashi, H Tachihara, M Mitsudomi, T Seto, T Nakagawa, K Yamamoto, N Okamoto, I, Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer, CLINICAL LUNG CANCER, 10.1016/j.cllc.2020.03.010, 21, 5, 472-476, 2020.09.
25. Hisatomi, T Enaida, H Yoshida, S Hirakata, A Ohji, M Nishida, K Kubota, T Ogata, N Matsui, T Kimura, K Sonoda, KH Uchiyama, M Kishimoto, J Todaka, K Nakanishi, Y Ishibashi, T, Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial, JAPANESE JOURNAL OF OPHTHALMOLOGY, 10.1007/s10384-020-00763-y, 64, 5, 455-461, 2020.09.
26. Nio, K Tsuchihashi, K Taguchi, K Yoshihiro, T Yamaguchi, K Ito, M Moriyama, S Fukata, M Fujiwara, T Setsu, N Endo, M Matsumoto, Y Nakashima, Y Wakasaki, T Yasumatsu, R Ariyama, H Kusaba, H Kishimoto, J Akashi, K Baba, E, Exploratory retrospective study of risk factors for thromboembolism treated with multi-kinase inhibitor pazopanib or Lenvatinib., International Journal of Surgery Oncology, 5, e89, 2020.05.
27. Sakai, D Taniguchi, H Sugimoto, N Tamura, T Nishina, T Hara, H Esaki, T Denda, T Sakamoto, T Okuda, H Satoh, T Tsushima, T Makiyama, A Tsuda, T Hosokawa, A Kuramochi, H Tokunaga, S Moriwaki, T Yasui, H Ishida, H Tsuji, A Otsu, S Shimokawa, H Baba, E Sato, M Matsumoto, S Ozaki, Y Shinozaki, K Tamagawa, H Goto, M Kadowaki, S Fujii, H Koh, Y Yamazaki, K Hironaka, S Kishimoto, J Boku, N Hyodo, I Muro, K, Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G), EUROPEAN JOURNAL OF CANCER, 10.1016/j.ejca.2020.04.014, 135, 11-21, 2020.08.
28. Uchida, N Matsumoto, K Sakura, T Hidaka, M Miyamoto, T Eto, T Maeda, Y Murayama, T Fujishima, N Yoshimoto, G Morita, K Kishimoto, J Teshima, T Taniguchi, S Yamashita, T Mori, S Akashi, K Harada, M, Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies, INTERNATIONAL JOURNAL OF HEMATOLOGY, 10.1007/s12185-020-02941-7, 112, 4, 510-523, 2020.10.
29. Machida, N Okumura, T Kishimoto, J Boku, N Nishina, T Suyama, K Ohde, Y Shinozaki, K Baba, H Tokunaga, S Kawakami, H Tsuda, T Kotaka, M Okuda, H Yasui, H Denda, T Yamazaki, K Hironaka, S Muro, K Hyodo, I, Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G., JOURNAL OF CLINICAL ONCOLOGY, 38, 15, 2020.05.
30. Matsuoka, H Ogata, Y Nakamura, M Shibata, Y Munemoto, Y Bando, H Nishijima, K Okuda, H Terada, I Shiroiwa, T Kishimoto, J Maeda, K, An Observational Study of Team Management Approach for CapeOX Therapy in Patients with Advanced and Recurrent Colorectal Cancer: SMILE Study (The Study of Metastatic colorectal cancer to investigate the Impact of Learning Effect), JOURNAL OF THE ANUS RECTUM AND COLON, 4, 2, 79-84, VL 4
IS 2
BP 79
EP 84, 2020.04, Objectives: In recent years, CapeOX therapy for patients with colorectal cancer is widely used. We previously reported that a multidisciplinary approach decreases the worsening of adverse events and increases patient satisfaction. In this study, we conducted a multicenter, prospective, observational study to evaluate the incidence of adverse events, health-related quality of life (HRQOL) of the patient, and efficacy of a management (intervention) according to the support system (SMILE study).
Methods: As the interventional method, the following more than one method was carried out in each institute, 1: support with telephone, 2: dosing instruction by a pharmacist, 3: skin care instruction by a nurse, and 4: patient instruction by a doctor. The primary endpoint was the incidence of hand-foot syndrome (IMS) of more than grade 2. The secondary endpoint was the IIRQOL evaluation and efficacy. The questionnaire (HADS) was administered before the start of the chemotherapy and in 1, 2, 4, 5, and 8 courses to evaluate quality of life (QOL).
Results: From April 2011 to September 2012, 80 patients were enrolled from 14 sites, and all patients were the subjects of analysis. The demographic background was as follows: man/woman: 46/34, age median: 63 (36-75), and management interventional method 1/2/3/4: 36/68/73/78. The overall percentage of HFS that exceeded grade 2 within 6 months was 16.3%. It was 11.1% with the telephone support group and 20.5% without the telephone support group (p = 0.26).
Conclusions: A multi-professional telephone support may reduce the deterioration of HFS. Further study which includes larger cohort is needed in the future..
31. Ouchi, K Hosokawa, R Yamanaka, H Nakajima, Y Nakamura, Y Kishimoto, J, Mallampati test with phonation, tongue protrusion and supine position is most correlated with Cormack-Lehane test, ODONTOLOGY, UT WOS:000516006200002
PM 32040653, 2020.02, Many modified Mallampati tests have been developed to date. Samsoon's modified Mallampati test (standard Mallampati test) is currently widely used. We newly designed seven types of assessment protocol of Mallampati test, in addition to standard Mallampati test. In this study, we studied the correlation between eight types of protocol (standard and seven alternative protocols) of Mallampati test and Cormack-Lehane test. We newly designed assessment protocols as new Mallampati test. These are different protocols depending on the presence or absence of phonation, those of protrusion of tongue, and sitting position or supine position. The oropharyngeal structures visualized by these eight types of Mallampati test for total of 145 patients undergoing dental oral surgery were evaluated. The scores derived via eight types of Mallampati test were recorded. The influence of phonation, tongue protrusion and body position on Mallampati test score was analyzed, respectively. The relationships between eight types of Mallampati test and Cormack-Lehane test were analyzed. Tongue protrusion, phonation and sitting position tended to lower the score of Mallampati test (p < 0.001, respectively). The standard Mallampati test was not correlated with Cormack-Lehane test. In the new Mallampati tests, assessment protocol with tongue protrusion, phonation and sitting position, that with tongue protrusion and supine position, or that with tongue protrusion, phonation and supine position were significantly correlated with Cormack-Lehane test, respectively. (p = 0.020, p = 0.007 and p = 0.004, respectively). The standard Mallampati test did not correlate with Cormack-Lehane test. Mallampati test with phonation, tongue protrusion and supine position were most correlated with Cormack-Lehane test..
32. Kubo, H Urata, H Sakai, M Nonaka, S Saito, K Tateno, M Kobara, K Hashimoto, N Fujisawa, D Suzuki, Y Otsuka, K Kamimae, H Muto, Y Usami, T Honda, Y Kishimoto, J Kuroki, T Kanba, S Kato, TA, Development of 5-day hikikomori intervention program for family members: A single-arm pilot trial, HELIYON, 6, 1, PD JAN
PY 2020
VL 6
IS 1, 2020.01, Backgrounds: Hikikomori, a severe form of social withdrawal, is increasingly a serious mental health issue worldwide. Hikikomori is comorbid with various psychiatric conditions including depression, social anxiety and suicidal behaviors. Family support is encouraged as a vital first step, however evidence-based programs have yet to be established. Mental Health First Aid (MHFA) is one of the most well-validated educational programs encouraging lay people such as family members, to support close persons suffering from various psychiatric conditions such as depression, anxiety and suicidal behaviors.
Methods: We newly developed an educational program for family members of hikikomori sufferers mainly based on MHFA and 'Community Reinforcement and Family Training (CRAFT)' with role-play and homework. As a single-arm trial, 21 parents (7 fathers and 14 mothers) living with hikikomori sufferers participated in our program with five once-a-week sessions (2 h per session) and six monthly follow-ups, and its effectiveness was evaluated using various self-rated questionnaires.
Results: Perceived skills toward a depressed hikikomori case vignette, stigma held by participants, and subscales of two problematic and one adaptive behaviors of hikikomori sufferers were improved throughout the sessions and follow-ups. In addition, positive behavioral changes of hikikomori sufferers such as improved social participation were reported by participants.
Limitations: Single-arm design and evaluation using self-rated questionnaires are the main limitations of the present study.
Conclusions: Our newly developed program has positive effects on family members in their contact and support of hikikomori sufferers. Future trials with control groups are required to validate the effectiveness of this program..
33. Osoegawa, A Yamaguchi, M Nakamura, T Morinaga, R Tanaka, K Kashiwabara, K Taguchi, K Nabeshima, K Kishimoto, J Sugio, K, Revealing the mechanisms of acquired resistance to osimertinib from re-biopsy specimens in advanced non-small cell lung cancer with EGFR T790M mutation (LOGIK1607), MOLECULAR CANCER THERAPEUTICS, 18, 12, 2019.12.
34. Tsuchiya-Kawano, Y Sasaki, T Yamaguchi, H Hirano, K Horiike, A Satouchi, M Hosokawa, S Morinaga, R Komiya, K Inoue, K Fujita, Y Toyozawa, R Kimura, T Takahashi, K Nishikawa, K Kishimoto, J Nakanishi, Y Okamoto, I, Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer, ONCOLOGIST, 25, 6, 475, 2019.06, Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen. Background We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). Methods Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m(2) for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m(2) on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS). Results Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period. Conclusion Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC..
35. Iwama, E Sakai, K Hidaka, N Inoue, K Fujii, A Nakagaki, N Ota, K Toyozawa, R Azuma, K Nakatomi, K Harada, T Hisasue, J Sakata, S Shimose, T Kishimoto, J Nakanishi, Y Nishio, K Okamoto, I, Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors, CANCER, 2019.09, Background The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. Results One hundred patients, including 87 who were EGFR-TKI naive, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naive patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P < .001) for EGFR-TKI-naive patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy..
36. Horiike, A Kawano, Y Sasaki, T Yamaguchi, H Hirano, K Satouchi, M Hosokawa, S Morinaga, R Komiya, K Inonue, K Fujita, Y Toyozawa, R Kimura, T Takahashi, K Nishikawa, K Kishimoto, J Nakanishi, Y Okamoto, I, Updated survival date of phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer., JOURNAL OF CLINICAL ONCOLOGY, 37, 15, 2019.05.
37. Epp, DA Kubota, T Yoshida, M Kishimoto, J Kobayashi, D Shimazoe, T, Promoting Patient Care Through Communication Training in a Pre-clerkship Pharmacy Education Course in Japan, AMERICAN JOURNAL OF PHARMACEUTICAL EDUCATION, 83, 5, VL 83
IS 5, 2019.06, Objective. The purpose of this study was to teach communication skills for patient care to pre-clerkship students and observe changes in student perspectives towards communication from pre- to post-training.
Methods. Two cohorts of fourth-year pharmacy students completed an eight-week pre-clerkship training course designed to improve their communication skills. The course involved class discussions and in-class research of medications, practicing communication skills, learning to give science-based responses, and developing an awareness of patient education for lifestyle, self-medication, quality of life, and medication adherence. A comparison of students' pre- and post-training responses to a questionnaire were used to assess changes in students' ability and confidence in communicating with patients. An exploratory factor analysis was used to analyze and compare the data results.
Results. Students' mean post-training scores for perceived ability to make small talk and confidence to communicate with patients increased compared to pre-training scores. Based on the results of the exploratory factor analysis, the greatest increase in students' scores was in the area of patient education skills.
Conclusion. The pre-clerkship communication training improved student understanding of the pharmacy communication skills needed to conduct effective patient education and pharmacist-patient interaction beyond dispensing, affirming the theory that specialized communication training before students' begin a clerkship may be essential..
38. Minoru Fukuda, Takeshi Kitazaki, Daiki Ogawara, Masao Ichiki, Hiroshi Mukae, Riichiroh Maruyama, Noriaki Nakagaki, Midori Shimada, Takaya Ikeda, Junji Kishimoto, Taishi Harada, Takashi Seto, Noriyuki Ebi, Koichi Takayama, Isamu Okamoto, Yukito Ichinose, Kenji Sugio, Randomized phase II study of pemetrexed or pemetrexed plus bevacizumab for elderly patients with previously untreated non-squamous non-small cell lung cancer
Results of the Lung Oncology Group in Kyushu (LOGIK1201), Lung Cancer, 10.1016/j.lungcan.2019.01.008, 132, 1-8, 2019.06, Objectives: To evaluate the efficacy and safety, we conducted a randomized phase II study of pemetrexed (Pem) versus Pem + bevacizumab (Bev) for elderly patients with non-squamous non-small cell lung cancer (NSqNSCLC). Patients and methods: The eligibility criteria were as follows: NSqNSCLC, no prior therapy, stage IIIB/IV disease or postoperative recurrence, age: ≥75 years, performance status (PS): 0–1, and adequate bone marrow function. The patients were randomly assigned (1:1 ratio) to receive Pem or Pem + Bev. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the response rate, OS, toxicities, and cost-effectiveness. Results: Forty-one patients were enrolled and 40 (20 from each group) were assessable. Their characteristics were as follows: male/female = 23/17; median age (range) = 78 (75–83); stage IIIB/IV/postoperative recurrence = 1/30/9; PS 0/1 = 11/29. All cases involved adenocarcinoma. There was no significant intergroup difference in PFS and the median PFS (95% confidence interval) values of the Pem and Pem + Bev groups were 5.4 (3.0–7.4) and 5.5 (3.6–9.9) months, respectively (p = 0.66). The response rate was significantly higher in the Pem + Bev group (15% vs. 55%, p = 0.0146), and there was no significant difference in OS (median: 16.0 vs. 16.4 months, p = 0.58). Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia were seen in 10 and 30, 20 and 55, and 5 and 5 cases, respectively. Drug costs were higher in the Pem + Bev group (median: 1,522,008 vs. 3,368,428 JPY, p = 0.01). No treatment-related deaths occurred. Conclusions: Adding Bev to Pem did not result in improved survival in the elderly NSqNSCLC patients. Compared with Pem + Bev, Pem monotherapy had similar effects on survival, a more favorable toxicity profile, and was more cost-effective in elderly NSqNSCLC patients. Pem monotherapy might be one of the optional regimen for NSqNSCLC patients aged ≥75 years..
39. Hitomi Mori, Makoto Kubo, Masaya Kai, Mai Yamada, Kanako Kurata, Hitomi Kawaji, Kazuhisa Kaneshiro, Tomofumi Osako, Reiki Nishimura, Nobuyuki Arima, Masayuki Okido, Junji Kishimoto, Yoshinao Oda, Masafumi Nakamura, T-bet
lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer, Breast Cancer Research and Treatment, 10.1007/s10549-019-05256-2, 2019.01, Purpose: T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells. Methods: This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10
. Results: Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet
tumors had longer overall survival (OS) compared with patients with T-bet

tumors (p = 0.047). The combination of CD8
and T-bet
was associated with a better recurrence-free survival (RFS) and OS compared to CD8

tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet
tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12–0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07–0.95, p = 0.039 for OS). Conclusions: OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC..
40. Masafumi Sanefuji, Hiroshi Yamashita, Michiko Torio, Daisuke Katsuki, Satoshi Akamine, Yoshito Ishizaki, Junji Kishimoto, Yasunari Sakai, Hidetoshi Takada, Keiko Yoshida, Shoichi Ohga, A rightward saccade to an unexpected stimulus as a marker for lateralised visuospatial attention /631/378/2649/1310 /631/378/2617/1795 /631/477/2811 article, Scientific reports, 10.1038/s41598-018-25890-y, 8, 1, 2018.12, The human brain is lateralised to the right for visuospatial attention, particularly when reorienting attention to unexpected stimuli. However, the developmental characteristics of lateralisation remain unclear. To address this question, we devised a saccade task applicable for both adults and children. To assess the utility of this system, we investigated the correlation between line bisection test performance and the saccade task for 54 healthy adult volunteers. Participants followed a visual target that jumped 10 times, alternating between two fixed positions across the midline with a constant pace. In both the rightward and leftward directions, saccadic reaction time (RT) to the target jump decreased and reached a plateau from the first to the tenth jumps. Furthermore, we obtained the time required for reorienting in the contralateral hemisphere using the corrected value of the first RT. We found that longer corrected RTs in the rightward saccade were associated with greater deviation to the left in the line bisection task. This correlation was not observed for leftward saccades. Thus, corrected RTs in rightward saccades reflected the strength of individual hemispheric lateralisation. In conclusion, the rightward saccade task provides a suitable marker for lateralised visuospatial attention, and for investigating the development of lateralisation..
41. Kohei Hayakawa, Takahiro Kato, Motoki Watabe, Alan R. Teo, Hideki Horikawa, Nobuki Kuwano, Norihiro Shimokawa, Mina Sato-Kasai, Hiroaki Kubo, Masahiro Ohgidani, Noriaki Sagata, Hiroyuki Toda, Masaru Tateno, Naotaka Shinfuku, Junji Kishimoto, Shigenobu Kanba, Blood biomarkers of Hikikomori, a severe social withdrawal syndrome, Scientific reports, 10.1038/s41598-018-21260-w, 8, 1, 2018.12, Hikikomori, a severe form of social withdrawal syndrome, is a growing social issue in Japan and internationally. The pathophysiology of hikikomori has not yet been elucidated and an effective treatment remains to be established. Recently, we revealed that avoidant personality disorder is the most common comorbidity of hikikomori. Thus, we have postulated that avoidant personality is the personality underpinning hikikomori. First, we herein show relationships between avoidant personality traits, blood biomarkers, hikikomori-related psychological features, and behavioural characteristics assessed by a trust game in non-hikikomori volunteers. Avoidant personality traits were negatively associated with high-density lipoprotein cholesterol (HDL-C) and uric acid (UA) in men, and positively associated with fibrin degeneration products (FDP) and high sensitivity C-reactive protein (hsCRP) in women. Next, we recruited actual individuals with hikikomori, and compared avoidant personality traits, blood biomarkers, and psychological features between individuals with hikikomori and age-matched healthy controls. Individuals with hikikomori had higher avoidant personality scores in both sexes, and showed lower serum UA levels in men and lower HDL-C levels in women compared with healthy controls. This is the first report showing possible blood biomarkers for hikikomori, and opens the door to clarify the underlying biological pathophysiology of hikikomori..
42. Eiji Iwama, Kazuko Sakai, Koichi Azuma, Daijiro Harada, Kaname Nosaki, Katsuyuki Hotta, Makoto Nishio, Takayasu Kurata, Tatsuro Fukuhara, Hiroaki Akamatsu, Koichi Goto, Takayuki Shimose, Junji Kishimoto, Yoichi Nakanishi, Kazuto Nishio, Isamu Okamoto, Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing, Cancer Science, 10.1111/cas.13820, 109, 12, 3921-3933, 2018.12, Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance-conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non-small-cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression-free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR-TKI treatment..
43. Yoshihiro Kaizu, shintaro nakao, Haruka Sekiryu, Iori Wada, Muneo Yamaguchi, Toshio Hisatomi, Yasuhiro Ikeda, Junji Kishimoto, Kohei Sonoda, Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy, Graefe's Archive for Clinical and Experimental Ophthalmology, 10.1007/s00417-018-4122-6, 256, 12, 2275-2282, 2018.12, Purpose: Fluorescein angiography (FA) has been conventionally used for detection of retinal nonperfused area (NPA) in diabetic retinopathy (DR) in spite of its qualitative evaluation. Optical coherence tomography angiography (OCTA) has been recently reported to be useful for the quantification of retinal vascular disorder in DR. In this study, we examined whether retinal flow density (FD) measurement in OCTA was useful for NPA detection in DR. Methods: The study included 41 eyes from 29 patients with DR who underwent FA and OCTA. Regions surrounded by arteries or veins were extracted in the OCTA image, and the FDs in each region were measured by Image J. Furthermore, each region was classified as NPA or perfused area (PA) in FA. The receiver operating characteristic (ROC) curve was prepared by logistic regression analysis of the FD. The AUC (area under the ROC curve) and cutoff value of FD were also calculated. Results: Two hundred fifty-two regions were analyzed and classified into 38 NPA regions and 214 PA regions using FA. FD of each capillary plexus in NPA was significantly smaller than in PA (p < 0.0001). The AUC of total capillary plexus layers (TCP), superficial capillary plexus layer (SCP), and deep capillary plexus layer (DCP) was 0.975, 0.974, and 0.971, respectively. All areas, where the FD was more than the cutoff value (0.07 in TCP), were diagnosed with PA. Three areas with intraretinal microvascular abnormalities (IRMA) were diagnosed as PA despite being below the cutoff value. Conclusions: FD measurement in OCTA is useful for NPA detection in DR..
44. Kenji Tsuchihashi, Mamoru Ito, Toshikazu Moriwaki, Shota Fukuoka, Hiroya Taniguchi, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Kenji Katsumata, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Hiroyuki Okuyama, Daisuke Sakai, Hideki Ueno, Takao Tamura, Kimihiro Yamashita, Junji Kishimoto, Yasuhiro Shimada, Eishi Baba, Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer, Clinical Colorectal Cancer, 10.1016/j.clcc.2018.07.004, 17, 4, e687-e697, 2018.12, The survival and safety of patients with metastatic colorectal cancer treated with trifluridine/tipiracil or regorafenib as later-line chemotherapy were retrospectively examined according to the modified Glasgow Prognostic Score (mGPS). Overall and progression-free survival were strongly correlated with mGPS in all patients. The frequency of adverse events was generally similar in each mGPS group. Background: Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. Patients and Methods: A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared. Results: The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2-11.6 months), 6.5 months (95% CI, 5.3-7.1 months), and 3.9 months (95% CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1-3.0 months), 2.0 months (95% CI, 1.9-2.3 months), and 1.7 months (95% CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P <.001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95% CI, 0.93-2.25; P =.097; PFS: hazard ratio, 1.57, 95% CI, 1.01-2.44; P =.047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS. Conclusions: The mGPS before later-line chemotherapy is strongly correlated with survival in patients with mCRC..
45. Yuko Kawano, Tomonari Sasaki, Hiroyuki Yamaguchi, Katsuya Hirano, Atsushi Horiike, Miyako Satouchi, Shinobu Hosokawa, Ryotaro Morinaga, Kazutoshi Komiya, Koji Inoue, Yuka Fujita, Ryo Toyozawa, Tomoki Kimura, Kosuke Takahashi, Kazuo Nishikawa, Junji Kishimoto, Yoichi Nakanishi, Isamu Okamoto, Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non–small cell lung cancer, Lung Cancer, 10.1016/j.lungcan.2018.09.014, 125, 136-141, 2018.11, Objectives: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Patients and methods: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m
) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL
min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. Results: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m
, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2–85.9%), median progression-free survival was 11.8 months (60% CI, 10.6–16.2 months; 95% CI, 8.2–20.8 months), and median overall survival was not reached. Conclusion: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m
and carboplatin at an AUC of 2 in patients with locally advanced NSCLC..
46. Akira Nakao, Junji Uchino, Fumiyasu Igata, Rintaro On, Takato Ikeda, Hiroshi Yatsugi, Ryosuke Hirano, Tomoya Sasaki, Keiko Tanimura, Tatsuya Imabayashi, Nobuyo Tamiya, Yoshiko Kaneko, Tadaaki Yamada, Nobuhiko Nagata, Kentaro Watanabe, Junji Kishimoto, Koichi Takayama, Masaki Fujita, Nab-paclitaxel maintenance therapy following carboplatin + nab-paclitaxel combination therapy in chemotherapy naïve patients with advanced non-small cell lung cancer
multicenter, open-label, single-arm phase II trial, Investigational New Drugs, 10.1007/s10637-018-0617-6, 36, 5, 903-910, 2018.10, Background A global multicenter study demonstrated superiority of carboplatin + nab-paclitaxel (PTX) therapy compared to carboplatin + PTX in terms of response rate (RR) and non-inferiority in terms of progression free survival (PFS) and overall survival (OS) in untreated patients with stage IIIB/IV non-small cell lung cancer; no clinical findings have so far been reported on maintenance therapies with nab-PTX. The aim of this study was to determine the efficacy and safety of maintenance therapy with nab-PTX following carboplatin + nab-PTX combination therapy. Methods Carboplatin (AUC 6) was administered on Day 1; and nab-PTX 100 mg/m2 on Days 1, 8, and 15, and dosing was repeated in 4 courses of 4 weeks each. In patients with clinical response was observed at the end of the 4th course, nab-PTX maintenance therapy was repeated. Results Out of 39 patients included in the efficacy analysis, 19 (48.7%) patients completed the induction therapy and 15 (38.5%) were transitioned to maintenance therapy. The median PFS in the maintenance phase was 6.5 (90%CI 1.4–11.4) months. The median OS in 15 patients was 12.6 (95%CI: 7.4-not reached). Grade ≥ 3 toxicities observed in more than 5% of patients were neutropenia (55.0%), anemia (15.0%), and febrile neutropenia (5.0%), with no increase during the maintenance phase. Conclusions Although statistically significance was not demonstrated presumably due to a limited transition rate from induction to maintenance phase, nab-PTX was suggested to be a useful treatment option following the induction therapy with nab-PTX in patients with advanced NSCLC..
47. Chika Iwamoto, Kenoki Ouchida, Miki Okumura, Yosuke Usumoto, Junji Kishimoto, Masaharu Murata, Noriaki Ikeda, Makoto Hashizume, Postmortem interval estimation using the animal model of postmortem gas volume changes, Legal Medicine, 10.1016/j.legalmed.2017.12.010, 32, 66-70, 2018.05, It is important to estimate the postmortem interval in forensic autopsy. Many methods to estimate the postmortem interval have been reported, and are typically associated with internal examination. However, there are issues such as rejection of autopsy by the family and a lack of forensic doctor in internal examination. Therefore, it is necessary to develop new methods, such as autopsy imaging, that can substitute for internal examination. Here, we first evaluated whether gas volume in the body increased with postmortem interval. Time-dependent X-ray CT imaging of euthanized Crl:CD (SD) rats (n = 3) was performed immediately after euthanasia and at seven subsequent time points up to 168 h (7 days) at 24-hour intervals. The data revealed that gas volume in the body increased in a time-dependent manner. Next, we reconstructed 3D images of isolated gas and calculated the gas volume using Amira software. In all cases, the volume of both portal venous gas and intestinal gas increased in a time-dependent manner. The volume of portal venous gas increased exponentially, while the volume of intestinal gas increased in a linearly with time. These data might be suggested that the postmortem gas volume change is one of indicators for estimating the postmortem interval. In addition, it would be possible to estimate more accurate postmortem interval by combining not only gas volume changes at the above two sites but also gas volume changes of the other sites such as heart cavities, kidney parenchyma, or abdominal aorta..
48. Nobuki Kuwano, Takahiro Kato, Daiki Setoyama, Mina Sato-Kasai, Norihiro Shimokawa, Kohei Hayakawa, Masahiro Ohgidani, Noriaki Sagata, Hiroaki Kubo, Junji Kishimoto, Dongchon Kang, Shigenobu Kanba, Tryptophan-kynurenine and lipid related metabolites as blood biomarkers for first-episode drug-naïve patients with major depressive disorder
An exploratory pilot case-control study, Journal of Affective Disorders, 10.1016/j.jad.2018.01.014, 231, 74-82, 2018.04, Background: Early intervention in depression has been critical to prevent its negative impact including suicide. Recent blood biomarker studies for major depressive disorder (MDD) have suggested that tryptophan-kynurenine and lipid related metabolites are involved in the pathophysiology of MDD. However, there have been limited studies investigating these blood biomarkers in first-episode drug-naïve MDD, which are particularly important for early intervention in depression. Methods: As an exploratory pilot case-control study, we examined the above blood biomarkers, and analyzed how these biomarkers are associated with clinical variables in first-episode drug-naïve MDD patients, based on metabolome/lipidome analysis. Results: Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740). Lower serum high density lipoprotein-cholesterol (HDL-C) was the predictive biomarker for severity of depression in MDD group (R2 = 0.444). Interestingly, depressive symptoms were variously correlated with plasma tryptophan-kynurenine and lipid related metabolites. Moreover, plasma tryptophan-kynurenine metabolites and cholesteryl esters (CEs) were significantly correlated in MDD group, but not in HC group. Limitations: This study had small sample size, and we did not use the multiple test correction. Conclusions: This is the first study to suggest that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients. The present study sheds new light on early intervention in clinical practice in depression, and further clinical studies especially large-scale prospective studies are warranted..
49. Yasuki Hijikata, Toshihiko Okazaki, Yoshihiro Tanaka, Mutsunori Murahashi, Yuichi Yamada, Kazunari Yamada, Atsushi Takahashi, Hiroyuki Inoue, Junji Kishimoto, Yoichi Nakanishi, Yoshinao Oda, Yusuke Nakamura, Kenzaburo Tani, A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors, PloS one, 10.1371/journal.pone.0187878, 13, 1, 2018.01, The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m
CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8
T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors..
50. Kaku Nakano, Tetsuya Matoba, Jun Ichiro Koga, Yushi Kashihara, Masato Fukae, Ichiro Ieiri, Masanari Shiramoto, Shin Irie, Junji Kishimoto, Koji Todaka, Kensuke Egashira, Safety, tolerability, and pharmacokinetics of NK-104-NP a multicenter, randomized, placebo-controlled phase I investigator-initiated trial for intravenous administration of pitavastatin-loaded plga nanoparticles (Nk-104-NP) in healthy Japanese male subjects, International heart journal, 10.1536/ihj.17-555, 59, 5, 1015-1025, 2018.01, Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers..
51. Kohei Otsubo, Junji Kishimoto, Hirotsugu Kenmotsu, Yuji Minegishi, Eiki Ichihara, Akira Shiraki, Terufumi Kato, Shinji Atagi, Hidehito Horinouchi, Masahiko Ando, Yasuhiro Kondoh, Masahiko Kusumoto, Kazuya Ichikado, Nobuyuki Yamamoto, Yoichi Nakanishi, Isamu Okamoto, Treatment Rationale and Design for J-SONIC
A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non–Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis, Clinical Lung Cancer, 10.1016/j.cllc.2017.06.003, 19, 1, e5-e9, 2018.01, We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non–small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m
on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone..
52. Kohei Otsubo, Kaname Nosaki, Chiyo K. Imamura, Hiroaki Ogata, Akitaka Fujita, Shinya Sakata, Fumihiko Hirai, Gouji Toyokawa, Eiji Iwama, Taishi Harada, Takashi Seto, Mitsuhiro Takenoyama, Takeshi Ozeki, Taisei Mushiroda, Mieko Inada, Junji Kishimoto, Kenji Tsuchihashi, Kentaro Suina, Osamu Nagano, Hideyuki Saya, Yoichi Nakanishi, Isamu Okamoto, Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer, Cancer Science, 10.1111/cas.13309, 108, 9, 1843-1849, 2017.09, Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854..
53. Etsuro Nanishi, Hisanori Nishio, Hidetoshi Takada, Kenichiro Yamamura, Mitsuharu Fukazawa, Kenji Furuno, Yumi Mizuno, Kenjiro Saigo, Ryo Kadoya, Noriko Ohbuchi, Yasuhiro Onoe, Hironori Yamashita, Hideki Nakayama, Takuya Hara, Takuro Ohno, Yasuhiko Takahashi, Ken Hatae, Tatsuo Harada, Takayuki Shimose, Junji Kishimoto, Shoichi Ohga, Toshiro Hara, Clarithromycin plus intravenous immunoglobulin therapy can reduce the relapse rate of Kawasaki disease
A phase 2, open-label, randomized control study, Journal of the American Heart Association, 10.1161/JAHA.116.005370, 6, 7, 2017.07, Background-We previously reported that biofilms and innate immunity contribute to the pathogenesis of Kawasaki disease. Therefore, we aimed to assess the efficacy of clarithromycin, an antibiofilm agent, in patients with Kawasaki disease. Methods and Results-We conducted an open-label, multicenter, randomized, phase 2 trial at 8 hospitals in Japan. Eligible patients included children aged between 4 months and 5 years who were enrolled between days 4 and 8 of illness. Participants were randomly allocated to receive either intravenous immunoglobulin (IVIG) or IVIG plus clarithromycin. The primary end point was the duration of fever after the initiation of IVIG treatment. Eighty-one eligible patients were randomized. The duration of the fever did not differ between the 2 groups (mean±SD, 34.3±32.4 and 31.1±31.1 hours in the IVIG plus clarithromycin group and the IVIG group, respectively [P=0.66]). The relapse rate of patients in the IVIG plus clarithromycin group was significantly lower than that in the IVIG group (12.5% versus 30.8%, P=0.046). No serious adverse events occurred during the study period. In a post hoc analysis, the patients in the IVIG plus clarithromycin group required significantly shorter mean lengths of hospital stays than those in the IVIG group (8.9 days versus 10.3 days, P=0.049). Conclusions-Although IVIG plus clarithromycin therapy failed to shorten the duration of fever, it reduced the relapse rate and shortened the duration of hospitalization in patients with Kawasaki disease..
54. Nozomi Ishisaka, Satomi Shimano, Tomofumi Miura, Keisuke Motomura, Machiko Horii, Hisako Imanaga, Junji Kishimoto, Yasuhiro Kaneda, Ichiro Sora, Shigenobu Kanba, Neurocognitive profile of euthymic Japanese patients with bipolar disorder, Psychiatry and Clinical Neurosciences, 10.1111/pcn.12500, 71, 6, 373-382, 2017.06, Aim: Neurocognitive impairment is one of the core symptoms of bipolar disorder (BD). The MATRICS Cognitive Consensus Battery (MCCB) is a potential consensus assessment tool to evaluate cognitive function in patients with BD. Here, we report on cognitive deficits evaluated using the MCCB Japanese version (MCCB-J) in euthymic Japanese patients with BD, and compare them with scores in previous studies. Methods: We compared neurocognitive function in 25 patients with euthymic BD and 53 healthy controls (HC). Additionally, we searched all available databases for studies that have evaluated cognitive function in BD using the MCCB, and conducted a meta-analysis. Results: Canonical discriminant analysis revealed significant differences in MCCB-J domain scores between BD and HC. Patients with BD performed significantly worse on visual learning, social cognition, speed of processing, and MCCB composite scores. Our meta-analysis revealed that patients with BD performed worse than HC, as reflected by MCCB composite scores and scores on all seven cognitive domains. However, there are differences in the cognitive deficits identified in previous studies compared with our participants, particularly social cognition. Conclusion: As reported in previous studies, neurocognitive deficits were observed in Japanese euthymic BD patients assessed using the MCCB-J. Further study is needed to clarify whether differences in social cognition between this study and previous studies are a result of coping mechanisms for social settings in Japanese populations..
55. Akiko Fujii, Yu Yamada, Koichi Takayama, Takako Nakano, Junji Kishimoto, Tatsuya Morita, Yoichi Nakanishi, Longitudinal assessment of pain management with the pain management index in cancer outpatients receiving chemotherapy, Supportive Care in Cancer, 10.1007/s00520-016-3482-x, 25, 3, 925-932, 2017.03, Purpose: The adequacy of pain management for individuals with cancer who receive outpatient chemotherapy is unclear. The primary objective of this study was to assess pain prevalence and intensity in such patients. The secondary objectives included assessment of pain management with the pain management index (PMI) and exploration of predictors of inadequate pain management. Methods: Cancer patients who received outpatient chemotherapy were enrolled. Patients were required to complete questionnaires covering demographic data and including the Brief Pain Inventory and the Distress Thermometer and Impact Thermometer. The PMI score was determined twice with an interval of at least 3 weeks. Results: Of the 740 patients enrolled in the study, 524 individuals (70.8%) completed all questionnaires. Totals of 282 patients (53.8%) and 264 patients (50.4%) reported pain at baseline and follow-up, respectively, with ∼14% of patients having moderate or severe pain at each assessment. Totals of 365 patients (69.7%) at baseline and 320 patients (61.1%) at follow-up reported pain or were prescribed analgesics, with the rate of inadequate pain management for these patients being 39.7 and 51.6%, respectively. Multivariable analysis for 418 patients (79.8%) who had pain or required analgesics at baseline or follow-up (or both) revealed that the most significant predictor of inadequate pain management was depressive state. Conclusions: Pain in cancer patients receiving outpatient chemotherapy is prevalent and at risk for undertreatment. Pain management should be assessed on a regular basis and is likely to be improved by screening for depression..
56. Susumu Takase, Tetsuya Matoba, Soichi Nakashiro, Yasushi Mukai, Shuujirou Inoue, Keiji Oi, Taiki Higo, Shunsuke Katsuki, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Mitsutaka Yamamoto, Makoto Usui, Kenji Sadamatsu, Shinji Satoh, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Kensuke Egashira, Kenji Sunagawa, Ezetimibe in combination with statins ameliorates endothelial dysfunction in coronary arteries after stenting
the CuVIC trial (effect of cholesterol absorption inhibitor usage on target vessel dysfunction after coronary stenting), a multicenter randomized controlled trial, Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.116.308388, 37, 2, 350-358, 2017.02, Objectives - We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. Approach and Results - We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. Conclusions - The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels..
57. Mamoru Ito, Hitoshi Kusaba, Satomi Mukaide, Junji Kishimoto, Hozumi Shimokawa, Shingo Tamura, Akitaka Makiyama, Gen Hirano, Hisanobu Oda, Tsuyoshi Shirakawa, Masato Komoda, Keita Uchino, Risa Tanaka, Kenji Mitsugi, Taito Esaki, Shuji Arita, hiroshi ariyama, Koichi Akashi, Eishi Baba, Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer, Anti-cancer drugs, 10.1097/CAD.0000000000000562, 28, 10, 1166-1173, 2017.01, A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R 2 =0.429), whereas EETS and DPR were less correlated with OS (R 2 =0.0682, 0.186). EETS was well correlated with DPR (R 2 =0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy..
58. Koji Todaka, Junji Kishimoto, Masayuki Ikeda, Koji Ikeda, Haruko Yamamoto, Impact of Risk-Benefit Perception and Trust on Medical Technology Acceptance in Relation to Drug and Device Lag
A Tripartite Cross-Sectional Survey, Therapeutic Innovation and Regulatory Science, 10.1177/2168479017739267, 52, 5, 629-640, 2017.01, Background: New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets. Methods: A tripartite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included. Results: Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US (P <.01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as “useful,” “acceptable,” and “trustworthy,” whereas Japan was clustered with intermediate to negative responses such as “neither” and “untrustworthy.” Conclusions: Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan..
59. Eiji Iwama, K. Sakai, K. Azuma, T. Harada, D. Harada, K. Nosaki, K. Hotta, F. Ohyanagi, T. Kurata, T. Fukuhara, H. Akamatsu, K. Goto, T. Shimose, Junji Kishimoto, Yoichi Nakanishi, K. Nishio, Isamu Okamoto, Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations, Annals of Oncology, 10.1093/annonc/mdw531, 28, 1, 136-141, 2017.01, Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number ( < 10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance..
60. Hitomi Mori, Makoto Kubo, Rin Yamaguchi, Reiki Nishimura, Tomofumi Osako, Nobuyuki Arima, Yasuhiro Okumura, Masayuki Okido, Mai Yamada, Masaya Kai, Junji Kishimoto, Yoshinao Oda, Masafumi Nakamura, The combination of PD-L1 expression and decreased tumorinfiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer, Oncotarget, 10.18632/oncotarget.14698, 8, 9, 15584-15592, 2017.01, This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PDL1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILslow tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PDL1- positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies..
61. Yasuto Yoneshima, Satoshi Morita, Masahiko Ando, Satoru Miura, Hiroshige Yoshioka, Tetsuya Abe, Terufumi Kato, Masashi Kondo, Yukio Hosomi, Katsuyuki Hotta, Nobuyuki Yamamoto, Junji Kishimoto, Yoichi Nakanishi, Isamu Okamoto, Treatment Rationale and Design for J-AXEL
A Randomized Phase 3 Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer, Clinical Lung Cancer, 10.1016/j.cllc.2016.08.003, 18, 1, 100-103, 2017.01, Background Nanoparticle albumin-bound (nab) paclitaxel is a promising new therapeutic agent for all histologic types of non–small-cell lung cancer (NSCLC). We recently performed a phase 2 study of weekly nab-paclitaxel in patients with previously treated advanced NSCLC, finding promising activity and acceptable toxicity for this regimen. We have now designed a randomized phase 3 intergroup study (J-AXEL, UMIN000017487) to examine the clinical benefit and safety of nab-paclitaxel compared to docetaxel in patients with previously treated advanced NSCLC. Patients and Methods Patients are randomized to receive either docetaxel (60 mg/m2 on day 1 every 3 weeks, control arm) or nab-paclitaxel (100 mg/m2 on days 1, 8, and 15 every 3 weeks, experimental arm), with each drug being administered until disease progression or unacceptable toxicity. The study will evaluate the noninferiority of nab-paclitaxel relative to docetaxel for the primary end point of overall survival. Conclusion If the primary objective is achieved, this study will provide evidence for a new alternative treatment option for patients with previously treated advanced NSCLC..
62. Hitomi Mori, Makoto Kubo, Reiki Nishimura, Tomofumi Osako, Nobuyuki Arima, Yasuhiro Okumura, Masayuki Okido, Mai Yamada, Masaya Kai, Junji Kishimoto, Tetsuyuki Miyazaki, Yoshinao Oda, Takao Otsuka, Masafumi Nakamura, BRCAness as a biomarker for predicting prognosis and response to anthracycline-based adjuvant chemotherapy for patients with triple-negative breast cancer, PloS one, 10.1371/journal.pone.0167016, 11, 12, 2016.12, Background Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. Methods The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. Results Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC. Conclusions The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracyclinebased adjuvant chemotherapy for patients with TNBCs..
63. Minoru Fukuda, Takayuki Suetsugu, Midori Shimada, Takeshi Kitazaki, Kohji Hashiguchi, Junji Kishimoto, Taishi Harada, Takashi Seto, Noriyuki Ebi, Koichi Takayama, Kenji Sugio, Hiroshi Semba, Yoichi Nakanishi, Yukito Ichinose, Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer
Results of Lung Oncology Group in Kyusyu (LOGIK1004B), Thoracic Cancer, 10.1111/1759-7714.12360, 7, 4, 467-472, 2016.07, Background: Uridine 5′-diphospho-glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods: Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m2; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0–2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results: UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/−, *6/−, −/− observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion: Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients..
64. Hiroshi Enaida, Akito Hirakata, Masahito Ohji, Kohji Nishida, Toshiaki Kubota, Nahoko Ogata, Kohei Sonoda, Makiko Uchiyama, Junji Kishimoto, Koji Todaka, Yoichi Nakanishi, Tatsuro Ishibashi, Efficacy and Safety of A0001 (Brilliant Blue G250) for Internal Limiting Membrane Staining and Peeling
Phase III Investigator-initiated Multicenter Clinical Trial, Nippon Ganka Gakkai zasshi, 120, 6, 439-448, 2016.06, PURPOSE: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy.
METHODS: Patients (n = 31) requiring ILM peeling during vitrectomy were enrolled in this clinical trial. After injection of A0001 (range: 0.0625 to 0. 125 mg), the staining grade and the peeling ease of the ILM were evaluated in five steps (levels 0 to 4). The safety of A0001 was investigated for 7 days after surgery.
RESULTS: From the evaluation of a primary endpoint by the Independent Data Monitoring Committee (IDMC) and a secondary endpoint by each surgeon, A0001 was effective in all cases at three or more levels ( ≥ level 2 was defined as effective) for evaluation of the grade of visualization and operating ease. Adverse events occurring in two or more cases included elevated intraocular pressure, eye pain, eye discharges, and retinal bleeding. One serious adverse event was a case of unclosed macular hole after vitrectomy, but the patient recovered after reoperation.
CONCLUSIONS: A0001 was effective and safe for visualization of the ILM during vitrectomy, and there was an improvement in ease of operation..
65. Kazuhiko Yamada, Koichi Azuma, Masafumi Takeshita, Junji Uchino, Chinatsu Nishida, Takayuki Suetsugu, Akira Kondo, Taishi Harada, Hirofumi Eida, Junji Kishimoto, Goki Eriguchi, Koichi Takayama, Yoichi Nakanishi, Kenji Sugio, Phase II trial of erlotinib in elderly patients with previously treated non-small cell lung cancer
Results of the lung oncology group in kyushu (LOGiK-0802), Anticancer research, 36, 6, 2881-2887, 2016.06, Background: As the incidence of lung cancer in the elderly is increasing worldwide, there exists a need to develop a clinically effective, less toxic therapy for this patient population. Although erlotinib has shown proven effectiveness against non-small cell lung cancer (NSCLC), few studies have prospectively investigated its application to elderly patients. Patients and Methods: Patients aged 75 years with advanced or recurrent NSCLC including wild-type EGFR who had previously received one or two chemotherapy regimens were enrolled in this trial. Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred. The primary endpoint was the objective response rate. Results: Forty patients were enrolled between May 2009 and January 2014..
66. Kimiaki Hashiguchi, Takato Morioka, Nobuya Murakami, Osamu Togao, Hiwatashi Akio, Masayuki Ochiai, Goki Eriguchi, Junji Kishimoto, Koji Iihara, Sequential morphological change of Chiari malformation type II following surgical repair of myelomeningocele, Child's Nervous System, 10.1007/s00381-016-3041-2, 32, 6, 1069-1078, 2016.06, Purpose: To document long-term morphological changes of Chiari type II malformation (CM-II) following closure of spina bifida manifesta (SBM). Methods: We retrospectively evaluated postnatal magnetic resonance images of the CM-II and posterior fossa (PF) in 28 consecutive cases. We measured changes in vertebral level and length of the cerebellar peg (CP), cerebrospinal fluid (CSF) spaces anterior and posterior to the cerebrospinal junction, PF area, and the anteroposterior diameters of the foramen magnum (FM) and C1 vertebra. We examined the morphological differences between the cases with and without ventriculoperitoneal (VP) shunting and derived predicted means by nonlinear mixed-effect modeling. Results: At birth, there were significant differences in CP length, PF area, and FM and C1 diameters between those who underwent VP shunting and those who did not. In cases with a CP below C1, VP shunting was required in every case but one. In those with visible CSF space at birth, VP shunts were not required. In 17 of 18 cases with a CP below C1, the vertebral level ascended by mean two vertebral levels (range 0–5 levels) within 4–6 months of delivery. In the remaining case, slowly progressive hydrocephalus and delayed CP descent required VP shunting at 8 months. Predicted mean CP length and FM and C1 diameters were greater in those who underwent VP shunting, but there was no difference in predicted mean PF area. Conclusion: The morphology of CM-II and the presence of hydrocephalus influence each other in children who have undergone postnatal SBM repair..
67. Mutsunori Murahashi, Yasuki Hijikata, Kazunari Yamada, Yoshihiro Tanaka, Junji Kishimoto, Hiroyuki Inoue, Tomotoshi Marumoto, Atsushi Takahashi, Toshihiko Okazaki, Kazuyoshi Takeda, Masakazu Hirakawa, Hiroshi Fujii, Shinji Okano, Masaru Morita, Eishi Baba, Kazuhiro Mizumoto, Yoshihiko Maehara, Masao Tanaka, Koichi Akashi, Yoichi Nakanishi, Koji Yoshida, Takuya Tsunoda, Kazuo Tamura, Yusuke Nakamura, Kenzaburo Tani, Phase I clinical trial of a five-peptide cancer vaccine combined with cyclophosphamide in advanced solid tumors, Clinical Immunology, 10.1016/j.clim.2016.03.015, 166-167, 48-58, 2016.05, We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4 days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4 weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies..
68. , Masaki Fujita, Takemasa Matsumoto, Yuuichi Inoue, Hiroshi Wataya, Koichi Takayama, Masayuki Ishida, Noriyuki Ebi, Junji Kishimoto, Yukito Ichinose, The efficacy and safety of cefepime or meropenem in the treatment of febrile neutropenia in patients with lung cancer. A randomized phase II study, Journal of Infection and Chemotherapy, 10.1016/j.jiac.2016.01.005, 22, 4, 235-239, 2016.04, Febrile neutropenia frequently develops after chemotherapy. There is little evidence to indicate the type of antimicrobial agents that should be used in the treatment of febrile neutropenia in patients with solid tumors. The objective is to determine the efficacy and safety of cefepime (CFPM) and meropenem (MEPM) in the treatment of febrile neutropenia in lung cancer patients in a prospective randomized study. FN patients with lung cancer were randomly divided into CFPM or MEPM groups. The primary end-point was the response rate. The secondary end-points were the defervescence rates at 72 h, 7 days, 14 days and the incidence of adverse events. Twenty-one patients were treated with CFPM and 24 patients were treated with MEPM. One patient died of FN. The CFPM treatment completion rate was 17.65% (95% CI; 0.00–35.77%), while the MEPM treatment completion rate was 38.10% (95% CI; 17.33–58.87%). The defervescence rates at 72 h, 7 days, and 14 days were 70.59%, 86.67%, and 100.00%, respectively in the CFPM group; and 65.00%, 84.21%, and 92.31% in the MEPM group. Adverse events were observed in 33.33% of the CFPM group and 45.83% of the MEPM group. The response rate of the CFPM group was 94.12% (95% CI; 73.02–98.95%), while that of the MEPM group was 85.71% (95% CI; 65.36–95.02%). No differences were found in the efficacy or safety of CFPM and MEPM in the treatment of febrile neutropenia in patients with lung cancer..
69. Katsuyuki Hotta, Jiichiro Sasaki, Sho Saeki, Nagio Takigawa, Kuniaki Katsui, Koichi Takayama, Naoyuki Nogami, Yoshiyuki Shioyama, Akihiro Bessho, Junji Kishimoto, Mitsune Tanimoto, Katsuyuki Kiura, Yukito Ichinose, Gefitinib Combined with Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non-Small-Cell Lung Cancer
The LOGIK0902/OLCSG0905 Intergroup Study Protocol, Clinical Lung Cancer, 10.1016/j.cllc.2015.08.004, 17, 1, 75-79, 2016.01, Herein, we describe an ongoing phase II trial in patients with locally advanced non-small-cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Patients with chemotherapy-naive locally advanced disease with active EGFR mutations will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease has not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m2) on days 1, 8, 29, and 36, and concurrent 3-dimensional conformal thoracic radiotherapy with a single daily fraction of 2 Gy, for 5 consecutive days each week to provide a total dose of 60 Gy. The primary end point is overall survival at 24 months. A target sample size of 21 evaluable patients is considered sufficient to validate an expected rate of 85%, and 60% would be the lower limit of interest, with 80% power and a 1-sided α of 5%. Secondary end points include toxicity, response rate, and overall survival. This study will clarify whether tyrosine kinase inhibitors targeted to EGFR can produce a maximal effect in selected NSCLC patients with the relevant driver mutation, even in the locally advanced setting..
70. Koichi Takayama, Shunichi Sugawara, Yasuo Saijo, Makoto Maemondo, Atsushi Sato, Shinzo Takamori, Taishi Harada, Tetsuro Sasada, Tatsuyuki Kakuma, Junji Kishimoto, Akira Yamada, Masanori Noguchi, Kyogo Itoh, Yoichi Nakanishi, Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer, Journal of Immunology Research, 10.1155/2016/1745108, 2016, 2016.01, Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m
on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed..
71. Mio Akiyama, Taro Mawatari, Yasuharu Nakashima, Hisaaki Miyahara, Hisakata Yamada, Ken Okazaki, Jun-Ichi Fukushi, Masakazu Kondo, Junji Kishimoto, Chinami Hashimura, Yukihide Iwamoto, Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment, Clinical Rheumatology, 10.1007/s10067-015-3049-0, 34, 11, 1867-1875, 2015.08, Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2 %, respectively, and the overall prevalence of dyslipidemia was 56.5 %. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity..
72. kazufumi kikuchi, Hiwatashi Akio, Osamu Togao, Koji Yamashita, Masami Yoneyama, Makoto Obara, Junji Kishimoto, Takashi Yoshiura, Hiroshi Honda, 3D MR Sequence Capable of Simultaneous Image Acquisitions with and without Blood Vessel Suppression
Utility in Diagnosing Brain Metastases, European Radiology, 10.1007/s00330-014-3496-z, 25, 4, 901-910, 2015.03, Objective: Volume isotropic simultaneous interleaved bright- and black-blood examination (VISIBLE) is a recently developed 3D MR sequence that provides simultaneous acquisitions of images with blood vessel suppression (Black) and images without it (Bright). Our purpose was to evaluate the usefulness of VISIBLE in detecting brain metastases.Methods: This prospective study included patients with suspected brain metastasis imaged with both VISIBLE and MPRAGE. From a data set, we compared the number of visualized blood vessels and the lesion-to-normal contrast-to-noise ratio (CNR) in 60 patients. We also performed an observer test to compare their diagnostic performance with VISIBLE, MPRAGE and only Black in 34 patients. Diagnostic performance was evaluated using a figure of merit (FOM), sensitivity, false-positive results per case (FPs/case) and reading time.Results: The number of vessels was significantly fewer in Black compared to MPRAGE and Bright (P < 0.0001). CNR was significantly higher with both Black and Bright than with MPRAGE (P < 0.005). In the observer test, significantly higher sensitivity (P < 0.0001) and FOM (P < 0.0001), significantly shorter reading time (P = 0.0001) and similar FPs/case were achieved with VISIBLE compared to MPRAGE. Compared to only Black, VISIBLE resulted in comparable sensitivity, but significantly fewer FPs/case (P = 0.0008).Conclusion: VISIBLE can improve radiologists’ diagnostic performance for brain metastasis.Key Points: • VISIBLE can achieve higher sensitivity and shorter reading time than MPRAGE.• VISIBLE can achieve lower false-positive rates than blood vessel suppressed images.• Compared to MPRAGE, VISIBLE can improve diagnostic performance for brain metastasis..
73. Eiji Iwama, Koichi Takayama, Taishi Harada, Isamu Okamoto, Fumihiko Ookubo, Junji Kishimoto, Eishi Baba, Yoshinao Oda, Yoichi Nakanishi, Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR, Oncotarget, 10.18632/oncotarget.4058, 6, 24, 20466-20473, 2015.01, The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre- and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance..
74. Emi Yamada, Katsuya Ogata, Junji Kishimoto, Mutsuhide Tanaka, Tomokazu Urakawa, Takao Yamasaki, Shozo Tobimatsu, Neural substrates of species-dependent visual processing of faces
Use of morphed faces, Physiological Reports, 10.14814/phy2.12387, 3, 5, 2015.01, Face identification and categorization are essential for social communication. The N170 event-related potential (ERP) is considered to be a biomarker of face perception. To elucidate the neural basis of species-dependent face processing, we recorded 128-ch high-density ERPs in 14 healthy adults while they viewed the images of morphed faces. The morphed stimuli contained different proportions of human and monkey faces, and the species boundary was shifted away from the center of the morph continuum. Three experiments were performed to determine how task requirement, facial orientation, and spatial frequency (SF) of visual stimuli affected ERPs. In an equal SF condition, the latency, and amplitude of the occipital P100 for upright faces were modulated in a monotonic-like fashion by the level of morphing. In contrast, the N170 latency for upright faces was modulated in a step-like fashion, showing a flexion point that may reflect species discrimination. Although N170 amplitudes for upright faces were not modulated by morph level, they were modulated in a monotonic-like fashion by inverted faces. The late positive (LP) component (350–550 msec) in the parietal region was modulated in a U-shaped function by morph level during a categorization task, but not in a simple reaction task. These results suggest that P100 reflects changes in the physical properties of faces and that N170 is involved in own-species selectivity. The LP component seems to represent species categorization that occurs 350 msec after stimulus onset..
75. Daisuke Kakihara, Akihiro Nishie, Noboru Harada, Ken Shirabe, Tsuyoshi Tajima, Yoshiki Asayama, Kosei Ishigami, Tomohiro Nakayama, Yukihisa Takayama, Daisuke Okamoto, nobuhiro fujita, Junji Kishimoto, Hiroshi Honda, Performance of gadoxetic acid-enhanced MRI for detecting hepatocellular carcinoma in recipients of living-related-liver-transplantation
Comparison with dynamic multidetector row computed tomography and angiography-assisted computed tomography, Journal of Magnetic Resonance Imaging, 10.1002/jmri.24454, 40, 5, 1112-1120, 2014.11, Purpose: To clarify the diagnostic performance of gadoxetic acid-enhanced MRI for the detection of hepatocellular carcinoma (HCC) in recipients of living related-liver transplantation (LRLT).
Materials and Methods: This retrospective study group consisted of 15 patients with 61 HCCs who each underwent multidetector row computed tomography (MDCT), gadoxetic acid-enhanced MRI, and angiography-assisted computed tomography (CT) before LRLT. The three modalities were compared for their ability to detect HCC. Two blinded readers independently reviewed the images obtained by each modality for the presence of HCC on a segment-by-segment basis using a 5-point confidence scale. The diagnostic performance of the modalities was evaluated in a receiver operating characteristic (ROC) analysis. The area under the ROC curve (Az), sensitivity, specificity, and accuracy were compared for the three modalities.
Results: No significant difference in Az, sensitivity, specificity, or accuracy was obtained among gadoxetic acidenhanced MRI, MDCT, and angiography-assisted CT for both readers. For reader 1, the sensitivity (55.6%) and the accuracy (84.7%) of angiography-assisted CT were significantly higher than those of MDCT (33.3% and 78.0%) (P < 0.05).
Conclusion: Gadoxetic acid-enhanced MRI has a relatively high diagnostic ability to detect HCC even in recipients of LRLT, equivalent to the abilities of MDCT and angiography-assisted CT..
76. Ayami Tsuchimoto, Haruka Shinke, Miwa Uesugi, Mio Kikuchi, Emina Hashimoto, Tomoko Sato, Yasuhiro Ogura, Koichiro Hata, Yasuhiro Fujimoto, Toshimi Kaido, Junji Kishimoto, Motoko Yanagita, Kazuo Matsubara, Shinji Uemoto, Satohiro Masuda, Urinary neutrophil gelatinase-associated lipocalin
A useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients, PloS one, 10.1371/journal.pone.0110527, 9, 10, 2014.10, Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800-0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p= 0.0446) and day 7 (p=0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients..
77. Riichiroh Maruyama, Noriyuki Ebi, Junji Kishimoto, Masato Kato, Tokujiro Yano, Yoshinori Nagamatsu, Shuichi Tsukamoto, Shinji Akamine, Sho Saeki, Yukito Ichinose, A feasibility trial of postoperative adjuvant chemotherapy with S-1, an oral fluoropyrimidine, for elderly patients with non-small cell lung cancer
A report of the Lung Oncology Group in Kyushu (LOGIK) protocol 0901, International Journal of Clinical Oncology, 10.1007/s10147-013-0516-y, 19, 1, 57-62, 2014.02, Background: The present study was designed to determine whether adjuvant chemotherapy with S-1 after surgical resection is feasible in elderly patients with non-small cell lung cancer (NSCLC), using a multi-institutional trial. Methods: From July 2009 to July 2011, 25 patients received the following regimen: 2 weeks of administration and 1 week of withdrawal of S-1 at 50-100 mg/body per day in an outpatient setting. The primary endpoint of this trial was the completion rate of eight cycles. Results: The completion rate of eight cycles was 70.8 % [95 % confidence interval (CI) 52.7-89.0 %]. The perfect completion rate of eight cycles on schedule with full doses without delays was 50 % (95 % CI 30.0-70.0 %). The reasons for incomplete cycles were: patient refusal in four cases, anorexia in two cases and thrombocytopenia in one case. As a consequence of delays and/or dose reductions, the relative dose intensity of S-1 was 76.3 %. Conclusions: Adjuvant chemotherapy with S-1 at a reduced dose and schedule was therefore found to be a feasible treatment for elderly Japanese patients who had undergone surgical resection for NSCLC (UMIN Clinical Trials Registry number UMIN000002383)..
78. Kazu Kobayakawa, Hiromi Kumamaru, Hirokazu Saiwai, Kensuke Kubota, Yasuyuki Ohkawa, Junji Kishimoto, Kazuya Yokota, Ryosuke Ideta, Keiichiro Shiba, Hidetoshi Saitoh, Kazuhide Inoue, Yukihide Iwamoto, Seiji Okada, Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans, Science Translational Medicine, 10.1126/scitranslmed.3009430, 6, 256, 2014.01, Spinal cord injury (SCI) is a devastating disorder for which the identification of exacerbating factors is urgently needed. We demonstrate that transient hyperglycemia during acute SCI is a detrimental factor that impairs functional improvement in mice and human patients after acute SCI. Under hyperglycemic conditions, both in vivo and in vitro, inflammation was enhanced through promotion of the nuclear translocation of the nuclear factor κB (NF-κB) transcription factor in microglial cells. During acute SCI, hyperglycemic mice exhibited progressive neural damage, with more severe motor deficits than those observed in normoglycemic mice. Consistent with the animal study findings, a Pearson χ2 analysis of data for 528 patients with SCI indicated that hyperglycemia on admission (glucose concentration ≥126 mg/dl) was a significant risk predictor of poor functional outcome. Moreover, a multiple linear regression analysis showed hyperglycemia at admission to be a powerful independent risk factor for a poor motor outcome, even after excluding patients with diabetes mellitus with chronic hyperglycemia (regression coefficient, -1.37; 95% confidence interval, -2.65 to -0.10; P < 0.05). Manipulating blood glucose during acute SCI in hyperglycemic mice rescued the exacerbation of pathophysiology and improved motor functional outcomes. Our findings suggest that hyperglycemia during acute SCI may be a useful prognostic factor with a negative impact on motor function, highlighting the importance of achieving tight glycemic control after central nervous system injury..
79. Hiroyuki Daida, Ryuji Nohara, Mitsumasa Hata, Kohei Kaku, Ryuzo Kawamori, Junji Kishimoto, Masahiko Kurabayashi, Izuru Masuda, Ichiro Sakuma, Tsutomu Yamazaki, Hiroyoshi Yokoi, Masayuki Yoshida, Can intensive lipid-lowering therapy improve the carotid Intima-media thickness in Japanese subjects under primary prevention for cardiovascular disease?
The JART and JART extension subanalysis, Journal of atherosclerosis and thrombosis, 10.5551/jat.19109, 21, 7, 739-754, 2014.01, Aim: This subanalysis aimed to clarify whether intensive lipid-lowering therapy with statins slows the progression of atherosclerosis in Japanese subjects under treatment for primary prevention of cardiovascular disease. Methods: This was a subanalysis of the Justification for Atherosclerosis Regression Treatment (JART) Study. We compared the efficacy of intensive lipid-lowering therapy and conventional therapy with respect to changes in the mean intima-media thickness (IMT) and serum lipid levels. We also evaluated changes in the mean IMT over 24 months of treatment and assessed the relationship between these changes and reductions in the LDL-C levels using a post-hoc analysis. Results: Intensive lipid-lowering therapy with rosuvastatin was associated with significantly smaller changes in the mean IMT and a greater reduction in the serum lipid levels in comparison to conventional therapy with pravastatin. The average net change in the mean IMT was 0.010 mm (n= 121) at 12 months and -0.004 mm (n= 56) at 24 months. A decrease in LDL-C was found to be associated with a smaller change in the mean IMT (p=0.0009; Jonckheere-Terpstra trend test). A greater reduction in serum LDL-C was found to be associated with a smaller change in the mean IMT. Similar associations were observed for the serum TC and non-HDL-C levels and LDL-C/HDL-C ratio. There were no notable differences in the incidence of serious adverse events among the LDL-C quartiles. Conclusions: Lowering the LDL-C level with intensive lipid-lowering therapy is associated with reduced changes in the IMT among Japanese subjects at moderate to high risk under treatment for primary prevention. Subjects suitable for primary prevention may receive cardiovascular benefits from intensive lipid-lowering therapy, in association with significantly slower IMT progression than that observed with conventional therapy..
80. Hiroyoshi Yokoi, Ryuji Nohara, Hiroyuki Daida, Mitsumasa Hata, Kohei Kaku, Ryuzo Kawamori, Junji Kishimoto, Masahiko Kurabayashi, Izuru Masuda, Ichiro Sakuma, Tsutomu Yamazaki, Masayuki Yoshida, Change in carotid intima-media thickness in a high-risk group of patients by intensive lipid-lowering therapy with rosuvastatin subanalysis of the JART study, International heart journal, 10.1536/ihj.13-216, 55, 2, 146-152, 2014.01, Carotid intima-media thickness (IMT), a measure of atherosclerosis, is modulated by multiple risk factors. Accordingly, comprehensive control of risk factors is indispensable for management of atherosclerosis. In this study, as a posthoc analysis of the JART Study we planned two analyses. In the main analysis, we evaluated the effect of intensive lipidlowering therapy with rosuvastatin on carotid IMT in high-risk patients. We also evaluated effi cacy in the presence or absence of each risk factor using the full analysis population in the JART Study. Patients with low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL and max-IMT ≥ 1.1 mm were randomized to rosuvastatin or pravastatin therapy for 12 months. Dosages were allowed to increase to 10 mg/day and 20 mg/day to achieve LDL-goals (aggressive goals for rosuvastatin group and guideline goals for pravastatin group). For the main analysis, we assessed 200 high-risk patients (105 in the rosuvastatin group), as category III or secondary prevention according to the Japan Atherosclerosis Society guideline 2007, whereas we assessed 289 patients in the other analysis. Rosuvastatin signifi cantly slowed the percentage change in mean-IMT at 12 months compared with pravastatin (1.40 ± 10.03% versus 6.43 ± 13.77%, P = 0.005). LDLC was reduced by 48.1% in the rosuvastatin group and 27.9% in the pravastatin group. The rate of achieving the LDL-C goal was signifi cantly greater in the rosuvastatin group compared with the pravastatin group (P < 0.001). Rosuvastatin slowed the change in mean-IMT in the presence of every risk factor. Thus, intensive lipid-lowering therapy reduced progression of carotid IMT in high-risk patients..
81. kina miyoshi, Kenichi Kouhashi, Fumiyoshi Fushimi, Hidetaka Yamamoto, Junji Kishimoto, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda, Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma, Human Pathology, 10.1016/j.humpath.2014.05.012, 45, 9, 1900-1909, 2014.01, Summary CXC chemokine receptor 4 (CXCR4) expression is reportedly correlated with both vascular endothelial growth factor (VEGF) expression and poor prognosis in a variety of cancers. Its relation to CXC chemokine receptor 7 (CXCR7) is also noted in several malignancies, including rhabdomyosarcoma (RMS) cell lines. However, the correlations between these chemokine receptors and angiogenic factors have not yet been adequately investigated in RMS clinical specimens. By immunohistochemistry, we assessed CXCR4, CXCR7, CC chemokine receptor 6, CC chemokine receptor 7, VEGF expression, microvessel density, and MIB-1 labeling index in 82 formalin-fixed RMS specimens, including 34 primary alveolar RMS and 44 primary embryonal RMS (ERMS). Twenty-six frozen samples were available for investigation by quantitative reverse transcription polymerase chain reaction to detect the messenger RNA expression levels of these molecules. We also evaluated their significance with respect to clinicopathological factors and patient survival rates. Primary RMS showed high expression of CXCR7 (83.1%) regardless of the histologic subtype. High cytoplasmic CXCR4 and high VEGF expression revealed significant correlations in both ERMS and alveolar RMS (P =.0051 and P =.0003, respectively). By univariate analysis of ERMS cases, the tumors with high VEGF expression showed significantly poor prognoses (P =.0017). High VEGF expression also was the independent adverse prognostic factor for ERMS. Because CXCR4, CXCR7, and VEGF are widely expressed in RMS, the combination of these antagonists may provide a potential target for molecular therapy..
82. Masanori Kobayashi, Shigetaka Shimodaira, Kazuhiro Nagai, Masahiro Ogasawara, Hidenori Takahashi, Hirofumi Abe, Mitsugu Tanii, Masato Okamoto, Sun Ichi Tsujitani, Seiichi Yusa, Takefumi Ishidao, Junji Kishimoto, Yuta Shibamoto, Masaki Nagaya, Yoshikazu Yonemitsu, Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy
A multicenter analysis, Cancer Immunology, Immunotherapy, 10.1007/s00262-014-1554-7, 63, 8, 797-806, 2014.01, Objective: Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. Methods: Of 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed. Results: The mean survival time from diagnosis was 16.5 months (95 % CI 14.4-18.5) and that from the first vaccination was 9.9 months (95 % CI 8.0-12.9). Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and the prognostic nutrition index, were also representative. Importantly, we found that erythema reaction after vaccination was an independent and treatment-related prognostic factor for better survival and that OK-432 might be a good adjuvant enhancing the antitumor immunity during DC vaccination. Conclusions: This is the first report of a multicenter clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy. These findings need to be addressed in well-controlled prospective randomized trials..
83. Chika Iwamoto, Katsuto Takenaka, Shingo Urata, takuji yamauchi, Takahiro Shima, Takuro Kuriyama, Shinya Daitoku, Yasuyuki Saito, Toshihiro Miyamoto, Hiromi Iwasaki, Issay Kitabayashi, Katsuhiko Itoh, Junji Kishimoto, Daisuke Kohda, Takashi Matozaki, Koichi Akashi, The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment, Experimental Hematology, 10.1016/j.exphem.2013.11.005, 42, 3, 163-171.e1, 2014.01, It has been shown that in xenotransplantation of human cells into immunodeficient mice, the mouse strain background is critical. For example, the nonobese diabetic (NOD) strain is most efficient, the BALB/c is moderate, and the C57BL/6 is inefficient for human cell engraftment. We have shown that the NOD-specific polymorphism of the signal regulatory protein-alpha (Sirpa) allows NOD SIRPA to bind human CD47, and the resultant "don't eat me" signaling by this binding prevents host macrophages to engulf human grafts, thereby inhibiting rejection. Here we tested whether the efficient xenotransplantation capability of the BALB/c strain is also mediated by the SIRPA-CD47 self-recognition system. BALB/c SIRPA was capable of binding to human CD47 at an intermediate level between those of C57BL/6 SIRPA and NOD SIRPA. Consistent with its binding activity, BALB/c-derived macrophages exhibited a moderate inhibitory effect on human long-term culture-initiating cells in in vitro cultures, and showed moderate phagocytic activity against human hematopoietic stem cells. The increased affinity of BALB/c SIRPA for human CD47 was mounted at least through the BALB/c-specific L29V SNP within the IgV domain. Thus, the mouse strain effect on xenogeneic engraftment might be ascribed mainly to the binding affinity of strain-specific polymorphic SIRPA with human CD47. This information should be useful for developing a novel immunodeficient strain with superior efficiency for xenogeneic transplantation of human cells..
84. Jiro Ikeda, Toshihiro Ichiki, Hirohide Matsuura, E. Inoue Eriko, Junji Kishimoto, Aya Watanabe, Chikahiro Sankoda, Shiro Kitamoto, Tomotake Tokunou, Kotaro Takeda, Guo Hua Fong, Kenji Sunagawa, Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling, Journal of the American Heart Association, 10.1161/JAHA.113.000174, 2, 3, 2013.09, Background--Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-a (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling. Methods and Results--Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/ Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-b and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-a synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features Conclusions--Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling..
85. Masato Takii, Yasuko Uchigata, Junji Kishimoto, Akira Okada, Masahiro Matsumoto, Chihiro Morita, Tomokazu Hata, Takehiro Nozaki, Keisuke Kawai, Nobuyuki Sudo, The reliability and validity of a newly developed scale for measuring a negative cognition towards diabetes, Journal of the Japan Diabetes Society, 56, 8, 560-569, 2013.08, No studies have been conducted regarding a negative cognition towards diabetes, and there are currently no psychological tests to measure it. To address this problem, we developed and tested the "Diabetes Negative Cognition Scale" (DNCS) for reliability and validity. A preliminary questionnaire of 111 items was distributed to 200 patients with type 1 diabetes and 310 patients with type 2 diabetes. Five psychological tests were also administered, and demographic and medical data were collected. A cluster procedure of variance analysis identified seven clusters: "Absence of a reason for living," "Burden of diabetes," "Distrust toward medical treatment," "Watching and meddling by surrounding people," "Sense of alienation," "Rejection of antidiabetic drugs or insulin" and "Pressure related to diabetic self-management" In total, the DNCS has 26 items. The validity of this scale was demonstrated by a good factor structure and higher DNCS scores among the patients with poor glycemic control. The reliability of the scale was demonstrated by the good internal consistency of Cronbach's α and the high consistency in the test-retest method..
86. Toshihiko Maekawa, Satomi Katsuki, Junji Kishimoto, Toshiaki Onitsuka, Katsuya Ogata, Takao Yamasaki, Takefumi Ueno, Shozo Tobimatsu, Shigenobu Kanba, Altered visual information processing systems in bipolar disorder
Evidence from visual MMN and P3, Frontiers in Human Neuroscience, 10.3389/fnhum.2013.00403, JUL, 2013.07, Objective: Mismatch negativity (MMN) and P3 are unique ERP components that rovide objective indices of human cognitive functions such as short-term memory and rediction. Bipolar disorder (BD) is an endogenous psychiatric disorder characterized y extreme shifts in mood, energy, and ability to function socially. BD patients usually how cognitive dysfunction, and the goal of this study was to access their altered visual nformation processing via visual MMN (vMMN) and P3 using windmill pattern stimuli. ethods: Twenty patients with BD and 20 healthy controls matched for age, gender, nd handedness participated in this study. Subjects were seated in front of a monitor and listened to a story via earphones. Two types of windmill patterns (standard and deviant) and white circle (target) stimuli were randomly presented on the monitor. All stimuli were presented in random order at 200-ms durations with an 800-ms inter-stimulus interval. Stimuli were presented at 80% (standard), 10% (deviant), and 10% (target) probabilities. The participants were instructed to attend to the story and press a button as soon as possible when the target stimuli were presented. Event-related potentials were recorded throughout the experiment using 128-channel EEG equipment. vMMN was obtained by subtracting standard from deviant stimuli responses, and P3 was evoked from the target stimulus. Results: Mean reaction times for target stimuli in the BD group were significantly higher than those in the control group. Additionally, mean vMMN-amplitudes and peak P3-amplitudes were significantly lower in the BD group than in controls. Conclusions: Abnormal vMMN and P3 in patients indicate a deficit of visual information processing in bipolar disorder, which is consistent with their increased reaction time to visual target stimuli..
87. Jiro Ikeda, Toshihiro Ichiki, Hirohide Matsuura, Eriko Inoue, Junji Kishimoto, Aya Watanabe, Chikahiro Sankoda, Shiro Kitamoto, Tomotake Tokunou, Kotaro Takeda, Guo Hua Fong, Kenji Sunagawa, Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling., Journal of the American Heart Association, 2, 3, 2013.06, Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-α (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling. Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-α synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features. Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling..
88. Kazuhiko Yamada, Koichi Takayama, Satoru Kawakami, Kouichi Saruwatari, Ryotaro Morinaga, Taishi Harada, Naoko Aragane, Shuya Nagata, Junji Kishimoto, Yoichi Nakanishi, Yukito Ichinose, Phase II trial of erlotinib for Japanese patients with previously treated non-small-cell lung cancer harboring EGFR mutations
Results of lung oncology group in Kyushu (LOGiK0803), Japanese journal of clinical oncology, 10.1093/jjco/hyt056, 43, 6, 629-635, 2013.06, Objective: Erlotinib has been reported to be useful for treatment of non-small-cell lung cancer harboring mutation of the epidermal growth factor receptor gene EGFR-mt. However, no prospective trial has yet assessed the utility of erlotinib in Japanese patients. Methods: Patients with EGFR-mt (exon 19/21) non-small-cell lung cancer who had previously received one to two chemotherapy regimens were enrolled in this trial. Erlotinib was initially administered at a dose of 150 mg/day orally until disease progression or unacceptable toxicities occurred. The primary endpoint was the objective response rate. Results: Twenty-six patients were enrolled between February 2009 and January 2011. Objective response was observed in 14 patients (53.8%, 95% confidence interval: 33.4-73.4%), and the disease control rate reached 80.8% (95% confidence interval: 60.7-93.5%). After a median follow-up time of 17.3 months (range: 5.8-29.5 months), the median progression- free survival was 9.3 months (95% confidence interval: 7.6-11.6 months). The median survival time is yet to be determined. Major toxicities were skin disorder and liver dysfunction; most episodes were grade 2 or less, and all were tolerable. Only one patient with grade 3 skin rash discontinued the study. No patients developed interstitial lung disease, and there were no treatment-related deaths. Conclusions: This prospective study is the first to have investigated the usefulness of erlotinib in Japanese patients with previously treated EGFR-mt non-small-cell lung cancer. Although this trial could not meet the primary endpoint, erlotinib was well tolerated and showed clinical benefit such as promising disease control rate or progression-free survival in this population, similar to gefitinib..
89. Ryuji Nohara, Hiroyuki Daida, Mitsumasa Hata, Kohei Kaku, Ryuzo Kawamori, Junji Kishimoto, Masahiko Kurabayashi, Izuru Masuda, Ichiro Sakuma, Tsutomu Yamazaki, Hiroyoshi Yokoi, Masayuki Yoshida, Effect of long-term intensive lipid-lowering therapy with rosuvastatin on progression of carotid intima-media thickness
Justification for atherosclerosis regression treatment (JART) extension study, Circulation Journal, 10.1253/circj.CJ-12-1149, 77, 6, 1526-1533, 2013.05, Background: Recently, it was reported from the Justification for Atherosclerosis Regression Treatment (JART) Study that intensive therapy with rosuvastatin significantly slowed progression of carotid intima-media thickness (IMT) compared with conventional therapy with pravastatin at 12 months. To assess the long-term efficacy of intensive therapy, the present extension study was conducted. Methods and Results: Subjects in the intensive therapy group of the JART Study were asked to participate in the extension study and to continue rosuvastatin treatment. A total of 113 subjects were enrolled into the extension study and were included in the analysis. At 24 months, the mean daily dose of rosuvastatin (± SD) was 7.9±2.9 mg. Mean change in mean IMT was -0.005 mm (range, -0.024 to 0.015 mm) at 24 months (P=0.633, compared with baseline). Rosuvastatin lowered low-density lipoprotein cholesterol (mean ± SD) by 46.4±13.8% and elevated high-density li-poprotein cholesterol (mean ± SD) by 8.9±24.0% at 24 months compared with baseline. Gray scale median was measured in 25 subjects. It increased by 16.93±33.12 (mean ± SD) % at 12 months and by 22.50±52.83% at 24 months from baseline (P=0.017, P=0.044, respectively). Conclusions: Two-year treatment with rosuvastatin inhibited progression of carotid IMT. Rosuvastatin also improved the plaque composition, and this qualitative change occurred relatively early after starting therapy..
90. Hidenori Takahashi, Masato Okamoto, Shigetaka Shimodaira, Shun Ichi Tsujitani, Masaki Nagaya, Takefumi Ishidao, Junji Kishimoto, Yoshikazu Yonemitsu, Impact of dendritic cell vaccines pulsed with Wilms' tumour-1 peptide antigen on the survival of patients with advanced non-small cell lung cancers, European Journal of Cancer, 10.1016/j.ejca.2012.11.005, 49, 4, 852-859, 2013.03, Purpose: Dendritic cell (DC)-based vaccines have been expected to serve as new therapeutic approaches for advanced non-small cell lung cancers (NSCLCs); however, their clinical outcomes have not been fully elucidated. We report a single-centre clinical study analysing factors affecting the survival of patients with advanced NSCLCs who received DC vaccines pulsed with or without Wilms' tumour protein-1 (WT1) peptide. Methods: Among 62 patients with previously treated inoperable or postoperatively relapsed NSCLCs who met the inclusion criteria, DCs from 47 (76%) patients who showed HLA-A2402/0201/0206 were pulsed with one or more corresponding WT1 peptide antigens. DC vaccines were intradermally injected biweekly. Results: Clinical responses based on response evaluation criteria in solid tumours (RECIST) were found in 31 (50%) patients at 3 months after the first DC vaccine (complete response: 1 (1.6%), partial response: 4 (6.5%), stable disease: 26 (41.9%)). Median survival time was 27 months (82% in 1 year and 54% in 2 years) from initial diagnosis, and that was 12 months (48% in 1 year and 22% in 2 years) from the first DC vaccination. Importantly, multivariate analyses revealed that only two factors, blood haemoglobin and the use of WT1 peptides, significantly affected the overall survival of patients from both initial diagnosis and first vaccination. Conclusions: This study is the first to suggest that DC vaccines pulsed with WT1 may hold a significant impact to prolong the overall survival of patients with advanced NSCLCs..
91. Tsutomu Yamazaki, Ryuji Nohara, Hiroyuki Daida, Mitsumasa Hata, Kohei Kaku, Ryuzo Kawamori, Junji Kishimoto, Masahiko Kurabayashi, Izuru Masuda, Ichiro Sakuma, Hiroyoshi Yokoi, Masayuki Yoshida, Intensive lipid-lowering therapy for slowing progression as well as inducing regression of atherosclerosis in Japanese patients
Subanalysis of the JART study, International Heart Journal, 10.1536/ihj.54.33, 54, 1, 33-39, 2013.02, This paper describes a subanalysis of the JART Study comparing rosuvastatin and pravastatin treatment. A total of 314 subjects were analyzed in this subanalysis, 282 of whom were eligible for evaluation of the relationship between LDL-C and carotid mean-IMT change. In the subanalysis, we evaluated the extent to which intensive lipid-lowering therapy slowed the mean-IMT progression by a correlation analysis between LDL-C and mean-IMT change after 12 months of statin treatment. Nearly half were male (49.4%) and elderly (49.7%). The majority (84.4%) were treated for primary prevention. Patients with hypertension and diabetes mellitus accounted for 65.3% and 44.0%, respectively. At the 12-month measurement point, mean-IMT change was correlated with LDL-C (R = 0.187; P = 0.0016), LDL-C/ HDL-C ratio (R = 0.152; P = 0.0105), and non-HDL-C (R = 0.132; P = 0.0259). Mean-IMT after 12 months was divided into 4 subgroups by LDL-C at 12 months; < 80, ≥ 80 to < 100, ≥ 100 to < 120, and ≥ 120 mg/dL. A trend analysis using the Jonckheere-Terpstra test showed statistical significance (P = 0.0002). Even for prevention in Japanese patients who have lower risk of atherosclerotic disease than Western patients, lowering the LDL-C level to below the therapeutic target prevented mean-IMT progression after 12 months more strongly. These fi ndings suggest that more intensive control of LDL-C to levels lower than those in current JAS guidelines should be required to achieve slowing of progression as well as induction of regression of atherosclerosis..
92. Noriaki Tsukie, Kaku Nakano, Tetsuya Matoba, Seigo Masuda, Eiko Iwata, Miho Miyagawa, Gang Zhao, Wei Meng, Junji Kishimoto, Kenji Sunagawa, Kensuke Egashira, Pitavastatin-incorporated nanoparticle-eluting stents attenuate in-stent stenosis without delayed endothelial healing effects in a porcine coronary artery model, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.13862, 20, 1, 32-45, 2013.02, Aim: The use of currently marketed drug-eluting stents presents safety concerns including increased late thrombosis, which is thought to result mainly from delayed endothelial healing effects (impaired re-endothelialization resulting in abnormal inflammation and fibrin deposition). We recently developed a bioabsorbable polymeric nanoparticle (NP)-eluting stent using a novel cationic electrodeposition technology. Statins are known to inhibit the proliferation of vascular smooth muscle cells (VSMC) and to promote vascular healing. We therefore hypothesized that statin-incorporated NPeluting stents would attenuate in-stent stenosis without delayed endothelial healing effects. Methods: Among six marketed statins, pitavastatin (Pitava) was found to have the most potent effects on VSMC proliferation and endothelial regeneration in vitro. We thus formulated a Pitava-NP-eluting stent (20 μg Pitava per stent). Results: In a pig coronary artery model, Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as polymer-coated sirolimus-eluting stents (SES). At SES sites, delayed endothelial healing effects were noted, whereas no such effects were observed in Pitava-NP-eluting stent sites. Conclusion: Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as SES without the delayed endothelial healing effects of SES in a porcine coronary artery model. This nanotechnology platform could be developed into a safer and more effective device in the future..
93. Hitoshi Kusaba, Taito Esaki, Junji Kishimoto, Keita Uchino, Shuji Arita, Hozumi Kumagai, Kenji Mitsugi, Koichi Akashi, Eishi Baba, Phase i study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer, Cancer chemotherapy and pharmacology, 10.1007/s00280-012-2023-7, 71, 1, 29-34, 2013.01, Purpose: The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer. Methods: This study initially had been planned as a phase I/II study. Eighty mg/m2 of irinotecan on days 1 and 8, 80 mg/m2 of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level -1; 7.5 mg/kg) were administered on day 1 every 3 weeks. Results: Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity. Conclusions: This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer..
94. Takuro Kuriyama, Katsuto Takenaka, Kentaro Kohno, takuji yamauchi, Shinya Daitoku, Goichi Yoshimoto, Yoshikane Kikushige, Junji Kishimoto, Yasunobu Abe, Naoki Harada, Toshihiro Miyamoto, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis, Blood, 10.1182/blood-2012-02-408864, 120, 19, 4058-4067, 2012.11, Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development..
95. Kazuhiro Samura, Yasushi Miyagi, Tsuyoshi Okamoto, Takehito Hayami, Junji Kishimoto, Mitsuo Katano, Kazufumi Kamikaseda, Short circuit in deep brain stimulation, Journal of Neurosurgery, 10.3171/2012.8.JNS112073, 117, 5, 955-961, 2012.11, Object: The authors undertook this study to investigate the incidence, cause, and clinical influence of short circuits in patients treated with deep brain stimulation (DBS). Methods: After the incidental identification of a short circuit during routine follow-up, the authors initiated a policy at their institution of routinely evaluating both therapeutic impedance and system impendence at every outpatient DBS follow-up visit, irrespective of the presence of symptoms suggesting possible system malfunction. This study represents a report of their findings after 1 year of this policy. Results: Implanted DBS leads exhibiting short circuits were identified in 7 patients (8.9% of the patients seen for outpatient follow-up examinations during the 12-month study period). The mean duration from DBS lead implantation to the discovery of the short circuit was 64.7 months. The symptoms revealing short circuits included the wearing off of therapeutic effect, apraxia of eyelid opening, or dysarthria in 6 patients with Parkinson disease (PD), and dystonia deterioration in 1 patient with generalized dystonia. All DBS leads with short circuits had been anchored to the cranium using titanium miniplates. Altering electrode settings resulted in clinical improvement in the 2 PD cases in which patients had specific symptoms of short circuits (2.5%) but not in the other 4 cases. The patient with dystonia underwent repositioning and replacement of a lead because the previous lead was located too anteriorly, but did not experience symptom improvement. Conclusions: In contrast to the sudden loss of clinical efficacy of DBS caused by an open circuit, short circuits may arise due to a gradual decrease in impedance, causing the insidious development of neurological symptoms via limited or extended potential fields as well as shortened battery longevity. The incidence of short circuits in DBS may be higher than previously thought, especially in cases in which DBS leads are anchored with miniplates. The circuit impedance of DBS should be routinely checked, even after a long history of DBS therapy, especially in cases of miniplate anchoring..
96. Katsumi Miyauchi, Tsutomu Yamazaki, Hirotaka Watada, Yasushi Tanaka, Ryuzo Kawamori, Yutaka Imai, Shunya Ikeda, Akira Kitagawa, Yasuhiro Ono, Fumio Murayama, Jong Bock Choi, Satoru Suwa, Dobun Hayashi, Junji Kishimoto, Hiroyuki Daida, Management of home blood pressure by amlodipine combined with angiotensin II receptor blocker in type 2 diabetes, Circulation Journal, 10.1253/circj.CJ-11-1406, 76, 9, 2159-2166, 2012.09, Background: Angiotensin II receptor blocker (ARB) as a first-line drug for hypertension in diabetes often fails to control blood pressure adequately. The objective of the study was to evaluate the effect of amlodipine combined therapy on home blood pressure (HBP) useful for management of hypertension. Methods and Results: A total of 263 type 2 diabetes with hypertension refractory to standard dose of ARB were randomized to increased ARB regimen (n=132) or amlodipine combination regimen (n=131). The primary endpoint was change in morning HBP at 1 year. The combination regimen significantly lowered morning HBP than the increased ARB regimen (158.2/82.5 mmHg in the combination regimen, 157.3/84.4 mmHg in the increased ARB regimen, at baseline; 142.7/76.3 vs. 155.0/83.1 mmHg, respectively, P<0.001 for both, at 8 weeks; 139.6/74.6 vs. 149.1/78.1 mmHg, respectively, P<0.001 for systolic and P=0.010 for diastolic, at 1year). The combination regimen showed significantly higher rates of achieving target morning HBP at 8 weeks (11.3% vs. 2.7%, P=0.015). In the combination regimen, estimated glomerular filtration rate declined slower, and carotid intima-media thickness decreased in contrast to the increased ARB regimen. Conclusions: In type 2 diabetes patients with hypertension refractory to standard dose of ARB, the amlodipine combination regimen provides superior antihypertensive effect on HBP to the increased ARB regimen, and beneficial effects on reducing risks of cardiovascular events..
97. Daisuke Okamoto, Kengo Yoshimitsu, Akihiro Nishie, Tsuyoshi Tajima, Yoshiki Asayama, Kosei Ishigami, Masakazu Hirakawa, yasuhiro ushijima, Daisuke Kakihara, Tomohiro Nakayama, Yunosuke Nishihara, Shinichi Aishima, Akinobu Taketomi, Junji Kishimoto, Hiroshi Honda, Enhancement pattern analysis of hypervascular hepatocellular carcinoma on dynamic MR imaging with histopathological correlation
Validity of portal phase imaging for predicting tumor grade, European Journal of Radiology, 10.1016/j.ejrad.2011.02.056, 81, 6, 1116-1121, 2012.06, Purpose: To elucidate the correlation between hypervascular hepatocellular carcinoma (HCC) enhancement patterns on dynamic MR imaging and histological findings. Materials and methods: Surgically proven 46 hypervascular HCCs of forty-one patients were enrolled. For each HCC, the signal intensity in the portal phase (SIPP) was evaluated. In this study, high, iso-, or low intensity in the portal phase was hypothesized as late, moderate, or early washout pattern, respectively. The SIPP of each HCC was correlated to histological grade and architectural subtypes that represent degrees of trabecular structure. For the trabecular HCCs, the thickness of tumor plate was also correlated for indirect estimation of tumor sinusoid. Results: There was a significant correlation between the SIPP vs. histological grade and also vs. architectural subtypes, namely the degree of trabecular structure. Washout of hypervascular HCC occurred earlier as the histological grade advanced and the histological architecture got closer to pure trabecular HCC. For the trabecular HCCs, the thickness of tumor plate correlated significantly with SIPP or histological grade. Hypervascular HCCs with thicker tumor plates showed worse histological grade and earlier washout pattern. Conclusions: Histological grade of hypervascular HCC may be predicted using SIPP. The thickness of tumor plate, resultantly the size of sinusoid between tumor plates, can account for the relationship between washout pattern and histological grade in the trabecular HCCs..
98. Yasunao Mizuno, Junji Kishimoto, Nozomu Asukai, A nationwide random sampling survey of potential complicated grief in Japan, Death Studies, 10.1080/07481187.2011.553323, 36, 5, 447-461, 2012.05, To investigate the prevalence of significant loss, potential complicated grief (CG), and its contributing factors, we conducted a nationwide random sampling survey of Japanese adults aged 18 or older (N = 1,343) using a self-rating Japaneselanguage version of the Complicated Grief Brief Screen. Among them, 37.0% experienced their most significant loss by expected non-violent death, 17.9% by unexpected non-violent death, and 5.5% by violent death. The mean length of time since the loss was 11.9 years (SD = 11.6). The percentage of individuals with potential CG (5 or higher score on the scale) was 2.5% among those who experienced significant loss. The individuals with potential CG showed lower mental health scores than those without. Through regression analysis, we found the significant effects of gender difference, time since the loss, and the interaction of the mode of death, gender of the bereaved, and the kinship relationship to the deceased on the CG score. Women who had lost a child by sudden or violent death showed significantly higher CG scores, but men did not. By comparison, those (particularly men) who had lost a partner by expected or sudden nonviolent death showed significantly higher CG scores. The implications of the findings are discussed..
99. Yoichi Nakanishi, Junji Kishimoto, Management and Support of Clinical Trials in Clinical and Translational Research Center, Kyushu University Hospital, Japanese Pharmacology and Therapeutics, 40, SUPPL. 1, 2012.03.
100. Ryuji Nohara, Hiroyuki Daida, Mitsumasa Hata, Kohei Kaku, Ryuzo Kawamori, Junji Kishimoto, Masahiko Kurabayashi, Izuru Masuda, Ichiro Sakuma, Tsutomu Yamazaki, Hiroyoshi Yokoi, Masayuki Yoshida, Effect of intensive lipid-lowering therapy with rosuvastatin on progression of carotid intima-media thickness in Japanese patients, Circulation Journal, 10.1253/circj.CJ-11-0887, 76, 1, 221-229, 2012.01, Background: A recent trial in Western countries has shown that rosuvastatin slows progression of carotid intimamedia thickness (IMT) in patients with modest carotid IMT thickening and elevated levels of low-density lipoprotein cholesterol (LDL-C). We conducted a prospective, randomized, open-label, blinded-endpoint trial to determine whether rosuvastatin is more effective than pravastatin in slowing progression of carotid IMT in Japanese patients. Methods and Results: Adult patients with hypercholesterolemia who had a maximum IMT ≥?1.1 mm were randomly assigned to receive rosuvastatin or pravastatin. The primary endpoint was the percent change in the mean-IMT, which was measured by a single observer who was blinded to the treatment assignments. The trial was stopped on April 2011 according to the recommendation by the data and safety monitoring committee. A total of 348 patients (173 rosuvastatin; 175 pravastatin) were enrolled and 314 (159 rosuvastatin; 155 pravastatin) were included in the primary analysis. Mean (SD) percentage changes in the mean-IMT at 12 months were 1.91% (10.9) in the rosuvastatin group and 5.8% (12.0) in the pravastatin group, with a difference of 3.89% (11.5) between the groups (P=0.004). At 12 months, 85 patients (59.4%) in the rosuvastatin group achieved a LDL-C/high-density lipoprotein cholesterol ratio ≤ 1.5 compared with 24 patients (16.4%) in the pravastatin group (P<0.0001). Conclusions: Rosuvastatin significantly slowed progression of carotid IMT at 12 months compared with pravastatin..
101. Tsutomu Yamazaki, Junji Kishimoto, Chikako Ito, Mitsuhiko Noda, Masato Odawara, Yasuo Terauchi, Teruo Shiba, Hiroji Kitazato, Yasuhiko Iwamoto, Yasuo Akanuma, Takashi Kadowaki, Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance (the J-PREDICT study)
Rationale, study design, and clinical characteristics of 1269 patients, Diabetology International, 10.1007/s13340-011-0032-0, 2, 3, 134-140, 2011.10, Objective: The Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance (J-PREDICT study) is an open-label randomized controlled study in a population with impaired glucose tolerance (IGT) to evaluate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) pitavastatin on new onset of diabetes. Research design and methods: Patients with IGT by World Health Organization (WHO) criteria [2-h plasma glucose ≥140 and <200 mg/dl and fasting plasma glucose (FPG) <126 mg/dl] were randomly assigned in a 1:1 ratio to either the control group receiving lifestyle modification or the pitavastatin group receiving pitavastatin 1-2 mg/day in addition to lifestyle modification. The primary endpoint is cumulative incidence of diabetes based on the 75-g oral glucose tolerance test (OGTT). This study will be completed in March 2015. Results: A total of 1269 patients enrolled at 149 study sites in Japan were randomly assigned to two groups. The characteristics of these participants were: men 62. 4%, age ≥60 years 40. 8%, body mass index (BMI) ≥25 kg/m2 48. 3%, concomitant hypertension 44. 5%, and 2-h plasma glucose ≥170 mg/dl 36. 6%. This population had a mean FPG level of 104. 2 ± 10. 7 mg/dl, mean 2-h plasma glucose level of 163. 6 ± 17. 0 mg/dl, mean hemoglobin (Hb) A1c) level of 5. 85 ± 0. 37%, and mean low-density lipoprotein cholesterol (LDL-C) level of 129. 8 ± 23. 8 mg/dl at screening. Conclusions: The J-PREDICT study is a world first to evaluate the effect of a statin on the onset of diabetes as the primary endpoint and will providing useful information regarding the controversial effect of statins on new-onset of diabetes..
102. Katsuyuki Ando, Masakazu Haneda, Sadayoshi Ito, Naoki Kashihara, Koichi Node, Masaomi Nangaku, Tatsuo Shimosawa, Junji Kishimoto, Toshiro Fujita, Design and rationale of Japanese evaluation between formula of azelnidipine and amlodipine add on olmesartan to get antialbuminuric effect study (J-FLAG)
Evaluation of the antialbuminuric effects between calcium channel blocker with sympatholytic action in hypertensive patients with diabetes and albuminuria, Cardiovascular Drugs and Therapy, 10.1007/s10557-011-6309-5, 25, 4, 341-347, 2011.08, Purpose: Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine. Methods: A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8-16 mg/day) and amlodipine (2.5-5 mg/day) in olmesartan-treated hypertensive (blood pressure 130-180/80-110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥ 126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥ 30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment. Conclusions: The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy..
103. Katsuyuki Ando, Masakazu Haneda, Sadayoshi Ito, Naoki Kashihara, Koichi Node, Masaomi Nangaku, Tatsuo Shimosawa, Junji Kishimoto, Toshiro Fujita, Erratum
Design and rationale of japanese evaluation between formula of azelnidipine and amlodipine add on olmesartan to get antialbuminuric effect study (J-FLAG) : Ion of the antialbuminuric effects between calcium channel blocker with sympatholytic action in hypertensive patients with diabetes and albuminuria (Cardiovascular Drugs and Therapy (2011) 25 (365366) DOI 10.1007/s10557-011-6309-5)), Cardiovascular Drugs and Therapy, 10.1007/s10557-011-6315-7, 25, 4, 365-366, 2011.08.
104. Masato Takii, Yasuko Uchigata, Junji Kishimoto, Chihiro Morita, Tomokazu Hata, Takehiro Nozaki, Keisuke Kawai, Yasuhiko Iwamoto, Nobuyuki Sudo, Chiharu Kubo, The relationship between the age of onset of type 1 diabetes and the subsequent development of a severe eating disorder by female patients, Pediatric Diabetes, 10.1111/j.1399-5448.2010.00708.x, 12, 4 PART 2, 396-401, 2011.06, Objectives: To determine the age of onset of type 1 diabetes that is most closely related to the subsequent development of a severe eating disorder such as anorexia nervosa (AN) or bulimia nervosa (BN). Methods: Participants were 53 female type 1 diabetes patients with AN or BN referred to our outpatient clinic from the Diabetes Center of Tokyo Women's Medical University. Forty-nine female type 1 diabetes patients who regularly visited the Diabetes Center and had no eating disorder-related problems constituted the 'direct control' group, whereas 941 female patients who for the first time visited the Diabetes Center constituted the 'historical control' group. The kernel function method was used to generate a density estimation of the onset age of each group and the chi-square test was used to compare the distribution. Results: The control groups had similar density shapes for the onset age of type 1 diabetes, but both differed from the 'eating disorder' group. For onset age 7-18 yr, the density of the 'eating disorder' group was higher than those of the control groups, but for the younger and older onset ages the densities were lower. The 'eating disorder' group developed type 1 diabetes significantly more frequently than the 'historical control' group between 7 and 18 yr of age (χ2 = 9.066, p < 0.011). Conclusion: The development of type 1 diabetes in preadolescence or adolescence seems to place girls at risk for the subsequent development of AN or BN. Careful attention should be paid to these high-risk patients..
105. Mika Makimura, Kenji Ihara, Kanako Kojima-Ishii, Takafumi Nozaki, Kazuhiro Ohkubo, Hitoshi Kohno, Junji Kishimoto, Toshiro Hara, The signal transducer and activator of transcription 5B gene polymorphism contributes to the cholesterol metabolism in Japanese children with growth hormone deficiency, Clinical Endocrinology, 10.1111/j.1365-2265.2011.03980.x, 74, 5, 611-617, 2011.05, Summary Background and aims GH plays a significant role in the lipid metabolism. In this study, we focused on the JAK2 - signal transducer and activator of the transcription 5 (STAT5) pathway, which transmit the signals from the GH receptor, and selected the STAT5A/B gene as a candidate for the regulation of lipid metabolism in GH deficiency (GHD). Design and participants The study population comprised 83 children with idiopathic GHD. The serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and the non-HDL cholesterol (non-HDL-C) levels were monitored before and at 3, 6, 9 and 12 months after starting GH treatment. The height, weight, body mass index, and serum insulin-like growth factor-I (IGF-I) level were also measured before and 12 months after starting the GH treatment. For the genetic analysis of the STAT5A/B gene, five tag SNPs were selected using the tag SNP picker programme on the homepage of the HapMap project. The evaluation of promoter activity of the -44816A/G SNP in the STAT5B gene was performed by a luciferase assay in vitro. Results The TC and non-HDL-C levels were gradually decreased during the GH treatment. Five tag SNPs (rs4029774, rs6503691, rs9900213, rs16967637 and rs2272087) were picked up for the STAT5A/B gene, and the genetic study demonstrated that the paediatric GHD patients who were heterozygotes or homozygotes of minor alleles of the analysed SNPs in the same block of the STAT5B gene showed significantly higher serum TC or non-HDL-C levels both before and after GH treatment for 12 months. Most of the SNPs also demonstrated significant differences among genotypes in the decreases in serum TC or non-HDL-C levels during the 12 months of GH treatment. A luciferase assay showed that the -44816A/G SNP (rs4029774) in the STAT5B gene functionally affected the expression level in vitro. Conclusion These results indicate that STAT5B may therefore play a role in regulating the cholesterol metabolism in children with GHD..
106. Yoshitomo Maehata, Minako Hirahashi, Shinichi Aishima, Junji Kishimoto, Setsuo Hirohashi, Takashi Yao, Hiroshi Takashima, Masazumi Tsuneyoshi, Yoshinao Oda, Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion, Human Pathology, 10.1016/j.humpath.2010.08.016, 42, 4, 558-567, 2011.04, Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin-positive (≥50%) expression was higher in the mixed type (60.3%) than in the pure type (12.4%) (P < .0001), whereas the frequency of E-cadherin-negative (<50%) expression was higher in the mixed type (84.5%) than in the pure type (50.5%) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4%) was significantly higher than that in the primary tumors (45.7%) (P = .001). Dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be correlated with the mixed type. Combined dysadherin-positive (≥50%) expression and E-cadherin-negative (<50%) expression may be valuable information for predicting aggressive tumor behavior..
107. Toshiaki Watanabe, Tsuyoshi Konishi, Junji Kishimoto, Kenjiro Kotake, Tetsuichiro Muto, Kenichi Sugihara, Ulcerative colitis-associated colorectal cancer shows a poorer survival than sporadic colorectal cancer
A nationwide Japanese study, Inflammatory Bowel Diseases, 10.1002/ibd.21365, 17, 3, 802-808, 2011.03, Background: The clinicopathological features of ulcerative colitis-associated colorectal cancer (UC-CRC) have not yet been fully clarified, especially in Asian populations. This study aimed to clarify the prognosis and clinicopathological features of UC-CRC in comparison with sporadic CRC in the Japanese population. Methods: Histologically diagnosed UC-CRC patients between 1978 to 1998 were extracted from the Multi-Institutional Registry of Large-Bowel Cancer in Japan, a large nationwide CRC database, and the clinicopathological features and postoperative survival rates of UC-CRC patients and sporadic CRC patients were compared. Results: Among the 108,536 CRC patients registered between 1978 and 1998, a total of 169 UC-CRC patients were identified, including 121 patients who had been treated surgically. The proportion of UC-CRC patients increased in the period between 1995 and 1998 compared to that between 1978 and 1994. Comparisons with the sporadic CRC patients showed that the UC-CRC patients were younger, had a higher proportion of multiple cancer lesions, had higher proportions of superficial type lesions and invasive type lesions morphologically, and had higher proportions of mucinous or signet ring cell carcinomas. In stage III, UC-CRC patients had a poorer survival rate than the sporadic CRC patients (43.3% versus 57.4%, P = 0.0320). Conclusions: UC-CRC increased over the investigated time periods and showed a poorer survival than sporadic CRC in the advanced stage, while no difference was observed in the early stage. By detecting UC-CRC at an early stage we can expect a similar postoperative outcomes to that of sporadic CRC. These results stress the importance of surveillance for the early detection of UC-CRC. Inflamm Bowel Dis 2011.
108. Ling Chen, Kaku Nakano, Satoshi Kimura, Tetsuya Matoba, Eiko Iwata, Miho Miyagawa, Hiroyuki Tsujimoto, Kazuhiro Nagaoka, Junji Kishimoto, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension, Hypertension, 10.1161/HYPERTENSIONAHA.110.157032, 57, 2, 343-350, 2011.02, Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH..
109. Kohei Fujita, Hidetaka Yamamoto, Takayuki Matsumoto, Minako Hirahashi, Masaki Gushima, Junji Kishimoto, Ken Ichi Nishiyama, Tomoaki Taguchi, Takashi Yao, Yoshinao Oda, Sessile serrated adenoma with early neoplastic progression
A clinicopathologic and molecular study, American Journal of Surgical Pathology, 10.1097/PAS.0b013e318205df36, 35, 2, 295-304, 2011.02, Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, β-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of β-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear β-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and β-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma..
110. Izumi Nishimura, Yoshihiro Ohishi, Yoshinao Oda, Junji Kishimoto, Masafumi Yasunaga, Emi Okuma, Hiroaki Kobayashi, Norio Wake, Masazumi Tsuneyoshi, Expression and localization of E-cadherin and β-catenin in uterine carcinosarcoma, Virchows Archiv, 10.1007/s00428-010-1002-9, 458, 1, 85-94, 2011.01, This study was designed to analyze the subcellular localization of E-cadherin and β-catenin both of which play a critical role in cell-cell adhesion in uterine carcinosarcoma (UCS). We performed an immunohistochemical reaction analysis of the subcellular localization of E-cadherin and β-catenin proteins in 46 cases of UCSs consisting of 28 UCSs with heterologous sarcoma and 18 UCSs with homologous sarcoma and compared their clinicopathological features. In most UCSs, membranous expression of E-cadherin and β-catenin was completely lost in sarcomatous components, but it was preserved in carcinomatous components. Nuclear β-catenin expression was observed significantly more frequently in sarcomatous components (31/46, 67.4%) than in carcinomatous components (22/46, 47.8%; P=0.0025). In sarcomatous components, nuclear β-catenin expression was found significantly more frequently in heterologous sarcoma (23/28, 82.1%) than in homologous sarcoma (8/18, 44.4%; P=0.0279). The stage was the only independent prognostic significant factor. These results suggest that reduced membranous expression of E-cadherin and β-catenin may contribute to the biphasic morphology of UCS. Furthermore, although the precise mechanism is unclear, nuclear β-catenin expression in sarcomatous components may also be associated with biphasic morphology and heterologous sarcomatous differentiation..
111. Nozomu Asukai, Azusa Saito, Nobuko Tsuruta, Junji Kishimoto, Toru Nishikawa, Efficacy of exposure therapy for Japanese patients with posttraumatic stress disorder due to mixed traumatic events
A randomized controlled study, Journal of Traumatic Stress, 10.1002/jts.20589, 23, 6, 744-750, 2010.12, The authors examined the efficacy of Prolonged Exposure (PE) therapy in Japanese patients with posttraumatic stress disorder (PTSD). Twenty-four patients (21 women, 3 men) with PTSD due to mixed trauma were randomly assigned to the PE group (PE with or without treatment as usual [TAU]) or the control group (TAU) only. The control group received PE after a 10-week period. Intention-to-treat analysis showed the PE group achieved significantly greater reduction than the control group at posttreatment in either PTSD or depressive symptoms. The control group had significantly decreased symptom severity after PE treatment. Symptom levels of 19 PE completers in the both groups remained low in 12-month follow-up assessments. The study's findings will promote the future dissemination and implementation of evidence-based treatment for PTSD in non-Western settings..
112. Kohei Fujita, Minako Hirahashi, Hidetaka Yamamoto, Takayuki Matsumoto, Masaki Gushima, Yoshinao Oda, Junji Kishimoto, Takashi Yao, Mitsuo Iida, Masazumi Tsuneyoshi, Mucin core protein expression in serrated polyps of the large intestine, Virchows Archiv, 10.1007/s00428-010-0959-8, 457, 4, 443-449, 2010.10, Sessile serrated adenoma (SSA) has been proposed as a precursor to microsatellite-unstable colorectal carcinoma. However, histological criteria dictating how to differentiate serrated lesions have not been completely established, and a histological overlap exists between SSA and hyperplastic polyps (HPs), particularly the microvesicular type. In this study, based on a critical review of histology, we aimed to elucidate the potential utility of the mucin phenotype in the identification of SSA. We evaluated mucin core protein expression (MUC2, MUC5AC, and MUC6) by immunohistochemical stain in 65 cases of microvesicular-type HPs, 51 SSAs, and 72 traditional serrated adenomas (TSAs). SSAs had clinicopathological and morphological features distinct from those of HPs and TSAs. MUC6 was more frequently positive in SSAs (39%) than in TSAs (4%) and HPs (19%) (P∈<∈0.001 and P∈=∈0.0107, respectively). Right-sided HPs more frequently expressed MUC6 than did left-sided HPs (60% vs. 4%, respectively; P∈<∈0.0001), but SSAs and TSAs showed no regional differences. These findings suggest that determination of mucin core protein expression is insufficient for differentiating SSAs from other types of serrated polyps, and that microvesicular-type HPs of the right colon and SSAs may belong to the same mucin spectrum..
113. Seido Oku, Katsuto Takenaka, Takuro Kuriyama, Kotaro Shide, Takashi Kumano, Yoshikane Kikushige, Shingo Urata, takuji yamauchi, Chika Iwamoto, Haruko K. Shimoda, Toshihiro Miyamoto, Koji Nagafuji, Junji Kishimoto, Kazuya Shimoda, Koichi Akashi, JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation
Research paper, British Journal of Haematology, 10.1111/j.1365-2141.2010.08249.x, 150, 3, 334-344, 2010.08, Summary The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation..
114. Masahiko Kurabayashi, Ichiro Sakuma, Ryuzo Kawamori, Hiroyuki Daida, Tsutomu Yamazaki, Masayuki Yoshida, Mitsumasa Hata, Izuru Masuda, Kohei Kaku, Hiroyoshi Yokoi, Junji Kishimoto, Ryuji Nohara, Can intensive lipid-lowering therapy with statins ameliorate atherosclerosis in japanese patients? - Rationale and design of the JART study, Journal of atherosclerosis and thrombosis, 10.5551/jat.2899, 17, 4, 416-422, 2010.01, Aim: In Japan, heart disease and cerebral ischemic disease are major causes of death. A decrease in the level of low-density lipoprotein cholesterol (LDL-C) through intensive treatment with statins positively correlates with a reduction in the volume of plaques in patients with cardiovascular disease. The METEOR trial, evaluating the effect of rosuvastatin on carotid intima-media thickness (IMT), was conducted only in Europe and the US. Here we planned another trial, the Justification for Atherosclerosis Regression Treatment (JART) study, to clarify the efficacy of intensive lipid-lowering therapy with rosuvastatin in Japanese with atherosclerosis. Methods and Results: Four hundred patients with hypercholesterolemia (LDL-C ≥140 mg/dL) and a maximum IMT of ≥1.1 mm will be treated for 24 months either with intensive lipid-lowering therapy with rosuvastatin (target LDL-C levels: 80 mg/dL for primary prevention, and 70 mg/dL for secondary prevention) or conventional lipid-lowering therapy with pravastatin (target LDL-C level: complying with JASGL2007). The primary endpoint will be the percent change of mean-IMT and the objectives of the study are to compare the two protocols. Conclusion: The JART trial is a prospective, randomized, open-label, blinded end-point evaluation, multi-center, parallel-group, comparative study to examine the regressive effect of intensive lipid-lowering therapy with statins on atherosclerosis by evaluating IMT in the Japanese population..
115. Yasushi Tanaka, Hiroyuki Daida, Yutaka Imai, Katsumi Miyauchi, Yasukazu Sato, Masao Hiwatari, Akira Kitagawa, Junji Kishimoto, Tsutomu Yamazaki, Ryuzo Kawamori, Morning home blood pressure may be a significant marker of nephropathy in Japanese patients with type 2 diabetes
ADVANCED-J study 1, Hypertension Research, 10.1038/hr.2009.96, 32, 9, 770-774, 2009.09, A 3-year multicenter, prospective, randomized, open-label trial (ADVANCED-J) compared the effect of an increased dose of angiotensin-II receptor blocker (ARB) with that of a maintenance dose of ARB plus calcium channel blocker (amlodipine) on blood pressure (BP) control, nephropathy and atherosclerosis in patients with type 2 diabetes and hypertension in whom the usual ARB dose failed to control BP. A cross-sectional analysis using baseline data was conducted. Of 316 patients (recruited between September 2004 and December 2005), 228 patients were evaluated by multiple regression analysis using two models after randomization and exclusions. Model 1 assessed 13 baseline variables (age, sex, estimated diabetes duration, estimated hypertension duration, HbA1c, brain natriuretic peptide (BNP), high-sensitive C-reactive protein (hsCRP), triglycerides (TGs), total cholesterol (TCHO), diabetic retinopathy (DMR), systolic morning home BP (HBP), diastolic morning HBP and brachial-ankle pulse wave velocity (baPWV)) for correlation with the urinary albumin creatinine excretion rate (UACR). In model 2, systolic and diastolic morning HBP was replaced by systolic and diastolic office BP. The systolic morning HBP and systolic office BP or diastolic morning HBP and diastolic office BP correlations were weak, but significant (r=0.43 and 0.48, respectively). BNP, HbA1c, DMR and estimated diabetes duration were significantly correlated with UACR in both models 1 and 2. Although systolic office BP did not show a significant correlation with UACR in model 2, systolic morning HBP showed a significant correlation with UACR in model 1. Morning HBP, but not office BP, may be a significant marker of nephropathy in Japanese patients with type 2 diabetes..
116. Fumiaki Yoshida, Yasushi Miyagi, Junji Kishimoto, Takato Morioka, Nobuya Murakami, Kimiaki Hashiguchi, Kazuhiro Samura, Nobutaka Sakae, Ryo Yamasaki, Minako Kawaguchi, Tomio Sasaki, Subthalamic nucleus stimulation does not cause deterioration of preexisting hallucinations in Parkinson's disease patients, Stereotactic and Functional Neurosurgery, 10.1159/000195719, 87, 1, 45-49, 2009.02, Background: Among the neuropsychiatric symptoms in Parkinson's disease (PD) patients, hallucination can result from the disease itself or medical treatment. Hallucination associated with subthalamic nucleus stimulation (STN-DBS) has been reported; however, it is still unclear whether PD patients with a history of hallucination are appropriate candidates for STN-DBS or not. Aims: We investigated the effect of STN-DBS on preexisting hallucination associated with advanced PD. Methods: Eighteen STN-DBS patients were investigated retrospectively. The severity of hallucination was assessed by the thought disorder score on the Unified Parkinson's Disease Rating Scale (UPDRS, part 1-item 2) in the patients' interviews; the score 6 months after the initiation of STN-DBS was compared with the highest score throughout the preoperative history and the score 2 weeks before surgery. Results: Hoehn-Yahr stage and motor score (UPDRS part 3) were significantly improved following STN-DBS. Six months after the initiation of STN-DBS, the severity of hallucination, assessed by thought disorder score, did not increase, but rather decreased compared with the preoperative level (p < 0.05 by McNemar's test). The daily levodopa equivalent dose was increased in 2 patients without the development of hallucination. On the other hand, anti-parkinsonian drugs were totally withdrawn in 1 patient, but without improvement of hallucination. Conclusions: Our findings indicate that STN-DBS surgery does not always lead to deterioration of preexisting hallucination in PD. In advanced PD, hallucination involves a multifactorial pathogenesis and a history of hallucination is not a contraindication to STN-DBS surgery..
117. Ko Matsudaira, Atsushi Seichi, Junichi Kunogi, Takashi Yamazaki, Atsuki Kobayashi, Yorito Anamizu, Junji Kishimoto, Kazuto Hoshi, Katsushi Takeshita, Kozo Nakamura, The efficacy of prostaglandin E1 derivative in patients with lumbar spinal stenosis, Spine, 10.1097/BRS.0b013e31818f924d, 34, 2, 115-120, 2009.01, STUDY DESIGN. Randomized controlled trial. OBJECTIVE. To examine the effect of limaprost, an oral prostaglandin (PG) E1 derivative, on health-related quality of life (HRQOL) in patients with symptomatic lumbar spinal stenosis (LSS), compared to etodolac, a NSAID. SUMMARY OF BACKGROUND DATA. Limaprost, an oral PGE1 derivative, was developed in Japan to treat numerous ischemic symptoms of thromboangiitis obliterans (TAO) and LSS. Previous studies have demonstrated the effectiveness of limaprost in the symptoms in patients with LSS. However, the evidence for effect on patient-reported outcomes, such as patient's HRQOL or satisfaction, is limited. METHODS. This study was conducted at 4 study sites in Japan. Briefly, inclusion criteria were: age between 50 and 85 years; presence of both neurogenic intermittent claudication (NIC) and cauda equina symptoms (at least presence of bilateral numbness in the lower limbs); and MRI-confirmed central stenosis with acquired degenerative LSS. Limaprost (15 μg/d) or etodolac (400 mg/d) was administered for 8 weeks. The primary outcome was Short Form (SF)-36, and the secondary outcomes were the verbal rating scale of low back pain and leg numbness, walking distance, subjective improvement, and satisfaction. RESULTS. A total of 79 participants were randomized (limaprost:etodolac = 39:40). Thirteen participants withdrew from the study (limaprost:etodolac = 5:8) and 66 completed the study (limaprost:etodolac = 34:32). Comparisons showed that limaprost resulted in significantly greater improvements in the SF-36 subscales of physical functioning, role physical, bodily pain, vitality, and mental health. Limaprost was also significantly better than etodolac for leg numbness, NIC distance, and subjective improvement and satisfaction. In the subgroup analysis stratified by symptom severity, limaprost seemed more effective for milder symptoms. No serious adverse effects were reported in either treatment group. CONCLUSION. In this study, limaprost was found to be efficacious on most outcome measures, such as HRQOL, symptoms and subjective satisfaction, in LSS patents with cauda equina symptoms..
118. Nozomu Asukai, Azusa Saito, Nobuko Tsuruta, Ritsuko Ogami, Junji Kishimoto, Pilot study on prolonged exposure of Japanese patients with posttraumatic stress disorder due to mixed traumatic events, Journal of Traumatic Stress, 10.1002/jts.20337, 21, 3, 340-343, 2008.06, This pilot study investigated the feasibility of Prolonged Exposure (PE) treatment for Japanese patients with posttraumatic stress disorder (PTSD) due to mixed traumatic events. Among 12 participants in this study, 9 women and 1 man completed between 9 and 15 weekly individual PE sessions; 2 female participants dropped out in early sessions. Among completers, the authors identified a significant reduction of symptom severity scores from pretreatment to posttreatment in terms of PTSD and depression on therapist-rated and self rated measurements. Symptom levels remained low in 3- and 6-month follow-up assessments. Our findings suggest that PE is feasible and can be accepted for PTSD patients not only in Western countries, but also for those in Japan..
119. Tadamasa Yoshitake, Katsumasa Nakamura, Yoshiyuki Shioyama, Satoshi Nomoto, Ohga Saiji, Takashi Toba, Takehiro Shiinoki, Shigeo Anai, Hiromi Terashima, Junji Kishimoto, Hiroshi Honda, Breath-hold monitoring and visual feedback for radiotherapy using a charge-coupled device camera and a head-mounted display
System development and feasibility, Radiation Medicine - Medical Imaging and Radiation Oncology, 10.1007/s11604-007-0189-4, 26, 1, 50-55, 2008.01, Purpose. The aim of this study was to present the technical aspects of the breath-hold technique with respiratory monitoring and visual feedback and to evaluate the feasibility of this system in healthy volunteers. Methods and materials. To monitor respiration, the vertical position of the fiducial marker placed on the patient's abdomen was tracked by a machine vision system with a charge-coupled device camera. A monocular head-mounted display was used to provide the patient with visual feedback about the breathing trace. Five healthy male volunteers were enrolled in this study. They held their breath at the end-inspiration and the end-expiration phases. They performed five repetitions of the same type of 15-s breath-holds with and without a head-mounted display, respectively. A standard deviation of five mean positions of the fiducial marker during a15-s breath-hold in each breath-hold type was used as the reproducibility value of breath-hold. Results. All five volunteers well tolerated the breath-hold maneuver. For the inspiration breath-hold, the standard deviations with and without visual feedback were 1.74 mm and 0.84 mm, respectively (P = 0.20). For the expiration breath-hold, the standard deviations with and without visual feedback were 0.63 mm and 0.96 mm, respectively (P = 0.025). Conclusion. Our newly developed system might help the patient achieve improved breath-hold reproducibility..
120. Guangyao Liu, Hiroshi Kawaguchi, Toru Ogasawara, Yukiyo Asawa, Junji Kishimoto, Tsuguharu Takahashi, Ung Il Chung, Hisayo Yamaoka, Hirotaka Asato, Kozo Nakamura, Tsuyoshi Takato, Kazuto Hoshi, Optimal combination of soluble factors for tissue engineering of permanent cartilage from cultured human chondrocytes, Journal of Biological Chemistry, 10.1074/jbc.M608383200, 282, 28, 20407-20415, 2007.07, Since permanent cartilage has poor self-regenerative capacity, its regeneration from autologous human chondrocytes using a tissue engineering techniquemaygreatly benefit the treatment of various skeletal disorders. However, the conventional autologous chondrocyte implantation is insufficient both in quantity and in quality due to two major limitations: dedifferentiation during a long term culture for multiplication and hypertrophic differentiation by stimulation for the redifferentiation. To overcome the limitations, this study attempted to determine the optimal combination in primary human chondrocyte cultures under a serum-free condition, from among 12 putative chondrocyte regulators. From the exhaustive 212 = 4,096 combinations, 256 were selected by fractional factorial design, and bone morphogenetic protein-2 and insulin (BI) were statistically determined to be the most effective combination causing redifferentiation of the dedifferentiated cells after repeated passaging. Wefurther found that the addition of triiodothyronine (T3) prevented the BI-induced hypertrophic differentiation of redifferentiated chondrocytes via the suppression of Akt signaling. The implant formed by the human chondrocytes cultured in atelocollagen and poly(L-latic acid) scaffold under the BI + T3 stimulation consisted of sufficient hyaline cartilage with mechanical properties comparable with native cartilage after transplantation in nude mice, indicating that BI + T3 is the optimal combination to regenerate a clinically practical permanent cartilage from autologous chondrocytes..
121. Tsuyoshi Konishi, Toshiaki Watanabe, Junji Kishimoto, Kenjiro Kotake, Tetsuichiro Muto, Hirokazu Nagawa, Prognosis and risk factors of metastasis in colorectal carcinoids
Results of a nationwide registry over 15 years, Gut, 10.1136/gut.2006.109157, 56, 6, 863-868, 2007.06, Background: Colorectal carcinoids are often described as low-grade malignant. However, no study has compared the survival between patients with colorectal carcinoids and those with carcinomas, in a large series. In addition, no global consensus has been established on the crucial determinants of metastasis in colorectal carcinoids. Aim: To determine the predictive factors for metastasis in colorectal carcinoids and clarify their prognosis compared with adenocarcinomas. Methods: Data of all patients diagnosed as having colorectal carcinoids were extracted from a large nationwide database of colorectal tumours, the Multi-Institutional Registry of Large-Bowel Cancer in Japan, for the period from 1984 to 1998. Risk factors for lymph node (LN) metastases and distant metastases were analysed among those who were undergoing surgery, by univariate and multivariate analysis. Cancer-specific survival was also compared between patients with colorectal carcinoids and those with adenocarcinomas registered in the same period. Results: Among the 90 057 cases of colorectal tumours that were diagnosed, a total of 345 cases of carcinoids were identified, including 247 colorectal carcinoids of those undergoing surgery. Risk factors for LN metastasis were tumour size ≥11 mm and lymphatic invasion, whereas those for distant metastasis were tumour size ≥21 mm and venous invasion. Colorectal carcinoids without these risk factors exhibited no LN metastasis or distant metastasis. Cancer-specific survival of patients with colorectal carcinoids without metastasis was better than that of those with adenocarcinomas. However, the survival was similar between carcinoids and adenocarcinomas if the tumours had LN metastasis or distant metastasis. Conclusions: The presence of metastasis in colorectal carcinoids could lead to survival that is as poor as in adenocarcinomas. Tumours ≤10 mm and without lymphatic invasion could be curatively treated by local resection, but others would need radical LN dissection..
122. Osada A, Iwabuchi T, Kishimoto J, Hamazaki TS, Okochi H., Long-term culture of mouse vibrissal dermal papilla cells and de novo hair follicle induction., Tissue Engineering, 13(5);975-982., 2007.05.
123. Keisuke Maruyama, Masahiro Shin, Masao Tago, Junji Kishimoto, Akio Morita, Nobutaka Kawahara, Radiosurgery to reduce the risk of first hemorrhage from brain arteriovenous malformations, Neurosurgery, 10.1227/01.NEU.0000255341.03157.00, 60, 3, 453-458, 2007.03, OBJECTIVE: It remains unclear whether or not and to what extent stereotactic radiosurgery can reduce the risk of first intracranial hemorrhage from brain arteriovenous malformations. METHODS: We performed a retrospective observational investigation of 500 patients with arteriovenous malformations who were treated with gamma knife radiosurgery. The risk of first hemorrhage was analyzed using the Cox proportional-hazards model with age at radiosurgery and angiographic obliteration included as time-dependent covariates. Three periods were defined: from birth to radiosurgery (before radiosurgery); from radiosurgery to angiographic obliteration (latency period); and from angiographic obliteration to end of the follow-up period (after obliteration). RESULTS: Hemorrhage was documented before radiosurgery in 318 patients (median observation period, 30.0 yr), during the latency period in 11 patients (median observation period, 2.2 yr), and after obliteration in two patients (median observation period, 5.5 yr). Compared with the period before radiosurgery, the risk of hemorrhage decreased by 86% after obliteration (hazard ratio, 0.14; 95% confidence interval, 0.03-0.55; P = 0.005), whereas the reduction observed during the latency period was not statistically significant (hazard ratio, 0.56; 95% confidence interval, 0.31-1.04; P = 0.07). Irrespective of obliteration, the risk of hemorrhage decreased by 62% after radiosurgery (hazard ratio, 0.38; 95% confidence interval, 0.22-0.67; P = 0.001). Similar results were observed when the 33 patients who had undergone previous therapy were excluded from the analysis. CONCLUSION: Stereotactic radiosurgery significantly reduces the risk of first hemorrhage from brain arteriovenous malformations. The extent of the decrease might be greater if angiography indicates the evidence of obliteration..
124. Kayo INOKO, Aya NISHIZONO-MAHER, Satoko TANI, Yukiko KANO, Junji KISHIMOTO, Norika HAYAKAWA, Shuji HONJO, Mari KASAHARA, Kazuhiko SAITO, Kayano ISHII, Makiko OSAWA, Reliability and Validity of a Japanese Version of the Yale Global Tic Severity Scale: A Preliminary Study, Japanese Journal of Child and Adolescent Psychiatry, Vol.47 Supplement 38-48., 2006.12.
125. Tsuyoshi Konishi, Toshiaki Watanabe, Junji Kishimoto, Hirokazu Nagawa, Elective colon and rectal surgery differ in risk factors for wound infection
Results of prospective surveillance, Annals of Surgery, 10.1097/01.sla.0000219017.78611.49, 244, 5, 758-763, 2006.11, OBJECTIVE: The objective of this study was to clarify the incidence and risk factors for developing incisional surgical site infection (SSI) in both elective colon and rectal surgery. SUMMARY BACKGROUND DATA: SSI is a frequent complication after elective colorectal resection. The National Nosocomial Infection Surveillance system surveys all colorectal surgeries together, without differentiating the type of colorectal surgery performed. However, rectal surgery may have a higher risk for SSI, and identifying risk factors that are more specific to each procedure would be more predictive. METHODS: We conducted prospective SSI surveillance of all elective colorectal resections performed by a single surgeon in a single institution from November 2000 to July 2004. The data for colon and rectal surgeries were collected separately. The outcome of interest was incisional SSI. Univariate and multivariate analyses were performed to determine the predictive significance of variables in each type of surgery. RESULTS: A total of 556 colorectal resections, consisting of 339 colon and 217 rectal surgeries, were admitted to the program. The incisional SSI rates in colon and rectal surgeries were 9.4% and 18.0%, respectively (P = 0.0033). Risk factors for developing incisional SSI in colon surgery were ostomy closure (OR = 7.3) and lack of oral antibiotics (OR = 3.3), while in rectal surgery, risk factors were preoperative steroids (OR = 3.7), preoperative radiation (OR = 2.8), and ostomy creation (OR = 4.9). CONCLUSIONS: Colon and rectal surgeries differ with regard to incidence and risk factors for developing incisional SSI. SSI surveillance for such surgeries should be performed separately, as this should lead to more efficient identification of risk factors and a reduction in SSI..
126. Ryuzo Kawamori, Hiroyuki Daida, Yasushi Tanaka, Katsumi Miyauchi, Akira Kitagawa, Dobun Hayashi, Junji Kishimoto, Shunya Ikeda, Yutaka Imai, Tsutomu Yamazaki, Amlodipine versus angiotensin II receptor blocker; control of blood pressure evaluation trial in diabetics (ADVANCED-J), BMC Cardiovascular Disorders, 10.1186/1471-2261-6-39, 6, 2006.10, Background: The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist. Methods/Design: Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included. Discussion: We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of anti hypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness..
127. Tsuguharu Takahashi, Toru Ogasawara, Junji Kishimoto, Guangyao Liu, Hirotaka Asato, Takashi Nakatsuka, Eijyu Uchinuma, Kozo Nakamura, Hiroshi Kawaguchi, Ung Il Chung, Tsuyoshi Takato, Kazuto Hoshi, Erratum
Synergistic effects of FGF-2 with insulin or IGF-I on the proliferation of human auricular chondrocytes [Cell Transplantation 14, 9 [683-693]], Cell Transplantation, 15, 4, 2006.08.
128. Satoko Hamanaka, Nozomu Asukai, Yoshito Kamijo, Kotaro Hatta, Junji Kishimoto, Hitoshi Miyaoka, Acute stress disorder and posttraumatic stress disorder symptoms among patients severely injured in motor vehicle accidents in Japan, General Hospital Psychiatry, 10.1016/j.genhosppsych.2006.02.007, 28, 3, 234-241, 2006.05, Objective: The prevalence of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) in seriously injured survivors of motor vehicle accidents (MVAs) in Japan was investigated. Furthermore, predictive factors in the early stage for development of PTSD were evaluated. Method: Subjects were consecutive samples (N=100) of patients hospitalized with severe MVA injuries surveyed at two time points: within 1 month after the MVA and then 6 months later. In the first survey, we conducted the Acute Stress Disorder Interview and compiled results of a self-rating questionnaire; in the second survey, we conducted a structured clinical interview via telephone. Results: The prevalence of ASD and PTSD were 9.0% and 8.5%, respectively. The shift from ASD to PTSD was more pronounced when we included partial diagnoses of ASD and PTSD. Three predictive factors for PTSD were identified through multiple logistic analysis: ASD-positive, presence of persistent physical disability and physical injury severity. Conclusions: Even among severely injured MVA survivors, most acute stress symptoms subside over time. However, having ASD or partial ASD in the early stage, and the presence of physical disability as an aftereffect are strong predictive factors for PTSD. These findings validate the importance of evidence-based intervention for ASD to forestall PTSD..
129. Tsuyoshi Konishi, Toshiaki Watanabe, Keita Morikane, Kazuhiko Fukatsu, Joji Kitayama, Naoyuki Umetani, Junji Kishimoto, Hirokazu Nagawa, Prospective surveillance effectively reduced rates of surgical site infection associated with elective colorectal surgery at a university hospital in Japan, Infection Control and Hospital Epidemiology, 10.1086/504444, 27, 5, 526-528, 2006.05, At a university hospital in Japan, the introduction of prospective surveillance and subsequent interventions was effective in reducing the rate of surgical site infection associated with elective colorectal surgery from 27.5% to 17.8% of surgeries. Japan should both recognize the importance of broader surveillance for surgical site infection and establish its own nationwide surveillance database..
130. Tsuyoshi Konishi, Toshiaki Watanabe, Junji Kishimoto, Hirokazu Nagawa, Risk factors for anastomotic leakage after surgery for colorectal cancer
Results of prospective surveillance, Journal of the American College of Surgeons, 10.1016/j.jamcollsurg.2005.10.019, 202, 3, 439-444, 2006.03, BACKGROUND: Anastomotic leakage in operations for colorectal cancer not only results in morbidity and mortality, but also increases the risk of local recurrence and worsens prognosis. So a better understanding of risk factors for developing anastomotic leakage in colorectal cancer surgery is important to surgeons. The aim of this study was to determine the incidence and risk factors for clinical anastomotic leakage after elective surgery for colorectal cancer. STUDY DESIGN: We conducted prospective surveillance of all elective colorectal resections performed by a single surgeon in a single university hospital from November 2000 to July 2004. The outcomes of interest was clinical anastomotic leakage. Eighteen independent clinical variables were examined by univariate and multivariate analyses. RESULTS: A total of 391 patients undergoing elective operations for colorectal cancer were admitted to the program. Clinical anastomotic leakage was identified in 11(2.8%) patients. Univariate and multivariate analyses showed that preoperative steroid use (odds ratio = 8.7), longer duration of operation (odds ratio = 9.9), and wound contamination (odds ratio = 7.8) were independently predictive of clinical anastomotic leakage. Although there were no statistical differences in leakage rates between patients with and without covering stoma, all four patients requiring reoperation for leakage were without covering stoma. CONCLUSIONS: Preoperative steroid use, longer duration of operation, and contamination of the operative field were independent risk factors for developing clinical anastomotic leakage after elective resection for colorectal cancer. Surgeons should be aware of such high-risk patients, which would help them to decide whether to create a diversion stoma during surgery..
131. Tsuguharu Takahashi, Toru Ogasawara, Junji Kishimoto, Guangyao Liu, Hirotaka Asato, Takashi Nakatsuka, Eijyu Uchinuma, Kozo Nakamura, Hiroshi Kawaguchi, Tsuyoshi Takato, Kazuto Hoshi, Synergistic effects of FGF-2 with insulin or IGF-I on the proliferation of human auricular chondrocytes, Cell Transplantation, 10.3727/000000005783982675, 14, 9, 683-693, 2005.12, Chondrocyte preparation with the safety and efficiency is the first step in cartilage regenerative medicine. To prepare a chondrocyte proliferation medium that does not contain fetal bovine serum (FBS) and that provides more than a 1000-fold increase in cell numbers within approximately 1 month, we attempted to use the medium containing 5% human serum (HS), but it exerted no more than twofold increase in 2 weeks. To compensate for the limited proliferation ability in HS, we investigated the combinational effects of 12 factors [i.e., fibroblast growth factor(FGF)-2, insulin-like growth factor(IGF)-I, insulin, bone morphogenetic protein-2, parathyroid hormone, growth hormone, dexamethasone, 1α25-dihydroxy vitamin D3, L-3,3′, 5′-triodothyronine, interleukine-1 receptor antagonist, 17β-estradiol, and testosterone] on the proliferation of human auricular chondrocytes by analysis of variance in fractional factorial design. As a result, FGF-2, dexamethasone, insulin, and IGF-I possessed promotional effects on proliferation, while the combination of FGF-2 with insulin or IGF-I synergistically enhanced the proliferation. Actually, the chondrocytes increased 7.5-fold in number in 2 weeks in a medium containing 5% HS with 10 ng/ml FGF-2, while the cell number synergistically gained a 10-12-fold increase with 5 μg/ml insulin or 100 ng/ml IGF-I in the same period. The proliferation effects were more enhanced at a concentration of 100 ng/ml for FGF-2, and especially for the combination of 100 ng/ml FGF-2 and 5 μg/ml insulin (approximately 16-fold within 2 weeks). In the long-term culture with repeated passaging, this combination provided more than 10,000-fold within 8 weeks (i.e., passage 4). Thus, we concluded that such a combination of FGF-2 with insulin or IGF-I may be useful for promotion of auricular chondrocyte proliferation in a clinical application for cartilage regeneration..
132. Ko Matsudaira, Takashi Yamazaki, Atsushi Seichi, Katsushi Takeshita, Kazuto Hoshi, Junji Kishimoto, Kozo Nakamura, Spinal stenosis in grade I degenerative lumbar spondylolisthesis
A comparative study of outcomes following laminoplasty and laminectomy with instrumented spinal fusion, Journal of Orthopaedic Science, 10.1007/s00776-005-0887-7, 10, 3, 270-276, 2005.01, The management of grade I lumbar degenerative spondylolisthesis remains controversial. There have been few reports comparing any form of surgery with conservative treatment. As for surgical management, the need for arthrodesis with instrumentation has not been established. A series of 53 patients with single-level spinal stenosis at L4/5 due to grade I degenerative spondylolisthesis entered into a study to compare outcomes of two surgical methods of treatment with those of a control group treated conservatively: group 1, 19 patients treated by decompression laminectomy combined with posterolateral fusion and pedicle screw instrumentation; group 2, 18 patients treated by decompression of the spinal canal using a laminoplasty technique to preserve the integrity of the midline structure; group 3, 16 patients treated conservatively after being recommended that they have surgery. We compared the 2-year results among the three groups. Alleviation of symptoms was noted in groups 1 and 2, whereas the controls (group 3) showed no improvement. There was no significant difference in the degree of clinical improvement between groups 1 and 2. Spondylolisthesis was controlled in group 1, but it did not lead to better clinical results than those achieved in group 2. Our findings indicate that the technique for decompressing the spinal canal with preservation of the posterior elements of its roof can be useful for treating patients with grade I degenerative spondylolisthesis with symptoms of spinal stenosis..
133. Keisuke Maruyama, Nobutaka Kawahara, Masahiro Shin, Masao Tago, Junji Kishimoto, Hiroki Kurita, Shunsuke Kawamoto, Akio Morita, Takaaki Kirino, The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations, New England Journal of Medicine, 10.1056/NEJMoa040907, 352, 2, 146-153, 2005.01, BACKGROUND: Angiography shows that stereotactic radiosurgery obliterates most cerebral arteriovenous malformations after a latency period of a few years. However, the effect of this procedure on the risk of hemorrhage is poorly understood. METHODS: We performed a retrospective observational study of 500 patients with malformations who were treated with radiosurgery with use of a gamma knife. The rates of hemorrhage were assessed during three periods: before radiosurgery, between radiosurgery and the angiographic documentation of obliteration of the malformation (latency period), and after angiographic obliteration. RESULTS: Forty-two hemorrhages were documented before radiosurgery (median follow-up, 0.4 year), 23 during the latency period (median follow-up, 2.0 years), and 6 after obliteration (median follow-up, 5.4 years). As compared with the period between diagnosis and radiosurgery, the risk of hemorrhage decreased by 54 percent during the latency period (hazard ratio, 0.46; 95 percent confidence interval, 0.26 to 0.80; P=0.006) and by 88 percent after obliteration (hazard ratio, 0.12; 95 percent confidence interval, 0.05 to 0.29; P<0.001). The risk was significantly reduced during the period after obliteration, as compared with the latency period (hazard ratio, 0.26; 95 percent confidence interval, 0.10 to 0.68; P=0.006). The reduction was greater among patients who presented with hemorrhage than among those without hemorrhage at presentation and similar in analyses that took into account the delay in confirming obliteration by means of angiography and analyses that excluded data obtained during the first year after diagnosis. CONCLUSIONS: Radiosurgery significantly decreases the risk of hemorrhage in patients with cerebral arteriovenous malformations, even before there is angiographic evidence of obliteration. The risk of hemorrhage is further reduced, although not eliminated, after obliteration..
134. Aya Nishizono-Maher, Junji Kishimoto, Hiromichi Yoshida, Kyoko Urayama, Miki Miyato, Yuki Otsuka, Hiroko Matsui, The role of self-report questionnaire in the screening of postnatal depression - A community sample survey in central Tokyo, Social Psychiatry and Psychiatric Epidemiology, 10.1007/s00127-004-0727-7, 39, 3, 185-190, 2004.03, Background. Numerous studies have shown that health rare professionals often experience difficulty in detecting postnatal depression. In Japan, where mental illness has traditionally been stigmatized, detection seems even more difficult. This study investigates the prevalence of postnatal depression in the community and its relation to screening methodology. Methods. The Edinburgh Postnatal Depression Scale (EPDS) was distributed at community health centers in a district in central Tokyo. The results from both non-identifiable questionnaires and identifiable questionnaires were compared. Screening by EPDS and clinical judgment by community nurses were compared. Results. Making the questionnaire identifiable did not change the score distribution pattern. Among mothers with 3- to 4-month-old babies in the community, 13.9% scored high (9 or above) on EPDS. In 51.1% of high scorers, nurses did not detect postnatal depression. Clinically, postnatal depression can be easily missed in the community health-check setting especially when there was hitherto no report of obstetric abnormality during pregnancy or delivery. Conclusion. The prevalence of high scorers is comparable to those reported in other countries. The use of the questionnaire was helpful in drawing the attention of mothers and health care professionals to issues of mental health..
135. Tomoko Ishii, Nozomu Asukai, Takako Konishi, Miwa Kojimoto, and Junji Kishimoto, The Mental Influence of Sexual Trauma on Victims: From the Results of An Investigation of Female College Students in Japan, Family Violence & Sexual Assault Bulletin, Vol.19, No.1: 12-19, 2003.01.
136. ドメスティックバイオレンス(DV)簡易スクリーニング尺度(DVSI)の作成および信頼性・妥当性の検討.
137. Nozomu Asukai, Hiroshi Kato, Noriyuki Kawamura, Yoshiharu Kim, Kohei Yamamoto, Junji Kishimoto, Yuko Miyake, Aya Nishizono-Maher, Reliability and validity of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J)
Four studies of different traumatic events, Journal of Nervous and Mental Disease, 10.1097/00005053-200203000-00006, 190, 3, 175-182, 2002.04, The authors developed the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J) and investigated its reliability and validity in four different groups: workers with lifetime mixed traumatic events, survivors of an arsenic poisoning case, survivors of the Hanshin-Awaji earthquake, and survivors of the Tokyo Metro sarin attack. Evidence includes retest reliability and internal consistency of the IES-R-J. Posttraumatic stress disorder (PTSD) and partial PTSD cases indicated significantly higher scores than non-PTSD cases. The IES-R-J can be a useful self-rating diagnostic instrument particularly for survivors with PTSD symptoms as a clinical concern (PTSD + partial PTSD) by using a 24/25 cutoff in total score. In analysis of scale structure, the majority of intrusion and hyperarousal items were subsumed under the same cluster, whereas avoidance items made up a separate cluster. Female patients indicated higher scores than male patients. A negative weak correlation between age and the score was found only among female earthquake survivors. The IES-R-J can be used as a validated instrument in future international comparative research..