論文 - 長島　健悟

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma

Okui J*, Nagashima K*, Matsuda S*, Sato Y, Okamura A, Kawakubo H, Muto M, Kakeji Y, Kono K, Takeuchi H, Watanabe M, Doki Y, Bamba T, Fukuda T, Fujiwara H, Sato S, Noma K, Miyata H, Fujita T, Kitagawa Y

British Journal of Surgery 111 （ 2 ） znae038 2024年02月

共著, 筆頭著者, 査読有り,  ISSN  00071323

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Bias in odds ratios from logistic regression methods with sparse data sets

Masahiko Gosho, Tomohiro Ohigashi, Kengo Nagashima, Yuri Ito, Kazushi Maruo

Journal of Epidemiology 33 （ 6 ） 265 - 275 2023年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0917-5040

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Sample size calculations for single‐arm survival studies using transformations of the Kaplan–Meier estimator

Nagashima K, Noma H, Sato Y, Gosho M

Pharmaceutical Statistics 20 （ 3 ） 499 - 511 2021年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15391604

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Prediction intervals for random-effects meta-analysis: a confidence distribution approach

Nagashima K, Noma H, Furukawa TA

Statistical Methods in Medical Research 28 （ 6 ） 1689 - 1702 2019年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09622802

　概要を見る

Prediction intervals are commonly used in meta-analysis with random-effects models. One widely used method, the Higgins–Thompson–Spiegelhalter prediction interval, replaces the heterogeneity parameter with its point estimate, but its validity strongly depends on a large sample approximation. This is a weakness in meta-analyses with few studies. We propose an alternative based on bootstrap and show by simulations that its coverage is close to the nominal level, unlike the Higgins–Thompson–Spiegelhalter method and its extensions. The proposed method was applied in three meta-analyses.

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Information criteria for Firth's penalized partial likelihood approach in Cox regression models

Nagashima K, Sato Y

Statistics in Medicine 36 （ 21 ） 3422 - 3436 2017年09月

研究論文（学術雑誌）, 共著, 査読有り

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Statistical methods in the Journal — an update

Sato Y, Gosho M, Nagashima K, Takahashi S, Ware JH, Laird NM

New England Journal of Medicine 376 （ 11 ） 1086 - 1087 2017年03月

研究論文（学術雑誌）, 共著, 査読有り

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An efficient and robust method for analyzing population pharmacokinetic data in genome-wide pharmacogenomic studies: a generalized estimating equation approach

Nagashima K, Sato Y, Noma H, Hamada C

Statistics in Medicine 32 （ 27 ） 4838 - 4858 2013年11月

研究論文（学術雑誌）, 査読有り

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Meta-analysis using flexible random-effects distribution models

Noma H, Nagashima K, Kato S, Teramukai S, Furukawa TA

Journal of Epidemiology 32 （ 10 ） 441 - 448 2022年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0917-5040

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Frequentist performances of Bayesian prediction intervals for random‐effects meta‐analysis

Hamaguchi Y, Noma H, Nagashima K, Yamada T, Furukawa TA

Biometrical Journal 63 （ 2 ） 394 - 405 2021年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03233847

　概要を見る

The prediction interval has been increasingly used in meta-analyses as a useful measure for assessing the magnitude of treatment effect and between-studies heterogeneity. In calculations of the prediction interval, although the Higgins–Thompson–Spiegelhalter method is used most often in practice, it might not have adequate coverage probability for the true treatment effect of a future study under realistic situations. An effective alternative candidate is the Bayesian prediction interval, which has also been widely used in general prediction problems. However, these prediction intervals are constructed based on the Bayesian philosophy, and their frequentist validities are only justified by large-sample approximations even if noninformative priors are adopted. There has been no certain evidence that evaluated their frequentist performances under realistic situations of meta-analyses. In this study, we conducted extensive simulation studies to assess the frequentist coverage performances of Bayesian prediction intervals with 11 noninformative prior distributions under general meta-analysis settings. Through these simulation studies, we found that frequentist coverage performances strongly depended on what prior distributions were adopted. In addition, when the number of studies was smaller than 10, there were no prior distributions that retained accurate frequentist coverage properties. We also illustrated these methods via applications to two real meta-analysis datasets. The resultant prediction intervals also differed according to the adopted prior distributions. Inaccurate prediction intervals may provide invalid evidence and misleading conclusions. Thus, if frequentist accuracy is required, Bayesian prediction intervals should be used cautiously in practice.

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Permutation inference methods for multivariate meta‐analysis

Noma H, Nagashima K, Furukawa TA

Biometrics 76 （ 1 ） 337 - 347 2020年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006341X

　概要を見る

Multivariate meta-analysis is gaining prominence in evidence synthesis research because it enables simultaneous synthesis of multiple correlated outcome data, and random-effects models have generally been used for addressing between-studies heterogeneities. However, coverage probabilities of confidence regions or intervals for standard inference methods for random-effects models (eg, restricted maximum likelihood estimation) cannot retain their nominal confidence levels in general, especially when the number of synthesized studies is small because their validities depend on large sample approximations. In this article, we provide permutation-based inference methods that enable exact joint inferences for average outcome measures without large sample approximations. We also provide accurate marginal inference methods under general settings of multivariate meta-analyses. We propose effective approaches for permutation inferences using optimal weighting based on the efficient score statistic. The effectiveness of the proposed methods is illustrated via applications to bivariate meta-analyses of diagnostic accuracy studies for airway eosinophilia in asthma and a network meta-analysis for antihypertensive drugs on incident diabetes, as well as through simulation experiments. In numerical evaluations performed via simulations, our methods generally provided accurate confidence regions or intervals under a broad range of settings, whereas the current standard inference methods exhibited serious undercoverage properties.

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Bartlett‐type corrections and bootstrap adjustments of likelihood‐based inference methods for network meta‐analysis

Noma H, Nagashima K, Maruo K, Gosho M, Furukawa TA

Statistics in Medicine 37 （ 7 ） 1178 - 1190 2018年03月

研究論文（学術雑誌）, 共著, 査読有り

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A note on the Mantel–Haenszel estimators when the common effect assumptions are violated

Noma H, Nagashima K

Epidemiologic Methods 5 （ 1 ） 19 - 35 2016年05月

研究論文（学術雑誌）, 共著, 査読有り

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Impact of the COVID‐19 pandemic on gastric surgery in Japan: A nationwide study using interrupted time‐series analyses

Fujita M, Yamaguchi K, Nagashima K, Suzuki K, Kasai T, Hashimoto H, Onouchi Y, Sato D, Fujisawa T, Hata A

Journal of Gastroenterology and Hepatology    In press 2024年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0815-9319

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Risk factors for recurrence in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in Japan: a systematic literature review and meta-analysis

Miyazaki N, Iwasaki T, Sakai H, Watanuki R, Tanizawa Y, Cai Z, Kawaguchi T, Tsurutani J, Nagashima K

Current Medical Research and Opinion    In press 2024年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

Prevalence and clinical profiles of anti‐myelin‐associated glycoprotein neuropathy in Japan: A nationwide survey study of 133 patients

Aotsuka Y, Misawa S, Suichi T, Shibuya K, Nakamura K, Kano H, Otani R, Marie M, Ogushi M, Nagashima K, Sato Y, Kuriyama N, Kuwabara S

European Journal of Neurology 31 （ 5 ） e16249 2024年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1351-5101

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Live two-way video versus face-to-face treatment for depression, anxiety, and obsessive-compulsive disorder: A 24-week randomized controlled trial

Kishimoto T, Kinoshita S, Kitazawa M, Hishimoto A, Asami T, Suda A, Bun S, Kikuchi T, Sado M, Takamiya A, Mimura M, Sato Y, Takemura R, Nagashima K, Nakamae T, Abe Y, Kanazawa T, Kawabata Y, Tomita H, Abe K, Hongo S, Kimura H, Sato A, Kida H, Sakuma K, Funayama M, Sugiyama N, Hino K, Amagai T, Takamiya M, Kodama H, Goto K, Fujiwara S, Kaiya H, Nagao K, on behalf of the J-PROTECT collaborators

Psychiatry and Clinical Neurosciences 78 （ 4 ） 220 - 228 2024年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1323-1316

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Factors affecting motivation for receiving a booster dose of the COVID-19 vaccine among Japanese university students and staff: a cross-sectional questionnaire survey

Uchida S, Uno S, Kondo M, Uwamino Y, Namkoong H, Nishimura T, Misawa K, Kashimura S, Yamato K, Ishizaka T, Nagashima K, Kitagawa Y, Hasegawa N

Scientific Reports 14 （ 1 ） 8009 2024年04月

研究論文（学術雑誌）, 共著, 査読有り

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Predictive and prognostic value of excision repair cross-complementing group 1 in patients with advanced gastric cancer

Yamada Y, Nagashima K, Azuma M, Masutani M, Ichikawa H, Iwasa S, Takahashi N, Hirano H, Kanato K, Machida N, Kinoshita T, Hata H, Kawakami H, Takahari D, Boku N, Kurokawa Y, Terashima M, Yoshikawa T, Sekine S, Hiraoka N

BJC Reports 2   18 2024年03月

研究論文（学術雑誌）, 共著, 査読有り

Clinical development of a blood biomarker using apolipoprotein-A2 isoforms for early detection of pancreatic cancer

Kashiro A, Kobayashi M, Oh T, Miyamoto M, Atsumi J, Nagashima K, Takeuchi K, Nara S, Hijioka S, Morizane C, Kikuchi S, Kato S, Kato K, Ochiai H, Obata D, Shizume Y, Konishi H, Nomura Y, Matsuyama K, Xie C, Wong C, Huang Y, Jung G, Srivastava S, Kutsumi H, Honda K

Journal of Gastroenterology 59 （ 3 ） 263 - 278 2024年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0944-1174

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Prevalence, clinical profiles, and prognosis of CIDP in Japanese nationwide survey: analyses of 1257 diagnosis-confirmed patients

Aotsuka Y, Misawa S, Suichi T, Shibuya K, Nakamura K, Kano H, Otani R, Morooka M, Ogushi M, Nagashima K, Sato Y, Kuriyama N, Kuwabara S

Neurology 102 （ 6 ） e209130 2024年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0028-3878

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Synergistic effect of motivation for the elderly and support for going out II; measures to induce elderly men to go out

Tsutsui K, Ukita S, Kondo M, Toshima G, Miyazaki N, Nagashima K, Ohmura M, Tsuchihashi S, Tsuji Y, Katoh M, Aida N, Kobayashi Y, Ohtsu Y, Fujita Y, Tanaka S, Watanabe H, Naruse Y, Iizuka I, Kato H, Mashimo Y, Senbonmatsu T

Geriatrics 9 （ 1 ） 21 2024年02月

研究論文（学術雑誌）, 共著, 査読有り

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Impact of the coronavirus disease 2019 pandemic on primary and metastatic lung cancer treatments in Japan: A nationwide study using an interrupted time series analysis

Fujita M, Fujisawa T, Suzuki K, Nagashima K, Kasai T, Hashimoto H, Yamaguchi K, Onouchi Y, Sato D, Hata A

Cancer Epidemiology 90   102549 2024年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  18777821

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Upper respiratory symptoms as long COVID revealed through a cohort study of patients with COVID-19

Okada M, Ishida N, Kanzaki S, Kawada I, Nagashima K, Terai H, Hiruma G, Namkoong H, Asakura T, Masaki K, Ohgino K, Miyata J, Chubachi S, Kodama N, Maeda S, Sakamoto S, Okamoto M, Nagasaki Y, Umeda A, Miyagawa K, Shimada H, Minami K, Hagiwara R, Ishii M, Sato Y, Fukunaga K

OTO Open 8 （ 1 ） e120 2024年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2473-974X

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A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer

Hashimoto T, Takayanagi D, Yonemaru J, Naka T, Nagashima K, Machida E, Kohno T, Yatabe Y, Kanemitsu Y, Hamamoto R, Takashima A, Shiraishi K, Sekine S

British Journal of Cancer 129 （ 7 ） 1176 - 1183 2023年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0007-0920

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The quantity and quality of scientific evidence about the health of working women in occupational health of Japan: A scoping review

Nomura K, Kitagawa K, Tsuji M, Iida M, Aoki M, Miyauchi K, Hirayama J, Nagashima K, Takebayashi T, Tsutsumi A

Journal of Occupational Health 65 （ 1 ） e12427 2023年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419145

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Efficacy and safety of trastuzumab deruxtecan and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer: a single-institution retrospective study

Shimozaki K, Nakayama I, Takahari D, Nagashima K, Yoshino K, Fukuda K, Fukuoka S, Osumi H, Ogura M, Wakatsuki T, Ooki A, Shinozaki E, Chin K, Yamaguchi K

Journal of Gastric Cancer 23 （ 4 ） 609 - 621 2023年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2093582X

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Diagnostic value of adding magnifying chromoendoscopy to magnifying narrow-band imaging endoscopy for colorectal polyps

Matsumura T, Ebigbo A, Römmele C, Ikematsu H, Ishigami H, Suzuki T, Harada H, Yada T, Takatori Y, Takeuchi M, Okimoto K, Akizue N, Maruoka D, Kitagawa Y, Minamide T, Iwaki T, Amano Y, Matsusaka K, Nagashima K, Maehata T, Yahagi N, Messmann H, Kato N

Clinical Gastroenterology and Hepatology 21 （ 10 ） 2551 - 2559.e2 2023年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1542-3565

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Changes in the number of cancer diagnosis practices due to the COVID-19 pandemic: interrupted time-series analysis using the National Database of Japan

Fujita M, Nagashima K, Suzuki K, Kasai T, Hashimoto H, Yamaguchi K, Onouchi Y, Sato D, Fujisawa T, Hata A

Journal of Cancer Research and Clinical Oncology 149 （ 9 ） 6023 - 6033 2023年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01715216

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Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G)

Takahashi N, Hara H, Nagashima K, Hirata K, Masuishi T, Matsumoto T, Kawakami H, Yamazaki K, Hironaka S, Boku N, Muro K

BMC cancer 23 （ 1 ） 726 2023年08月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION: jRCTs041220120.

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Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis

Takahashi R, Uchiyama K, Washida N, Shibagaki K, Yanai A, Nakayama T, Nagashima K, Sato Y, Kanda T, Itoh H

Hypertension Research 46 （ 6 ） 1536 - 1546 2023年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09169636

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Acceptability of self-sampling human papillomavirus test for cervical cancer screening in Japan: A questionnaire survey in the ACCESS trial

Fujita M, Nagashima K, Shimazu M, Suzuki M, Tauchi I, Sakuma M, Yamamoto S, Hanaoka H, Shozu M, Tsuruoka N, Kasai T, Hata A

PLoS ONE 18 （ 6 ） e0286909 2023年06月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Purpose In terms of medical policy for cervical cancer prevention, Japan lags far behind other industrialized countries. We initiated a randomized controlled trial to evaluate the self-sampling human papillomavirus (HPV) test as a tool to raise screening uptake and detection of precancer. This study was conducted to explore the acceptability and preference of self-sampling using a subset of the data from this trial. Methods A pre-invitation letter was sent to eligible women, aged 30−59 years who had not undergone cervical cancer screening for three or more years. After excluding those who declined to participate in this trial, the remaining women were assigned to the self-sampling and control groups. A second invitation letter was sent to the former group, and those wanting to undergo the self-sampling test ordered the kit. A self-sampling HPV kit, consent form, and a self-administered questionnaire were sent to participants who ordered the test. Results Of the 7,340 participants in the self-sampling group, 1,196 (16.3%) administered the test, and 1,192 (99.7%) answered the questionnaire. Acceptability of the test was favorable; 75.3 −81.3% of participants agreed with positive impressions (easy, convenient, and clarity of instruction), and 65.1−77.8% disagreed with negative impressions (painful, uncomfortable, and embarrassing). However, only 21.2% were confident in their sampling procedure. Willingness to undergo screening with a self-collected sample was significantly higher than that with a doctor-collected sample (89.3% vs. 49.1%; p<0.001). Willingness to undergo screening with a doctor-collected sample was inversely associated with age and duration without screening (both p<0.001), but that with a self-collected sample was not associated. Conclusions Among women who used the self-sampling HPV test, high acceptability was confirmed, while concerns about self-sampling procedures remained. Screening with a self-collected sample was preferred over a doctor-collected sample and the former might alleviate disparities in screening rates.

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Progression patterns and site-specific responses in advanced gastric cancer patients treated with nivolumab

Kadono T, Iwasa S, Nagashima K, Oshima K, Yamamoto S, Hirano H, Okita N, Shoji H, Honma Y, Takashima A, Kato K, Ushijima T, Boku N

Cancer Medicine 12 （ 8 ） 9322 - 9331 2023年04月

研究論文（学術雑誌）, 共著, 査読有り

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Epidemiological and clinical characteristics of myelin oligodendrocyte glycoprotein antibody-associated disease in a nationwide survey

Nakamura M, Ogawa R, Fujimori J, Uzawa A, Sato Y, Nagashima K, Kuriyama N, Kuwabara S, Nakashima I

Multiple Sclerosis Journal 29 （ 4–5 ） 530 - 539 2023年04月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

BACKGROUND: To our knowledge, no nationwide epidemiological study of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has been conducted. OBJECTIVE: We examined the epidemiology and clinical features of MOGAD in Japan. METHODS: We distributed questionnaires on the clinical characteristics of patients with MOGAD to neurology, pediatric-neurology, and neuro-ophthalmology facilities throughout Japan. RESULTS: In total, 887 patients were identified. The estimated number of total and newly diagnosed MOGAD patients was 1,695 [95% confidence interval (CI): 1483-1907] and 487 (95% CI: 414-560), respectively. The estimated prevalence and incidence were 1.34/100,000 (95% CI: 1.18-1.51) and 0.39/100,000 (95% CI: 0.32-0.44), respectively. The median age at onset was 28 years (range: 0-84 years). At onset, optic neuritis was present in approximately 40% of patients, irrespective of the onset age. Acute disseminated encephalomyelitis was more frequent in younger patients, whereas brainstem encephalitis, encephalitis, and myelitis were more frequent in elderly patients. Immunotherapy was highly effective. CONCLUSION: The prevalence and incidence rates of MOGAD in Japan are similar to those in other countries. Notable characteristics such as the preferential occurrence of acute disseminated encephalomyelitis in children exist; however, general characteristics including symptoms and treatment response are common irrespective of the onset age.

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Impaired dynamic response of oxygen saturation during the 6-min walk test is associated with mortality in chronic fibrosing interstitial pneumonia

Imamura S, Inagaki T, Abe M, Terada J, Kawasaki T, Nagashima K, Tatsumi K, Suzuki T

Respiratory Care 68 （ 3 ） 356 - 365 2023年03月

研究論文（学術雑誌）, 共著, 査読有り

Evaluating the efficacy of post-operative chemotherapy after curative resection of stage IV gastric cancer with synchronous oligo metastasis: a multicenter retrospective study

Yamaguchi Y, Takashima A, Nagashima K, Kumagai K, Yamada T, Terashima M, Yabusaki H, Nishikawa K, Tanabe K, Yunome G, Kawachi Y, Yamada T, Fukagawa T, Kinoshita T, Watanabe M, Ishiyama K, Inoue K, Boku N

Gastric Cancer 26 （ 2 ） 307 - 316 2023年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14363291

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Impact of coronavirus disease 2019 pandemic on breast cancer surgery using the National Database of Japan

Fujita M, Hashimoto H, Nagashima K, Suzuki K, Kasai T, Yamaguchi K, Onouchi Y, Sato D, Fujisawa T, Hata A

Scientific Reports 13 （ 1 ） 4977 2023年03月

研究論文（学術雑誌）, 共著, 査読有り

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Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan

Aoki M, Kadowaki S, Takahashi N, Suzuki T, Oshima K, Ando T, Yamamoto Y, Kawakami K, Kito Y, Matsumoto T, Shimozaki K, Miyazaki Y, Yamaguchi T, Nagase M, Tamura T, Amanuma Y, Esaki T, Miura Y, Akiyoshi K, Baba E, Makiyama A, Negoro Y, Nakashima K, Sugimoto N, Nagashima K, Shoji H, Boku N

Gastric Cancer 26 （ 1 ） 132 - 144 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

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Diverse and divergent functions of IL-32β and IL-32γ isoforms in the regulation of malignant pleural mesothelioma cell growth and the production of VEGF-A and CXCL8

Numasaki M, Ito K, Takagi K, Nagashima K, Notsuda H, Ogino H, Ando R, Tomioka Y, Suzuki T, Okada Y, Nishioka Y, Unno M

Cellular Immunology （Cellular Immunology）  383   104652 - 104652 2023年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0008-8749

　概要を見る

In this study, we sought to elucidate the roles of the interleukin (IL)-32β and IL-32γ in mesothelioma cell growth, and vascular endothelial growth factor (VEGF)-A and C-X-C motif chemokine ligand 8 (CXCL8) expression. IL-32 elicited a growth-promoting effect against one of the six mesotheliomas lines and exerted diverse regulatory functions in VEGF-A and CXCL8 secretion from mesotheliomas stimulated with or without IL-17A. Retroviral-mediated transduction of mesothelioma lines with IL-32γ resulted in enhanced IL-32β expression, which facilitated or suppressed the in vitro growth, and VEGF-A and CXCL8 expression. Overexpressed IL-32β-augmented growth and VEGF-A and CXCL8 production were mainly mediated through the phosphatidylinositol-3 kinase (PI3K) signaling pathway. On the other hand, overexpressed IL-32β-deceased growth was mediated through mitogen-activated protein kinase (MAPK) pathway. NCI-H2373IL-32γ tumors grew faster than NCI-H2373Neo tumors in a xenograft model, which was associated with increased vascularity. These findings indicate that IL-32 are involved in the regulation of growth and angiogenic factor production in mesotheliomas.

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The body mass index change is associated with death or hemodialysis transfer in Japanese patients initiating peritoneal dialysis

Kojima D, Washida N, Uchiyama K, Hama EY, Nagasaka T, Kusahana E, Nakayama T, Nagashima K, Sato Y, Morimoto K, Kanda T, Itoh H

Renal Failure 45 （ 1 ） 2163904 2023年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0886-022X

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Polysulfide Serves as a Hallmark of Desmoplastic Reaction to Differentially Diagnose Ductal Carcinoma In Situ and Invasive Breast Cancer by SERS Imaging

Kubo A, Masugi Y, Hase T, Nagashima K, Kawai Y, Takizawa M, Hishiki T, Shiota M, Wakui M, Kitagawa Y, Kabe Y, Sakamoto M, Yachie A, Hayashida T, Suemats M

Antioxidants 12 （ 2 ） 240 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

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Group multi‐component programme based on cognitive behavioural therapy and positive psychology for family caregivers of people with dementia: a randomised controlled study (3C study)

Noriko Takasaki Tamura, Ryo Shikimoto, Kengo Nagashima, Yasunori Sato, Atsuo Nakagawa, Sachiko Irie, Satoru Iwashita, Masaru Mimura, Daisuke Fujisawa

Psychogeriatrics （Psychogeriatrics）  23 （ 1 ） 141 - 156 2023年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1346-3500

　概要を見る

Background: Caregivers of people with dementia frequently experience an elevated level of psychological distress and burden. This study aimed to examine the effectiveness of a group-format multi-component programme which is based on cognitive behavioural therapy and positive psychology. Methods: Family caregivers of dementia were allocated (1:1) to the intervention group and the wait-list control group, stratified by age (<65 years, ≥65 years) and care status (at home or in an institution). The intervention group received a six-session, 10-week, group-format programme. The primary outcome was the Hospital Anxiety Depression Scale (HADS). Secondary outcomes were the short-version of the Zarit Burden Interview (personal strain and role strain), Neuropsychiatric Inventory Questionnaire, Dementia Caregiver Positive Feeling Scale, and Self-Compassionate Reactions Inventory. The evaluations were conducted at baseline, 10 weeks (post-intervention), and 14 weeks (follow-up). Results: The analyses were performed with 64 registered participants. In the whole sample, no significant effect was observed on HADS. There was medium effect on role strain (P = 0.04, partial η2 = 0.08). Positive feelings of caregiving increased after the intervention but were not maintained at follow-up. In the subgroup analysis of caregivers under 65 years of age, a statistically significant effect was observed for personal strain (P = 0.03, partial η2 = 0.16). An interaction effect was also found for the total score of positive feelings of caregiving (P < 0.05, partial η2 = 0.02) and the meaning of caregiving (P = 0.02, partial η2 = 0.10). Conclusions: This programme did not show significant improvement in depression and anxiety of caregivers of dementia; however, it reduced the burden of their role conflict (role strain) and yielded favourable short-term effects on the positive feelings and the meaning of caregiving among the participants. Also, the programme effectively reduced the personal strain of caregivers under 65 years.

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WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study)

Keitaro Shimozaki, Kenro Hirata, Taro Sato, Maho Nakamura, Kyoko Kato, Hidekazu Hirano, Yosuke Kumekawa, Kaori Hino, Kentaro Kawakami, Yosuke Kito, Toshihiko Matsumoto, Takeshi Kawakami, Masato Komoda, Kengo Nagashima, Yasunori Sato, Kentaro Yamazaki, Shuichi Hironaka, Hiromasa Takaishi, Yasuo Hamamoto, Kei Muro

Clinical Colorectal Cancer 21 （ 4 ） 339 - 346 2022年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15330028

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HPV vaccine intention among university students during suspension of active recommendation in Japan

Suzuki T, Ota Y, Sakata N, Fujita N, Kamatsuka M, Nagashima K, Hirayama J, Terada Y, Nomura K

Human Vaccines & Immunotherapeutics 18 （ 6 ） 2116900 2022年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2164-5515

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Influence of LINE-Assisted Provision of Information about Human Papillomavirus and Cervical Cancer Prevention on HPV Vaccine Intention: A Randomized Controlled Trial

Ota Y, Nomura K, Fujita N, Suzuki T, Kamatsuka M, Sakata N, Nagashima K, Hirayama J, Fujita N, Shiga K, Oyama N, Terada Y

Vaccines （Vaccines）  10 （ 12 ） 2005 - 2005 2022年11月

研究論文（学術雑誌）, 共著, 査読有り

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We conducted a prospective, randomized two-arm, parallel group, and open label trial to investigate whether the use of LINE would increase HPV vaccine intention among not completely vaccinated university students. In June 2020, we recruited students aged between 18 and 35 years from four universities in Japan. Among the 357 enrollees (female, 53%), 178 and 179 participants were randomized into the LINE and Mail groups, respectively. At baseline, within three years, vaccine intention was observed in 40% vs. 42% of participants, respectively. At the first intervention, which provided similar PDF leaflets about HPV vaccine and cervical cancer prevention, there was no significant difference in vaccine intention between the two groups. However, at the second intervention of LINE-assisted knowledge intervention for 5 days per week for 7 weeks, the LINE group had a higher proportion of vaccine intention than the no intervention group (66% vs. 44%, OR: 2.62, 95% confidence interval (CI): 1.59–4.35) in per-protocol analysis. The significance remained in the intention-to-treat analysis of multiply imputed datasets. Although LINE did not directly increase HPV vaccine intention compared to conventional posts, the LINE-assisted provision of information was effective in improving HPV vaccine intention among Japanese university and college students.

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Real impact of oxaliplatin in adjuvant chemotherapy for patients with stage III colon cancer based on the Multi-Institutional Registry of Large Bowel Cancer in Japan

Yamada Y, Kobayashi H, Nagashima K, Sugihara K

Global Health & Medicine 4 （ 5 ） 259 - 267 2022年10月

研究論文（学術雑誌）, 共著, 査読有り

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Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum

Takahiko Ito, Atsuo Takashima, Kentaro Yamazaki, Hiroki Yukami, Hiroyuki Uetake, Masahiro Tsuda, Takeshi Suto, Toshikazu Moriwaki, Naotoshi Sugimoto, Hitoshi Ojima, Yasumasa Takii, Hisateru Yasui, Taito Esaki, Akihito Tsuji, Masahiro Goto, Masayuki Saruta, Satoshi Otsu, Katsunori Shinozaki, Toshiyoshi Fujiwara, Takao Tamura, Eishi Baba, Manabu Shiozawa, Tadamichi Denda, Hideki Ueno, Kengo Nagashima, Yasuhiro Shimada

International Journal of Clinical Oncology 27 （ 9 ） 1450 - 1458 2022年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

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Implementation of a self-sampling HPV test for non-responders to cervical cancer screening in Japan: secondary analysis of the ACCESS trial

Fujita M, Nagashima K, Shimazu M, Suzuki M, Tauchi I, Sakuma M, Yamamoto S, Hanaoka H, Shozu M, Tsuruoka N, Kasai T, Hata A

Scientific Reports 12 （ 1 ） 14531 2022年08月

研究論文（学術雑誌）, 共著, 査読有り

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Relationship between Dose Prescription Methods and Local Control Rate in Stereotactic Body Radiotherapy for Early Stage Non-Small-Cell Lung Cancer: Systematic Review and Meta-Analysis

Takahisa Eriguchi, Atsuya Takeda, Takafumi Nemoto, Yuichiro Tsurugai, Naoko Sanuki, Yudai Tateishi, Yuichi Kibe, Takeshi Akiba, Mari Inoue, Kengo Nagashima, Nobuyuki Horita

Cancers 14 （ 15 ） 3815 - 3815 2022年08月

共著, 査読有り

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Synergistic Effect of Motivation for the Elderly and Support for Going out

Mashimo Y, Tsuchihashi S, Tsutsui K, Arai T, Tsuji Y, Numai T, Kameda K, Nishizawa K, Kobati M, Tanaka S, Watanabe H, Naruse Y, Ohmura M, Ishida N, Iwasaki T, Hiruma G, Miyazaki N, Takemura R, Nagashima K, Sato Y, Ohtsu Y, Nakano T, Aida N, Iizuka I, Kato H, Kobayashi Y, Senbonmatsu T

Journal of Personalized Medicine 12 （ 8 ） 1257 - 1257 2022年07月

研究論文（学術雑誌）, 共著, 査読有り

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Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer

Hashimoto T, Takayanagi D, Yonemaru J, Naka T, Nagashima K, Yatabe Y, Shida D, Hamamoto R, Kleeman SO, Leedham SJ, Maughan T, Takashima A, Shiraishi K, Sekine S

British Journal of Cancer 127 （ 6 ） 1043 - 1050 2022年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00070920

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Non-invasive risk stratification of IPMN with malignant potential by serum apolipoprotein-A2-isoforms

Felix K, Honda K, Nagashima K, Kashiro A, Takeuchi K, Kobayashi T, Hinterkopf S, Gaida MM, Dang H, Brindl N, Kaiser J, Büchler MW, Strobel O

International Journal of Cancer 150 （ 5 ） 881 - 894 2022年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0020-7136

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Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas

Noro R, Honda K, Nagashima K, Motoi N, Kunugi S, Matsubayashi J, Takeuchi S, Shiraishi H, Okano T, Kashiro A, Meng X, Yoshida Y, Watanabe S-i, Usuda J, Inoue T, Wilber H, Ikeda N, Seike M, Gemma A, Kubota K

Cancer Science 113 （ 3 ） 1002 - 1009 2022年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1347-9032

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Impaired neuromuscular transmission in facial muscles of amyotrophic lateral sclerosis: A single-fiber electromyography study

Watanabe K, Shibuya K, Misawa S, Nagashima K, Suzuki Y-i, Suichi T, Kojima Y, Nakamura K, Kano H, Prado M, Uzawaa A, Kuwabara S

Neurology and Clinical Neuroscience 10 （ 2 ） 78 - 82 2022年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2049-4173

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Reliability and validity of the Japanese version of the 4A's Test for delirium screening in the elderly patient

Hasegawa T, Seo T, Kubota Y, Sudo T, Yokota K, Miyazaki N, Muranaka A, Hirano S, Yamauchi A, Nagashima K, Iyo M, Sakai I

Asian Journal of Psychiatry 67   102918 2022年02月

研究論文（学術雑誌）, 共著, 査読有り

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Study protocol of the ACCESS trial: A randomized trial to evaluate the effectiveness of human papillomavirus testing by self-sampling in cervical cancer screening uptake and precancer detection

Fujita M, Shimazu M, Nagashima K, Suzuki M, Tauchi I, Sakuma M, Yamamoto S, Shozu M, Hanaoka H, Tsuruoka N, Kasai T, Hata A

BMJ Open 12 （ 2 ） e049803 2022年02月

研究論文（学術雑誌）, 共著, 査読有り

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Evolution of survival impact of molecular target agents in patients with advanced hepatocellular carcinoma

Kobayashi K, Ogasawara S, Takahashi A, Seko Y, Unozawa H, Sato R, Watanabe S, Moriguchi M, Morimoto N, Tsuchiya S, Iwai K, Inoue M, Ogawa K, Ishino T, Iwanaga T, Sakuma T, Fujita N, Kanzaki H, Koroki K, Nakamura M, Kanogawa N, Kiyono S, Kondo T, Saito T, Nakagawa R, Suzuki E, Ooka Y, Nakamoto S, Tawada A, Chiba T, Arai M, Kanda T, Maruyama H, Nagashima K, Kato J, Isoda N, Aramaki T, Itoh Y, Kato N

Liver Cancer 11 （ 1 ） 48 - 60 2022年01月

研究論文（学術雑誌）, 共著, 査読有り

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Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer

Yamamoto S, Nagashima K, Kawakami T, Mitani S, Komoda M, Tsuji Y, Izawa N, Kawakami K, Yamamoto Y, Makiyama A, Yamazaki K, Masuishi T, Esaki T, Nakajima TE, Okuda H, Moriwaki T, Boku N

BMC Cancer 21 （ 1 ） 1 - 9 2021年10月

研究論文（学術雑誌）, 共著, 査読有り

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A Phase I study of pevonedistat plus capecitabine plus oxaliplatin in patients with advanced gastric cancer refractory to platinum (NCCH-1811)

Shoji H, Takahari D, Hara H, Nagashima K, Adachi J, Boku N

Future Science OA 7 （ 7 ） fso721 2021年08月

研究論文（学術雑誌）, 共著, 査読有り

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On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity

Honda K, Hishiki T, Yamamoto S, Yamamoto T, Miura N, Kubo A, Itoh M, Chen W-Y, Takano M, Yoshikawa T, Kasamatsu T, Sonoda S, Yoshizawa H, Nakamura S, Itai Y, Shiota M, Koike D, Naya M, Hayakawa N, Naito Y, Matsuura T, Iwaisako K, Masui T, Uemoto S, Nagashima K, Hashimoto Y, Sakuma T, Matsubara O, Huang W, Ida T, Akaike T, Masugi Y, Sakamoto M, Kato T, Ino Y, Yoshida H, Tsuda H, Hiraoka N, Kabe Y, Suematsu M

Redox Biology 41   101926 - 101926 2021年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  22132317

　概要を見る

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm ; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm , manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance. −1 −1

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Impact of preoperative chemotherapy as initial treatment for advanced gastric cancer with peritoneal metastasis limited to positive peritoneal lavage cytology (CY1) or localized peritoneal metastasis (P1a): A multi-institutional retrospective study

Yamaguchi T, Takashima A, Nagashima K, Terashima M, Aizawa M, Ohashi M, Tanaka R, Yamada T, Kinoshita T, Inada T, Ishiyama K, Ema A, Yuasa Y, Haruta S, Kakihara N, Nishikawa K, Yunome G, Satoh T, Fukagawa T, Katai H, Boku N

Gastric Cancer    In press 2021年04月

研究論文（学術雑誌）, 共著, 査読有り

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Biomechanical evaluation of opponensplasty for low median palsy: a cadaver study

Iwase M, Matsuura Y, Kuniyoshi K, Suzuki T, Nagashima K, Ohtori S

Journal of Hand Surgery Global Online 3 （ 2 ） 74 - 80 2021年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2589-5141

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Purpose: Impaired thumb opposition associated with advanced carpal tunnel syndrome may be treated by opponensplasty at the time of open carpal tunnel release. However, it is unclear which opponensplasty technique achieves the greatest functional improvement. This study aimed to compare the biomechanics of thumb opposition after Camitz, modified Camitz, and Burkhalter opponensplasties. Methods: We used 6 fresh-frozen cadaveric arms. Each procedure was reproduced on each arm: Camitz opponensplasty, modified Camitz opponensplasty involving palmaris longus transfer routed around the flexor carpi ulnaris pulley, and Burkhalter opponensplasty. Arms were fixed with the wrist in 0° flexion and the forearm in neutral pronosupination, and sensors were placed on the thumbnail, radial styloid, and dorsal aspect of the second metacarpal head. The donor tendon was pulled using a mechanical testing machine with a maximum force of 25 N, and the locations of the sensors in thumb opposition were recorded. The first web space and thumb pronation angles were measured for each procedure and compared. Results: The mean first web space and pronation angles produced using 25 N were 55° and 20°, 57° and 26°, and 53° and 29° for the Camitz, modified Camitz, and Burkhalter opponensplasties, respectively. The first web space angle was significantly larger after modified Camitz opponensplasty compared with Burkhalter opponensplasty with 25 N loading. Camitz opponensplasty resulted in a significantly smaller pronation angle compared with modified Camitz and Burkhalter opponensplasties with 25 N loading. Conclusions: The modified Camitz opponensplasty produces a relatively balanced biomechanical outcome in terms of the first web space and pronation angles. Conversely, Burkhalter opponensplasty has been shown to be a favorable technique for improving pronation. Clinical relevance: Modified Camitz opponensplasty with a pulley offers effective restoration of thumb opposition, including pronation. On the other hand, Burkhalter opponensplasty represents a suitable option not only for patients with high median palsy and injury to the palmar aponeurosis but also for those who require improved pronation.

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Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study)

Koshizaka M, Ishikawa K, Ishibashi R, Maezawa Y, Sakamoto K, Uchida D, Nakamura S, Yamaga M, Yokoh H, Kobayashi A, Onishi S, Kobayashi K, Ogino J, Hashimoto N, Tokuyama H, Shimada F, Ohara E, Ishikawa T, Shoji M, Ide S, Ide K, Baba Y, Hattori A, Kitamoto T, Horikoshi T, Shimofusa R, Takahashi S, Nagashima K, Sato Y, Takemoto M, Newby LK, Yokote K, on behalf of the PRIME-V study group

Journal of Diabetes Investigation 12 （ 2 ） 200 - 206 2021年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  20401116

　概要を見る

Aims/Introduction: Recent randomized clinical trials have suggested that sodium–glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium–glucose cotransporter 2 inhibitors on bone and muscle are unclear. Materials and Methods: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium–glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m and hemoglobin A1c 7–10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000–1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. Results: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs −10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. Conclusions: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin. 2

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Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy

Nagata Y, Kato K, Miyamoto T, Hirano H, Shoji H, Iwasa S, Honma Y, Takashima A, Hamaguchi T, Matsushita H, Nagashima K, Saruta M, Boku N

Supportive Care in Cancer 28 （ 12 ） 5861 - 5869 2020年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09414355

　概要を見る

Purpose: Gastrointestinal cancer is frequently associated with malignant ascites, resulting in poor prognosis. While cell-free and concentrated ascites reinfusion therapy (CART) improves ascites-related symptoms, its clinical impact in combination with systemic chemotherapy is unclear. The purpose of this study was to evaluate the safety and efficacy of CART in gastrointestinal cancer patients with massive ascites treated with chemotherapy. Methods: We retrospectively reviewed the medical records of gastrointestinal cancer patients with massive ascites who received CART and chemotherapy at our hospital between July 2015 and September 2017. Results: A total of 30 patients received CART and chemotherapy: gastric cancer (n = 21) and colorectal cancer (n = 9). The initial CART improved performance status in 20% of the patients, and the mean serum albumin and creatinine was significantly improved. Median time to treatment failure and overall survival of chemotherapy following CART were 2.1 and 3.5 months in gastric cancer patients and 5.8 and 5.8 months in colorectal cancer patients, respectively. The frequency of paracentesis was decreased after introduction of CART followed by chemotherapy in 83% of gastric cancer and in all colorectal cancer patients who had received paracentesis before the initial CART. There were no grade 3/4 adverse events during the CART procedure. Grade 3/4 hematotoxic and non-hematotoxic adverse events of chemotherapy following CART were 30% and less than 10%, respectively. Conclusions: The combination of CART followed by chemotherapy is safe and could be a treatment option for gastrointestinal cancer patients with massive ascites.

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Hepatic Arterial Infusion Chemotherapy versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma

Ueshima K, Ogasawara S, Ikeda M, Yasui Y, Terashima T, Yamashita T, Obi S, Sato S, Aikata H, Ohmura T, Kuroda H, Ohki T, Nagashima K, Ooka Y, Takita M, Kurosaki M, Chayama K, Kaneko S, Izumi N, Kato N, Kudo M, Omata M

Liver Cancer 9 （ 5 ） 583 - 595 2020年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  22351795

　概要を見る

Background: Prior to the approval of sorafenib, hepatic arterial infusion chemotherapy (HAIC) was offered to patients with advanced hepatocellular carcinoma (HCC) in East Asia, particularly Japan. According to the Japanese guidelines, HAIC is recommended as one of the treatment options in patients without extrahepatic metastasis (EHM). Methods: The present cohort study compared the use of HAIC and sorafenib on outcomes of patients with advanced HCC. Consecutive patients with advanced HCC who received HAIC or sorafenib as a first-line systemic therapy were enrolled from 10 Japanese institutions. The primary outcomes were overall survival (OS) in patients with macrovascular invasion (MVI), but without EHM, and OS in patients without both MVI and EHM. Results: Between 2009 and 2016, 2,006 patients were enrolled (541 HAIC patients, 1,465 sorafenib patients). After propensity score matching, the OS of patients with MVI but without EHM was significantly longer in the HAIC group compared with the sorafenib group (10.1 vs. 9.1 months for the HAIC and sorafenib groups, respectively; n = 170 for each group; hazard ratio [HR] 0.668; 95% confidence interval [95% CI] 0.475-0.935; p = 0.018). There was no significant difference in OS between patients without both MVI and EHM (12.2 vs. 15.4 months for the HAIC and sorafenib groups, respectively; n = 76 in each cohort after propensity score matching; HR 1.227; 95% CI 0.699-2.155; p = 0.475). Conclusion: HAIC is a potential front-line treatment choice in a subpopulation of patients with advanced HCC with MVI but without EHM.

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Long-term efficacy of pulmonary rehabilitation with home-based or low frequent maintenance programs in patients with chronic obstructive pulmonary disease: a meta-analysis

Imamura S, Inagaki T, Terada J, Nagashima K, Katsura H, Tatsumi K

Annals of Palliative Medicine 9 （ 5 ） 2606 - 2615 2020年09月

研究論文（学術雑誌）, 共著, 査読有り

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Maternal body mass index and breastfeeding non-initiation and cessation: a quantitative review of the literature

Nomura K, Minamizono S, Nagashima K, Ono M, Kitano N

Nutrients 12 （ 9 ） 1 - 22 2020年09月

研究論文（学術雑誌）, 共著, 査読有り

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This study aims to investigate which maternal body mass index (BMI) categories are associated with the non-initiation or cessation of breastfeeding (BF) based on a quantitative review of the literature. We searched Ovid MEDLINE and EBSCO CINAHL for peer-reviewed articles published between 1946 (MEDLINE) or 1981 (CINAHL), and 2019. Selected studies were either cross-sectional or cohort studies, of healthy mothers and infants, that reported nutrition method (exclusive/full or any) and period (initiation/duration/cessation) of breastfeeding according to maternal BMI levels. Pairwise meta-analyses of 57 studies demonstrated that the pooled odds risks (OR) of not initiating BF among overweight and obese mothers compared to normal weight mothers were significant across 29 (OR 1.33, 95% confidence interval (CI), 1.15–1.54, I = 98%) and 26 studies (OR 1.61, 95% CI, 1.33–1.95, I = 99%), respectively; the pooled risks for BF cessation were inconsistent in overweight and obese mothers with substantial heterogeneity. However, we found that overweight mothers (n = 10, hazard ratio (HR) 1.16, 95% CI, 1.07–1.25; I = 23%) and obese mothers (n = 7, HR 1.45, 95% CI: 1.27–1.65; I = 44%) were both associated with an increased risk of not continuing any BF and exclusive BF, respectively. Overweight and obese mothers may be at increased risk of not initiating or the cessation of breastfeeding. 2 2 2 2

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Prospective study using plasma apolipoprotein A2-isoforms to screen for high-risk status of pancreatic cancer

Sato Y, Kobayashi T, Nishiumi S, Okada A, Fujita T, Sanuki T, Kobayashi M, Asahara M, Adachi M, Sakai A, Shiomi H, Masuda A, Yoshida M, Takeuchi K, Kodama Y, Kutsumi H, Nagashima K, Honda K

Cancers 12 （ 9 ） 1 - 16 2020年09月

研究論文（学術雑誌）, 共著, 査読有り

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Apolipoprotein A2-ATQ/AT (apoA2-ATQ/AT) has been identified as a minimally invasive biomarker for detecting pancreatic cancer (PC) and high-risk (HR) individuals for PC. To establish an efficient enrichment strategy for HR, we carried out a plasma apoA2-ATQ/AT levelbased prospective screening study among the general population. The subjects for the screening study were recruited at six medical check-up facilities in Japan between October 2015 and January 2017. We evaluated the positive predictive value (PPV) of the plasma apoA2-ATQ/AT level of ≤35 μg/mL for detecting PC and HR. Furthermore, we prospectively confirmed its diagnostic accuracy with another post-diagnosis population in a cross-sectional study. We enrolled 5120 subjects in experimental screening, with 84 subjects (1.3%) showing positive results for apoA2-ATQ/AT. Pancreatic abnormalities were recognized in 26 of the 84 subjects from imaging examinations. Pancreatic abnormalities detected included 1 PC and 15 HR abnormalities, such as cystic lesions including intraductal papillary mucinous neoplasm. The PPV of apoA2-ATQ/AT for detecting PC and HR was 33.3%. Moreover, a combination study with another cross-sectional study revealed that the area under the curve for apoA2-ATQ/AT to distinguish PC from healthy controls was 0.903. ApoA2-ATQ/AT has the potential to enrich PC and HR by increasing the diagnostic probability before imaging examinations.

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Safety and efficacy of ranibizumab and luseogliflozin combination therapy in diabetic macular edema patients: protocol for a multicenter, randomized controlled, open-label trial

Ishibashi R, Takatsuna Y, Koshizaka M, Tatsumi T, Takahashi S, Nagashima K, Asaumi N, Arai M, Shimada F, Tachibana K, Watanabe Y, Ishikawa K, Hoshino A, Yamamoto K, Kubota-Taniai M, Mayama T, Yamamoto S, Yokote K

Diabetes Therapy 11 （ 8 ） 1891 - 1905 2020年08月

研究論文（学術雑誌）, 共著, 査読有り

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Safety and efficacy of ranibizumab and luseogliflozin combination therapy in diabetic macular edema patients: protocol for a multicenter, randomized controlled, open-label trial

Ishibashi R, Takatsuna Y, Koshizaka M, Tatsumi T, Takahashi S, Nagashima K, Asaumi N, Arai M, Shimada F, Tachibana K, Watanabe Y, Ishikawa K, Hoshino A, Yamamoto K, Kubota-Taniai M, Mayama T, Yamamoto S, Yokote K

Diabetes Therapy  11 （ 8 ） 1891 - 1905 2020年08月

研究論文（学術雑誌）, 共著

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Feasibility study of nivolumab as neoadjuvant chemotherapy for locally esophageal carcinoma: FRONTiER (JCOG1804E)

Yamamoto S, Kato K, Daiko H, Kojima T, Hara H, Abe T, Tsubosa Y, Nagashima K, Aoki K, Mizoguchi Y, Kitano S, Yachida S, Shiba S, Kitagawa Y

Future Oncology 16 （ 19 ） 1351 - 1357 2020年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14796694

　概要を見る

One of the standard treatments of resectable esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemotherapy followed by surgery. Nivolumab showed efficacy for metastatic ESCC. However, the safety and efficacy of neoadjuvant nivolumab with chemotherapy for ESCC is unknown. Therefore, we will conduct FRONTiER to evaluate the safety and efficacy of nivolumab adding to neoadjuvant chemotherapy. FRONTiER comprises four experimental cohorts: (A) including nivolumab plus 5-FU+CDDP (cisplatin and 5-fluorouracil [CF]); (B) including one prior administration of nivolumab and the cohort A regimen; (C) including nivolumab plus docetaxel+ CF; (D) including one prior administration of nivolumab and the cohort C regimen; an expanded cohort. The primary end point is the incidence of dose-limiting toxicities from the initial dose to the 30th postoperative day. Clinical Trial Identifier: NCT0391444.

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Lenalidomide Treatment for Thalidomide-refractory POEMS Syndrome: A Prospective Single-arm Clinical Trial

Suichi T, Misawa S, Nagashima K, Sato Y, Iwai Y, Katayama K, Sekiguchi Y, Shibuya K, Amino H, Suzuki Y-i, Tsuneyama A, Nakamura K, Kuwabara S

Internal Medicine 59 （ 9 ） 1149 - 1153 2020年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09182918

　概要を見る

Objective A randomized controlled trial has shown the efficacy of thalidomide against polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/ mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.

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Retrospective comparison of nab-paclitaxel plus ramucirumab and paclitaxel plus ramucirumab as second-line treatment for advanced gastric cancer focusing on peritoneal metastasis

Ishikawa M, Iwasa S, Aoki M, Imazeki H, Hirano H, Shoji H, Honma Y, Okita N, Nagashima K, Takashima A, Kato K, Saruta M, Boku N

Investigational New Drugs 38 （ 2 ） 533 - 540 2020年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01676997

　概要を見る

Background Ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard second-line chemotherapy for advanced gastric cancer (AGC). The subset analysis of the ABSOLUTE trial, which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis. We retrospectively evaluated the efficacy and safety of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC. Methods AGC patients who received RAM plus sb-PTX or nab-PTX as second-line chemotherapy from June 2015 to February 2019 were included in the study. Overall survival (OS), progression-free survival (PFS), response rate, and safety were assessed. Results A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group). PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95%CI 0.58–1.41, p = 0.643). OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95%CI 0.56–1.62, p = 0.847). A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively. RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 vs 3.5 months, HR 0.66; 95% CI 0.40–1.10, p = 0.109). Conclusion This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.

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Circulating anti-sorting nexins 16 antibodies as an emerging biomarker of coronary artery disease in patients with obstructive sleep apnea

Katsumata Y, Terada J, Matsumura T, Koshikawa K, Sakao S, Tomiyoshi G, Shinmen N, Nakamura R, Kuroda H, Nagashima K, Kobayashi Y, Kobayashi E, Iwadate Y, Zhang X-M, Hiwasa T, Tatsumi K

Diagnostics 10 （ 2 ） 71 2020年02月

研究論文（学術雑誌）, 共著, 査読有り

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Biomarkers are not available for monitoring the onset and progression of coronary artery disease (CAD) in patients with obstructive sleep apnea (OSA), a major risk factor for arteriosclerotic cardiovascular diseases. This study aimed to test for correlation between circulating anti-Sorting Nexins 16 antibody (SNX16-Ab) levels, CAD history and clinical parameters of patients with OSA. Sixty-four healthy donors, 82 adults with OSA, and 96 with acute coronary syndrome (ACS) were studied. Serum samples were collected at diagnostic polysomnography in the OSA group or at the disease onset in the ACS group. Serum SNX16-Ab levels were measured by amplified luminescence proximity homogeneous assay (AlphaLISA), and correlation between SNX16-Ab levels and clinical parameters was analyzed. SNX16-Ab levels and apnea-hypopnea index (AHI) were weakly correlated. Additionally, logistic regression analyses of OSA group identified that elevated SNX16-Ab level associated with the history of CAD. Circulating SNX16-Ab could increase during CAD pathogenesis in patients with OSA. Further prospective studies are required to prove the predictive potential of SNX16-Ab level in CAD onset of patients with OSA.

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Handheld flow meter improves COPD detectability regardless of using a conventional questionnaire: A split‐sample validation study

Fujita M, Nagashima K, Takahashi S, Suzuki K, Fujisawa T, Hata A

Respirology 25 （ 2 ） 191 - 197 2020年02月

研究論文（学術雑誌）, 共著, 査読有り

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Risk factors of severe benign cicatricial stricture after definitive chemoradiation for localized T3 esophageal carcinoma

Satomi NT, Honma Y, Nagashima K, Umezawa R, Ito Y, Hirano H, Shoji H, Takashima A, Iwasa S, Kato K, Hamaguchi T, Itami J, Boku N

Anticancer Research 40 （ 2 ） 1071 - 1077 2020年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02507005

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Background/Aim: Severe benign cicatricial stricture (SBCS) is a major complication after definitive chemoradiation therapy (dCRT) for esophageal squamous cell carcinoma (ESCC). This study was conducted to investigate risk factors of SBCS in patients with localized ESCC. Patients and Methods: This study included 197 patients with clinical stage (cSt) II/III ESCC with T3 primary tumor, treated with dCRT between 2000 and 2011. SBCS was defined as the inability to pass a 9-mm diameter endoscope or the presence of symptoms requiring treatment. Results: Complete response was obtained in 87 patients (44%). Multivariate analysis revealed that hypoalbuminemia (hazard ratio=5.65; 95% confidence interval=1.50-21.28; p=0.010) and the inability to pass an endoscope (hazard ratio=5.90; 95% confidence interval=1.52-22.85; p=0.010) were risk factors of SBCS. Conclusion: The inability to pass an endoscope and hypoalbuminemia were identified as risk factors of SBCS in patients with cSt II/III ESCC with T3 primary tumor.

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Efficacy of post-operative chemotherapy after resection leaving no macroscopically visible disease of gastric cancer with peritoneal lavage cytology positive (CY1) or localized peritoneum metastasis (P1a): a multicenter retrospective study

Yamaguchi T, Takashima A, Nagashima K, Makuuchi R, Aizawa M, Ohashi M, Tashiro K, Yamada T, Kinoshita T, Hata H, Kawachi Y, Kawabata R, Tsuji T, Hihara J, Sakamoto T, Fukagawa T, Katai H, Higuchi K, Boku N

Annals of Surgical Oncology （27(1):–292.）  27 （ 1 ） 284 - 292 2020年01月

研究論文（学術雑誌）, 共著, 査読有り

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Clinical outcomes of locally advanced esophageal neuroendocrine carcinoma treated with chemoradiotherapy

Honma Y, Nagashima K, Hirano H, Shoji H, Iwasa S, Takashima A, Okita N, Kato K, Boku N, Murakami N, Inaba K, Ito Y, Itami J, Kanamori J, Oguma J, Daiko H

Cancer Medicine 9 （ 2 ） 595 - 604 2020年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2045-7634

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Background: Neuroendocrine carcinoma (NEC) arising from the esophagus (EsoNEC) is extreme rare, accounting for approximately 1% of esophageal cancer. Even for localized NEC, multidisciplinary approach including chemotherapy is recommended in treatment guidelines because of its high rates of systemic recurrence. However, it is controversial whether adding surgery or radiotherapy is appropriate local treatment for EsoNEC. There have been few reports regarding the clinical outcomes of definitive chemoradiotherapy (dCRT) for EsoNEC. The purpose of this study was to clarify the survival outcome of patients with locally advanced EsoNEC treated with dCRT. Methods: Clinical outcomes, feasibility, and prognostic factors of patients with locally advanced EsoNEC treated with radiotherapy (60 Gy/30 fraction) in combination with platinum plus etoposide (CE-RT) or cisplatin plus 5-fluorouracil (CF-RT) at the National Cancer Center Hospital from 2001 to 2017 were retrospectively analyzed. Results: A total of 22 patients were identified as the subjects of this study. The overall response rate and clinical complete remission rate in all patients were 86.4% and 77.3%, respectively. The median progression-free survival and median survival time in all patients were 12.7 and 37.5 months, associated with a 5-year survival rate of 45.4%. Patients treated with CE-RT experienced more hematological adverse events, especially in neutropenia (≥grade 3) and febrile neutropenia(≥grade 3), but achieved more long-term progression-free survival than with CF-RT. Conclusions: Definitive chemoradiotherapy can be considered as an important treatment option for locally advanced esophageal neuroendocrine carcinoma.

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Quality and quantity of visceral fat tissue are associated with insulin resistance and survival outcomes after chemotherapy in patients with breast cancer

Iwase T, Sangai T, Fujimoto H, Sawabe Y, Matsushita K, Nagashima K, Sato Y, Nakagawa A, Masuda T, Nagashima T, Ohtsuka M

Breast Cancer Research and Treatment 179 （ 2 ） 435 - 443 2020年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01676806

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Purpose: Recent studies suggest that the quality and quantity of visceral adipose tissue (VAT) play significant roles in adipocyte function, and are related to insulin resistance. We tested the hypothesis that high amounts of upper VAT (aVAT) and low-quality VAT worsen treatment outcomes via altered insulin metabolism. Methods: Cohort 1 included 106 women with breast cancer who were undergoing surgery. Homeostasis model assessment of insulin resistance (HOMA-R), insulin-like growth factor (IGF)-1, and IGF-binding protein 3 (IGFBP3) were measured before the initiation of treatment. aVAT was measured via computed tomography (CT). VAT quality was assessed using CT-determined Hounsfield units (VAT-HU). Associations between the variables investigated and VAT quality and quantity were analyzed. Cohort 2 included 271 patients who underwent chemotherapy. Associations between the variables investigated and survival outcomes after chemotherapy were analyzed via retrospective chart review. Results: In cohort 1, aVAT was significantly correlated with insulin and HOMA-R levels. As body mass index (BMI) class increased, mean IGF-1 increased and mean IGFBP3 decreased, but these trends were not statistically significant. In cohort 2, aVAT was significantly positively correlated with BMI. The patients in the third aVAT tertiles had significantly shorter distant disease-free survival (dDFS) after neoadjuvant chemotherapy setting. In multivariate analysis, aVAT and VAT-HU were significantly associated with shorter dDFS. Conclusions: High aVAT and low-quality VAT were associated with poor survival outcome, increased insulin levels, and insulin resistance. The present study suggests the importance of evaluating the quality and quantity of VAT when estimating insulin resistance and treatment outcomes.

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Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy

Narita S, Nomura K, Hatakeyama S, Takahashi M, Sakurai T, Kawamura S, Hoshi S, Ishida M, Kawaguchi T, Ishidoya S, Shimoda J, Sato H, Mitsuzuka K, Tochigi T, Tsuchiya N, Ohyama C, Arai Y, Nagashima K, Habuchi T

Cancer Medicine 8 （ 15 ） 6566 - 6577 2019年11月

研究論文（学術雑誌）, 共著, 査読有り

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Background: The purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone-naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT). Methods: At nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer-specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models. Results: During a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5-year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5-year net CSS and OS survival gradually increased for all the patients. In patients given a 5-year survivorship, the conditional 5-year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors. Conclusions: The conditional 5-year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient's risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5-year follow-up. Conditional net survival can play a role in clinical decision-making, providing intriguing information for cancer survivors.

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Application of Japanese guidelines for gestational weight gain to multiple pregnancy outcomes and its optimal range in 101,336 Japanese women

Nomura K, Nagashima K, Suzuki T, Itoh H

Scientific Reports 9 （ 1 ） 17310 2019年11月

研究論文（学術雑誌）, 共著, 査読有り

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This study was performed to investigate whether the Japanese guidelines for gestational weight gain (GWG) can be used to determine the risks of multiple pregnancy outcomes and estimate optimal GWG in 101,336 women with singleton pregnancies in 2013. Multivariable logistic regression analyses indicated that the risks associated with low birth weight, small for gestational age, and preterm birth increased significantly with weight gain below the Japanese guidelines, and the risks of macrosomia and large for gestational age increased with weight gain above the guidelines regardless of Asian-specific pre-pregnancy body mass index (BMI). The GWG cutoff points estimated from the adjusted area under the receiver operating characteristics curve >0.6 corresponded to 10–13.8 kg in underweight women with pre-pregnancy BMI < 18.5 kg/m ; 10–13.7 kg in normal weight women with pre-pregnancy BMI 18.5–22.9 kg/m ; 8.5–11.4 kg in overweight women with pre-pregnancy BMI 23–24.9 kg/m , 5–13.3 kg in obese women with pre-pregnancy BMI 25–29.9 kg/m ; and 4.7 kg in obese women with pre-pregnancy BMI ≥ 30 kg/m . The optimal GWG ranges proposed by the present study are slightly higher than those recommended by the current Japanese guidelines. 2 2 2 2 2

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Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab

Masuda K, Shoji H, Nagashima K, Yamamoto S, Imazeki H, Aoki M, Miyamoto T, Hirano H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Boku N

BMC Cancer 19 （ 1 ） 1 - 10 2019年10月

研究論文（学術雑誌）, 共著, 査読有り

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Gastric mucosal injury and hemorrhage after definitive chemoradiotherapy for locally advanced esophageal cancer

Monma S, Kato K, Shouji H, Okita N, Takashima A, Honma Y, Iwasa S, Hamaguchi T, Yamada Y, Shimada Y, Boku N, Nagashima K, Ito Y, Itami J

Esophagus 16 （ 4 ） 402 - 407 2019年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  16129059

　概要を見る

Background: Definitive chemoradiotherapy is one of the treatment options for locally advanced esophageal cancer with curative intent. Esophagitis and pharyngitis are well-known adverse events that occur during chemoradiotherapy, but gastric mucosal injury has been less frequently reported compared to mucositis. Importantly, gastric mucosal injury is not well known, hard to manage, and sometimes fatal. Hence, we examined the clinical characteristics and the incidence of gastric mucosal injury after CRT for esophageal cancer. Methods: The medical records of patients who received definitive chemoradiotherapy combined with 5-fluorouracil and cisplatin for stage II/III (nonT4) esophageal squamous cell carcinoma from January 2001 to December 2010 at our institute were reviewed retrospectively. Results: We investigated 256 patients in whom, data for endoscopic abdomen examinations were both before and after CRT were available. Gastric mucosal damage was observed in 90 patients (35%) (grade 1/2/3 = 69/18/3). One of the possible risk factors identified in this study was the irradiation dose to abdomen. Compared to patients with cervical esophagus–upper thoracic esophagus tumor location, patients with middle thoracic esophagus–abdominal esophagus tumor location were more likely to develop gastric mucosal damage, although there was no statistically significant difference. Conclusions: It is important to consider gastric mucosal injury in patients who receive CRT, particularly when the irradiation field includes stomach.

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Inequality within a community at the neighborhood level and the incidence of mood disorders in Japan: a multilevel analysis

Fujita M, Nagashima K, Takahashi S, Hata A

Social Psychiatry and Psychiatric Epidemiology 54 （ 9 ） 1125 - 1131 2019年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09337954

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Purpose: This study analyzes whether income inequality within a community at the neighborhood level is associated with incidence of mood disorder in Japan. Methods: A retrospective cohort study was performed using the data of 116,658 National Health Insurance beneficiaries aged between 20 and 69 in Chiba City, Japan. To evaluate income inequality within a community, the Gini coefficient within a 30-min walking distance from an individual’s residence was calculated using income distribution estimated by the National Census and the Housing and Land Survey 2013. Incidence of mood disorder was determined through insurance claims submitted from April 1, 2013, to March 31, 2016. A multilevel logistic analysis with three levels—the individual, household, and residential district—was performed to evaluate the association. Results: Income inequality within a community at the neighborhood level was not associated with incidence of mood disorder in the models with and without equivalent household income (p for trend = 0.856 and 0.947, respectively). No difference was observed in the impact of the Gini coefficient among income levels, lower versus higher income groups (p for interaction between Gini coefficient and household income = 0.967). In contrast, lower equivalent income at the household level was significantly associated with higher incidence of mood disorder (p for trend < 0.001). Conclusions: While we confirmed that lower income at the household level itself had an adverse effect on mental health, income inequality within a community at the neighborhood level was not a significant factor for incidence of mood disorder in Japan.

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Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study)

Koshizaka M, Ishikawa K, Ishibashi R, Maezawa Y, Sakamoto K, Uchida D, Nakamura S, Yamaga M, Yokoh H, Kobayashi A, Onishi S, Kobayashi K, Ogino J, Hashimoto N, Tokuyama H, Shimada F, Ohara E, Ishikawa T, Shoji M, Ide S, Ide K, Baba Y, Hattori A, Kitamoto T, Horikoshi T, Shimofusa R, Takahashi S, Nagashima K, Sato Y, Takemoto M, Newby LK, Yokote K, On behalf of the PRIME-V study group

Diabetes, Obesity and Metabolism （Diabetes, Obesity and Metabolism）  21 （ 8 ） 1990 - 1995 2019年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14628902

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A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors. 2

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Prognostic significance of early changes in serum biomarker levels in patients with newly diagnosed metastatic prostate cancer

Narita S, Nomura K, Hatakeyama S, Takahashi M, Sakurai T, Kawamura S, Hoshi S, Ishida M, Kawaguchi T, Ishidoya S, Shimoda J, Sato H, Mitsuzuka K, Tochigi T, Tsuchiya N, Ohyama C, Arai Y, Nagashima K, Habuchi T

Scientific Reports 9 （ 1 ） 12071 2019年08月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

We evaluated the impact of early changes in serum biomarker levels on the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) who were initially treated with androgen deprivation therapy (ADT). We retrospectively investigated 330 patients with mHSPC whose serum maker levels were at baseline and at 2–4 months. An optimal Cox regression model was established with the highest optimism-corrected concordance index based on 10-fold cross-validation. The median cancer-specific survival (CSS) and overall survival (OS) were 7.08 and 6.47 years (median follow-up, 2.53 years), respectively. In the final optimal Cox model with serum biomarker levels treated as time-varying covariates, prostate-specific antigen (PSA), hemoglobin (Hb), and alkaline phosphatase (ALP) significantly increased the risk of poor survival in the context of both CSS and OS. Kaplan–Meier curves stratified by the three risk factors of high PSA, low Hb and high ALP desmondtated that median OS were not reached with none of these factors, 6.47 years with one or two factors, and 1.76 years with all three factors.Early changes in serum biomarker levels after ADT may be good prognostic markers for the survival of patients with mHSPC.

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Prognostic factors in patients who received end-of-life chemotherapy for advanced cancer

Hiramoto S, Tamaki T, Nagashima K, Hori T, Kikuchi A, Yoshioka A, Inoue A

International Journal of Clinical Oncology 24 （ 4 ） 454 - 459 2019年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

　概要を見る

Background: Clinical efficacy of aggressive end-of-life (EOL) chemotherapy remains unclear. Method: Medical records of patients with advanced cancer between August 2011 and August 2016 were retrospectively analyzed. The primary endpoint was to identify prognostic factors at the last administration of chemotherapy. The secondary endpoint was to analyze the relationship between EOL symptoms and EOL treatment details. Results: Among 300 evaluated patients, the number of patients who died within 14 and 30 days from the last administration of chemotherapy were 16 (5.3%) and 50 (16.7%), respectively. Multivariate analysis revealed that ECOG-PS (OR 3.698, p < 0.001) and GPS2 (OR 3.791, p = 0.028) were significant prognostic factors. The MST of patients with both PS 2–4 and GPS2 (+) was 38 days, while that in patients with both PS 0–1 and GPS2 (−) was 134.5 days. The prevalence rate of nausea and vomiting (25.0%) and the mean hydration volume (0.50 L/day) in patients who died within 30 days from the chemotherapy was significantly higher than others (7.4%) (0.20 L/day). Conclusion: ECOG-PS and GPS were significant prognostic factors for aggressive EOL chemotherapy. Information on these factors may aid clinical decision-making in terms of risk–benefit balance, particularly in patients with poor prognosis.

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Single-use suvorexant for treating insomnia during overnight polysomnography in patients with suspected obstructive sleep apnea: a single-center experience

Matsumura T, Terada J, Yoshimura C, Koshikawa K, Kinoshita T, Yahaba M, Nagashima K, Sakao S, Tatsumi K

Drug Design, Development and Therapy 13   809 - 816 2019年02月

研究論文（学術雑誌）, 共著, 査読有り

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Purpose: Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG. Patients and methods: An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant). Results: Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling. Conclusion: Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG.

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Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer

Aoki M, Shoji H, Nagashima K, Imazeki H, Miyamoto T, Hirano H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Higuchi K, Boku N

ESMO Open 4 （ 3 ） e000488 2019年01月

研究論文（学術雑誌）, 共著, 査読有り

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Background Nivolumab showed a survival benefit for advanced gastric cancer (AGC). However, an acceleration of tumour growth during immunotherapy, (hyperprogressive disease, HPD) has been reported in various cancers. This study reviewed the HPD in patients with AGC treated with nivolumab or irinotecan. Methods The subjects of this retrospective study were patients with AGC with measurable lesions, and their tumour growth rates (TGR) during nivolumab or irinotecan were compared with those during prior therapy. HPD was defined as an increase in TGR more than twofold. Results 34 and 66 patients received nivolumab and irinotecan in third or later line between June 2009 and September 2018 at our hospital; 22 patients receiving nivolumab had prior treatment with irinotecan, and one patient received irinotecan after nivolumab. Nivolumab and irinotecan showed no differences in disease control rates (38.2% and 34.8%) and in progression-free survival (PFS) (HR 1.1, 95% CI 0.7 to 1.6, p=0.802). The incidence of HPD was slightly higher after nivolumab (29.4%) than after irinotecan (13.5%) (p=0.0656), showing no differences in background between the patients with and without HPD. Compared between HPD and PD other than HPD after nivolumab, the HRs for PFS and overall survival (OS) were 1.1 (95% CI 0.5 to 2.7; p=0.756), and 2.1 (95% CI 0.7 to 5.8; p=0.168), but such clear difference in OS was not observed after irinotecan. Conclusions HPD was observed more frequently after nivolumab compared with irinotecan, which was associated with a poor prognosis after nivolumab but not so clearly after irinotecan.

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Phase II feasibility study of preoperative concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil and elective lymph node irradiation for clinical stage II/III esophageal squamous cell carcinoma

Hashimoto J, Kato K, Ito Y, Kojima T, Akimoto T, Daiko H, Hamamoto Y, Matsushita H, Katano S, Hara H, Tanaka Y, Saito Y, Nagashima K, Igaki H

International Journal of Clinical Oncology （International Journal of Clinical Oncology）  24 （ 1 ） 60 - 67 2019年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

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Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for stage II/III esophageal cancer. Preoperative chemotherapy is also considered a standard treatment for stage II/III esophageal squamous cell carcinoma (ESCC) in patients who undergo radical lymph node dissection. We conducted a feasibility study of preoperative CRT with cisplatin plus 5-fluorouracil (CF) and elective lymph node irradiation followed by esophagectomy with radical lymph node dissection in patients with stage II/III ESCC. Methods: Patients with clinical stage II/III, excluding T4, ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy comprised two courses of CF infusion repeated after 4-weeks. Radiation therapy was concurrently administered to the primary tumor, metastatic lymph nodes, and regional lymph nodes at a dose of 41.4 Gy. After the completion of CRT, transthoracic esophagectomy with 2–3 fields lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment with R0 resection. Results: Thirty-one eligible patients were enrolled. During CRT, the most common grade 3 or 4 toxicities were leukopenia (65%), neutropenia (65%), anemia (13%), thrombocytopenia (13%), febrile neutropenia (13%), anorexia (16%), esophagitis (16%) and hyponatremia (16%). Thirty patients (96.8%) underwent surgery. One patient received palliative chemotherapy because of appearance of lung metastasis during CRT. The completion rate of protocol treatment was 93.5% (29/31). There was one treatment-related death after surgery. Pathological complete response was achieved in 42% (13/30). Conclusion: Preoperative CRT with CF and elective lymph node irradiation showed an acceptable toxicity and promising activity especially in ESCC.

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大規模推測における最適なランキングと選択の方法：ベイズ流階層混合モデリングの応用

加藤 直広, 野間 久史, 長島 健悟

計算機統計学 32 （ 2 ） 105 - 117 2019年01月

研究論文（学術雑誌）, 共著, 査読有り

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Intravenous nicorandil versus adenosine for fractional flow reserve measurement: a crossover, randomized study

Nishi T, Kitahara H, Fujimoto Y, Nakayama T, Nagashima K, Hanaoka H, Kobayashi Y

Heart and Vessels 33 （ 12 ） 1570 - 1575 2018年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09108327

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Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. The objective of the present study was to investigate the effectiveness of intravenous (IV) nicorandil infusion for fractional flow reserve (FFR) measurement. In this crossover randomized study, 49 patients underwent FFR measurement with a consecutive randomized order of patient-blind infusions of continuous IV adenosine administration and a single bolus IV administration of nicorandil. The primary endpoint was the difference between the FFR by nicorandil and the FFR by adenosine, as assessed by the Bland–Altman method. The mean FFR value measured by nicorandil was not significantly different from that measured by adenosine [0.8125 ± 0.1349 vs. 0.7978 ± 0.124; mean difference, 0.0147 (95% confidence interval − 0.0373, 0.0667); P = 0.58]. There was no clinically significant diagnostic discordance, with the FFR by nicorandil > 0.80 and that by adenosine < 0.75. Hyperemia was achieved earlier using nicorandil than adenosine (34 ± 13 vs. 58 ± 15, P < 0.001). The duration of hyperemia after IV nicorandil was variable (6–570 s, mean 89 ± 98 s). IV nicorandil decreased systolic blood pressure by 32 ± 16 mm Hg (24 ± 10%) from baseline. Linear regression analysis showed that the average FFR value and the difference in systolic blood pressure were significantly associated with the bias in the FFR value between the two drugs. In conclusions, the results of the present study suggest that IV nicorandil can achieve maximal hyperemia easily and rapidly, providing an acceptable diagnostic performance for FFR assessment. However, a wide range of variation in hyperemic plateau and a decrease in blood pressure are the major limitations of this method.

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終末期進行がん患者における長期入院の予測因子と終末期症状・治療との関連

菊地綾子, 平本秀二, 堀哲雄, 吉岡亮, 長島健悟

Palliative Care Research 13 （ 4 ） 335 - 340 2018年12月

研究論文（学術雑誌）, 共著, 査読有り

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Hepatitis B virus reactivation in patients with rheumatoid arthritis: analysis of the National Database of Japan

Fujita M, Sugiyama M, Sato Y, Nagashima K, Takahashi S, Mizogami M, Hata A

Journal of Viral Hepatitis 25 （ 11 ） 1312 - 1320 2018年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13520504

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This study aimed to determine the incidence and risk factors for hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) undergoing immunosuppressive therapy. The National Database of Japan, in which insurance claim data have been comprehensively accumulated, was utilized. The subjects were 76 641 RA patients who were plausibly initiated on immunosuppressive therapy from April 2013 to March 2014. Laboratory tests of the hepatitis B surface antigen, anti-hepatitis B virus surface antibody, and anti-hepatitis B virus core antibody were performed in 28.23%, 12.52% and 14.63% of patients, respectively, when the therapy was initiated. We found that HBV reactivation and fulminant hepatitis occurred in both the patients with and without HBV DNA monitoring, indicating insufficient monitoring in Japan during the study. The cumulative incidence of HBV reactivation over 24 months was 1.57% (95% confidence interval [CI] = 1.28%-1.92%) in the monitoring group, which consisted of those with resolved HBV infection. Glucocorticoid administration was a potent risk factor for HBV reactivation (hazard ratio [HR] = 1.70, 95% CI = 1.26-2.29, P =.001 in all subjects, and HR = 1.82, 95% CI = 1.18-2.81, P =.007 in the nonmonitoring group), although it was not statistically significant in the monitoring group (HR = 1.49, 95% CI = 0.99-2.26 and P =.057). No significant risk difference was observed between single administration of methotrexate and biological drugs.

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Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain

Watanabe K, Hirano S, Kojima K, Nagashima K, Mukai H, Sato T, Takemoto M, Matsumoto K, Iimori T, Isose S, Omori S, Shibuya K, Sekiguchi Y, Beppu M, Amino H, Suichi T, Yokote K, Uno T, Kuwabara S, Misawa S

Journal of Neurology, Neurosurgery and Psychiatry 89 （ 10 ） 1082 - 1087 2018年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00223050

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Objective To assess the cerebral blood flow (CBF) in patients with diabetic neuropathic pain, and its changes after duloxetine therapy. Methods Using iodine-123-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (IMP-SPECT), we performed a cross-sectional study of 44 patients with diabetes, and compared CBF in those with (n = 24) and without neuropathic pain (n = 20). In patients with neuropathic pain, we also longitudinally assessed changes in CBF 3 months after treatment with duloxetine. Results IMP-SPECT with voxel-based analyses showed a significant increase in cerebral blood flow in the right anterior cingulate cortex and a decrease in the left ventral striatum in patients with neuropathic pain, compared with those without pain. After duloxetine treatment, volume of interest analyses revealed a decrease in cerebral blood flow in the anterior cingulate cortex in patients with significant pain relief but not in non-responders. Furthermore, voxel-based whole brain correlation analyses demonstrated that greater baseline CBF in the anterior cingulate cortex was associated with better pain relief on the numerical rating scale. Conclusions Our results suggest that the development of neuropathic pain is associated with increased activity in the anterior cingulate cortex, and greater baseline activation of this region may predict treatment responsiveness to pharmacological intervention. Trial registration number UMIN000017130;Results.

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Imaging peritoneal metastasis of gastric cancer with 18F-fluorothymidine positron emission tomography/computed tomography: a proof-of-concept study

Honma Y, Terauchi T, Tateishi U, Kano D, Nagashima K, Iwasa S, Takashima A, Kato K, Hamaguchi T, Boku N, Shimada Y, Yamada Y

British Journal of Radiology 91 （ 1089 ） 20180259 2018年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00071285

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objective: Peritoneal metastasis (PM) is the most frequent form of metastasis in gastric cancer (GC). The sensitivity of detecting PM by pre-operative imaging modalities is low. Utility of positron emission tomography (PET) with F-fluodeoxyglucose (FDG) for GC is limited, because diffuse-type tumors are not FDG-avid. F-fluothymidine ([F-18]FLT) is a radiotracer that reflects cellular proliferation and the utility of [F-18] FLT-PET in GC has been reported. In this proof-of-concept study, we explored the ability of [F-18]FLT-PET/CT to detect PM of GC previously identified by other imaging modalities. methods: The key eligibility criteria were as follows; (i) histologically proven gastric adenocarcinoma; (ii) evident PM detected by CT performed within 4 weeks prior to registration; (iii) no prior treatment of PM within 4 weeks before registration. [F-18]FLT-PET/CT was performed at National Cancer Center Hospital, and [F-18]FLT-PET/CT images were evaluated independently by two radiologists. Safety assessments were carried out before and after [F-18]FLT-PET/CT. The primary end point was the detection sensitivity of PM. results: A total of 19 eligible patients were analyzed, of which 15 (78.9%) had diffuse-type histology. Detection sensitivity of PM, primary lesion, and lymph node metastasis were 73.7% [maximum standardized uptake value (SUVmax): 1.697-13.21], 100% (SUVmax: 2.71-22.01), and 72.7% (SUVmax: 2.079-12.61), respectively. No patients experienced adverse events during or after [F-18] FLT-PET/CT. conclusion: This proof-of-concept study shows that [F-18]FLT-PET/CT is a sensitive method for detecting PM in GC, and paves the way for future studies investigating the clinical utility of this approach for the detection of clinically non-evident PM in GC. 18 18

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Medical costs attributable to overweight and obesity in Japanese individuals

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

Obesity Research and Clinical Practice 12 （ 5 ） 479 - 484 2018年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1871403X

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Objective: We aimed to reveal the association between body mass index (BMI) and medical costs in the current Japanese population, and to estimate the population attributable fraction (PAF) of medical costs due to overweight and obesity. Methods: A generalized linear mixed model with log link function and gamma distribution was used to evaluate the association between BMI and medical costs in 34,537 beneficiaries of the National Health Insurance aged 40–69 years in Chiba City. Medical cost data were obtained from insurance claims submitted between April 2012 and March 2016. PAFs due to overweight (BMI ≥25.0 and <30.0 kg/m ) and obesity (BMI ≥30.0 kg/m ) were calculated. Results: Overweight and obesity were significant predictors of excessive medical costs in all age and sex groups. PAF due to overweight and obesity was estimated to be 9.62% (95% confidence interval, 8.52–10.73%). Additionally, PAFs in 40–59-year-old individuals (12.76% in men and 11.63% in women) were greater than those in 60–69-year-old subjects (6.55% in men and 7.80% in women) for both sexes. Conclusions: In the Japanese population, overweight and obesity are an excessive financial burden with an estimated PAF of 9.62% of total medical costs. 2 2

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The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure (HOMES-HF)

Kotooka N, Kitakaze M, Nagashima K, Asaka M, Kinugasa Y, Nochioka K, Mizuno A, Nagatomo D, Mine D, Yamada Y, Kuratomi A, Okada N, Fujimatsu D, Kuwahata S, Toyoda S, Hirotani S-i, Komori T, Eguchi K, Kario K, Inomata T, Sugi K, Yamamoto K, Tsutsui H, Masuyama T, Shimokawa H, Momomura S-i, Seino Y, Sato Y, Inoue T, Node K, On behalf of the HOMES-HF study investigators

Heart and Vessels 33 （ 8 ） 866 - 876 2018年08月

研究論文（学術雑誌）, 共著, 査読有り

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Type of second primary malignancy after achieving complete response by definitive chemoradiation therapy in patients with esophageal squamous cell carcinoma

Yamaguchi T, Kato K, Nagashima K, Iwasa S, Honma Y, Takashima A, Hamaguchi T, Ito Y, Itami J, Boku N, Higuchi K

International Journal of Clinical Oncology 23 （ 4 ） 652 - 658 2018年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

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Background: While the standard treatment for stage II–III (non-T4) esophageal squamous cell carcinoma (ESCC) is neoadjuvant therapy followed by esophagectomy, definitive chemoradiation therapy (dCRT) is an option to treat ESCC patients who reject or may not tolerate surgical treatment. Second primary malignancy (SPM) is a problem for long-term survivors after achieving complete response (CR) by dCRT. Methods: The source of the subjects in this study was the patients with stage II/III (excluding T4 disease) ESCC (UICC6th) who underwent dCRT from 2000 to 2011 at the National Cancer Center Hospital, Japan. SPM, defined as malignancy newly detected at different site from the initial disease, was checked in patients who achieved CR by the initial dCRT. Results: Among the 285 patients with stage II/III (excluding T4 disease) ESCC who underwent dCRT, 185 patients achieved CR. SPM was detected in 49 patients (median time to developing SPM, 41.5 months), accounting for 19.3% (95% CI 0.137–0.257) as the 5-year cumulative risk of SPM. SPMs were head and neck cancer (n = 12), gastric cancer (n = 12), esophageal cancer (n = 7), lung cancer (n = 5), colon cancer (n = 4), diffuse large B-cell lymphoma (n = 3), bladder cancer (n = 2), small intestinal cancer (n = 1), cholangiocarcinoma (n = 1), malignant melanoma (n = 1), and breast cancer (n = 1). There were no significant differences in baseline characteristics between the patients who developed SPM (n = 49) and others (n = 136). Conclusions: Because second primary malignancy developed often after achieving CR by dCRT for ESCC, it should be followed carefully.

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Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial

Misawa S, Kuwabara S, Sato Y, Yamaguchi N, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kanouchi T, Kohara N, Kawamoto M, Ishii J, Kuwahara M, Suzuki H, Hirata K, Kokubun N, Masuda R, Kaneko J, Yabe I, Sasaki H, Kaida K-i, Takazaki H, Suzuki N, Suzuki S, Nodera H, Matsui N, Tsuji S, Koike H, Yamasaki R, Kusunoki S, for the Japanese Eculizumab Trial for GBS (JET-GBS) Study Group

The Lancet Neurology 17 （ 6 ） 519 - 529 2018年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14744422

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Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

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A phase II study of combination therapy with oral S-1 and cisplatin in elderly patients with advanced gastric cancer

Sasaki Y, Iwasa S, Okazaki S, Goto M, Kojima Y, Naganuma A, Nagashima K, Nagai Y, Hirano H, Honma Y, Takashima A, Kato K, Hamaguchi T

Gastric Cancer 21 （ 3 ） 439 - 445 2018年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14363291

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Background: A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer. Methods: Patients aged 76 years or older received S-1 40 mg/m orally twice daily for 21 days and cisplatin 60 mg/m intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events. Results: A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3–4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred. Conclusions: Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function. 2 2

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Heart rate and oxygen saturation change patterns during 6-min walk test in subjects with chronic thromboembolic pulmonary hypertension

Inagaki T, Terada J, Yahaba M, Kawata N, Jujo T, Nagashima K, Sakao S, Tanabe N, Tatsumi K

Respiratory Care 63 （ 5 ） 573 - 583 2018年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00201324

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BACKGROUND: The 6-min walk test (6MWT) is commonly performed to assess functional status in patients with chronic thromboembolic pulmonary hypertension. However, changes in heart rate and oxygen saturation (S ) patterns during 6MWT in patients with chronic thromboembolic pulmonary hypertension remain unclear. METHODS: Thirty-one subjects with chronic thromboembolic pulmonary hypertension were retrospectively evaluated to examine the relationships between the change in heart rate (Δheart rate), heart rate acceleration time, slope of heart rate acceleration, heart rate recovery during the first minute after 6MWT (HRR1), change in S (ΔS ), S reduction time, and S recovery time during 6MWT, and the severity of pulmonary hemodynamics assessed by right heart catheterization and echocardiography. RESULTS: Subjects with severe chronic thromboembolic pulmonary hypertension had significantly longer heart rate acceleration time (144.9 ± 63.9 s vs 96.0 ± 42.5 s, P = .033), lower Δheart rate (47.4 ± 16.9 vs 61.8 ± 13.6 beats, P = .02), and lower HRR1 (13.3 ± 9.0 beats vs 27.1 ± 9.2 beats, P < .001) compared to subjects with mild chronic thromboembolic pulmonary hypertension. Subjects with severe chronic thromboembolic pulmonary hypertension also had significantly longer S reduction time (178.3 ± 70.3 s vs 134.3 ± 58.4 s, P = .03) and S recovery time (107.6 ± 35.3 s vs 69.8 ± 32.7 s, P = .004) than did subjects with mild chronic thromboembolic pulmonary hypertension. Multivariate linear regression analysis showed only mean pulmonary arterial pressure independently was associated with heart rate acceleration time and slope of heart rate acceleration. CONCLUSIONS: Heart rate and S change patterns during 6MWT are predominantly associated with pulmonary hemodynamics in subjects with chronic thromboembolic pulmonary hypertension. Evaluating heart rate and S change patterns during 6MWT may serve as a safe and convenient way to follow the change in pulmonary hemodynamics. pO2 pO2 pO2 pO2 pO2 pO2 pO2 pO2 pO 2

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Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study)

Koshizaka M, Ishikawa K, Ishikawa T, Kobayashi K, Takemoto M, Horikoshi T, Shimousa R, Takahashi S, Nagashima K, Sato Y, Tatsuno I, Terano T, Hashimoto N, Kuribayashi N, Uchida D, Yokote K, on behalf of the PRIME-V Study Investigators

BMJ Open 7 （ 5 ） e015766 2018年05月

研究論文（学術雑誌）, 共著, 査読有り

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Introduction In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. Methods and analysis A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. Ethics and dissemination The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants.

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A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy

Yanai T, Iwasa S, Hashimoto H, Ohyanagi F, Takiguchi T, Takeda K, Nakao M, Sakai H, Nakayama T, Minato K, Arai T, Suzuki K, Shimada Y, Nagashima K, Terakado H, Yamamoto N

International Journal of Clinical Oncology 23 （ 2 ） 382 - 388 2018年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

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Purpose: The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). Methods: A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m ). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1–4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24–120 h after the start of cisplatin treatment). Results: 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3–83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2–90.7, P < 0.001) in the 5 mg group (P value for H : complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively. Conclusions: Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates. Clinical Trial Information: UMIN000014214. 2 0

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Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea

Matsumura T, Terada J, Kinoshita T, Sakurai Y, Yahaba M, Tsushima K, Sakao S, Nagashima K, Ozaki T, Kobayashi Y, Hiwasa T, Tatsumi K

PLoS ONE 13 （ 3 ） e0195015 2018年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1932-6203

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Objective Although severe obstructive sleep apnea (OSA) is an important risk factor for atherosclerosis-related diseases including coronary artery disease (CAD), there is no reliable biomarker of CAD risks in patients with OSA. This study aimed to test our hypothesis that circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1-Abs) are associated with the prevalence of CAD in patients with OSA. Methods Eighty-two adults diagnosed with OSA by polysomnography, 96 patients with a diagnosis of acute coronary syndrome (ACS) and 64 healthy volunteers (HVs) were consecutively enrolled. Serum samples were collected from patients with OSA at diagnostic polysomnography and from patients with ACS at disease onset. Serum NBL1-Ab level was measured by amplified luminescence proximity homogeneous assay and its association with clinical variables related to atherosclerosis was evaluated. Results NBL1-Ab level was significantly elevated in patients with both OSA and ACS compared with HVs. Subgroup analyses showed that NBL1-Ab level was markedly higher in patients with severe OSA and OSA patients with a history of CAD. Weak associations were observed between NBL1-Ab level and apnea-hypopnea index, age, mean SpO and arousal index, whereas significantly higher NBL1-Ab levels were observed in OSA patients with a history of CAD than in those without a history of CAD. Sensitivity analysis using a logistic regression model also demonstrated that increased NBL1-Ab levels were associated with the previous history of CAD in patients with OSA. Conclusions Elevated NBL1-Ab levels may be associated with the prevalence of CAD in patients with OSA, which needs to be confirmed further. 2

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Impact of arterial stiffness on WatchPAT variables in patients with obstructive sleep apnea

Kinoshita T, Yahaba M, Terada J, Matsumura T, Sakurai Y, Sakao S, Nagashima K, Tatsumi K

Journal of Clinical Sleep Medicine 14 （ 3 ） 319 - 325 2018年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15509389

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Study Objectives: The WatchPAT is a wrist-worn portable device that creates integration data regarding peripheral arterial tone (PAT), oxyhemoglobin saturation, heart rate, and actigraphy to diagnose or screen for obstructive sleep apnea (OSA). Previous studies have demonstrated the efficacy and validity of respiratory variables measured by the WatchPAT compared to those using polysomnography (PSG). However, the effects of arterial stiffness or atherosclerosis on WatchPAT parameters remain to be elucidated. Methods: Sixty-one consecutive patients with suspected OSA who underwent home-based testing with the WatchPAT 200, standard in-laboratory overnight polysomnography (PSG), and pulse wave velocity (PWV) as an index of arterial stiffness were studied. All PSG recordings were scored manually using the American Academy of Sleep Medicine criteria, whereas WatchPAT data were analyzed by an automatic algorithm. We evaluated how arterial stiffness affected respiratory event index data in WatchPAT (WP-AHI), because WP-AHI could be partly influenced by PAT, comparing WP-AHI and the apneahypopnea index measured by PSG (PSG-AHI) in consideration of PWV result. Results: Overall, WP-AHI was moderately correlated to PSG-AHI, but WP-AHI was significantly lower than PSG-AHI (28.4 ± 19.2 versus 53.6±30.2 events/h, P<.0001). For the lower PWV group, there was a significant correlation and good agreement between the WP-AHI and PSG-AHI, but as the PWV increased, there was low correlation between the WP-AHI and PSG-AHI. Conclusions: Arterial stiffness may affect the respiratory variables measured by WatchPAT in patients with OSA.

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Trends in study design and the statistical methods employed in a leading general medicine journal

Gosho M, Sato Y, Nagashima K, Takahashi S

Journal of Clinical Pharmacy and Therapeutics 43 （ 1 ） 36 - 44 2018年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02694727

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What is known and objective: Study design and statistical methods have become core components of medical research, and the methodology has become more multifaceted and complicated over time. The study of the comprehensive details and current trends of study design and statistical methods is required to support the future implementation of well-planned clinical studies providing information about evidence-based medicine. Our purpose was to illustrate study design and statistical methods employed in recent medical literature. Methods: This was an extension study of Sato et al. (N Engl J Med 2017; 376: 1086-1087), which reviewed 238 articles published in 2015 in the New England Journal of Medicine (NEJM) and briefly summarized the statistical methods employed in NEJM. Using the same database, we performed a new investigation of the detailed trends in study design and individual statistical methods that were not reported in the Sato study. Results and discussion: Due to the CONSORT statement, prespecification and justification of sample size are obligatory in planning intervention studies. Although standard survival methods (eg Kaplan-Meier estimator and Cox regression model) were most frequently applied, the Gray test and Fine-Gray proportional hazard model for considering competing risks were sometimes used for a more valid statistical inference. With respect to handling missing data, model-based methods, which are valid for missing-at-random data, were more frequently used than single imputation methods. These methods are not recommended as a primary analysis, but they have been applied in many clinical trials. Group sequential design with interim analyses was one of the standard designs, and novel design, such as adaptive dose selection and sample size re-estimation, was sometimes employed in NEJM. What is new and conclusion: Model-based approaches for handling missing data should replace single imputation methods for primary analysis in the light of the information found in some publications. Use of adaptive design with interim analyses is increasing after the presentation of the FDA guidance for adaptive design.

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The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure …

N Kotooka, M Kitakaze, K Nagashima, M Asaka, Y Kinugasa, K Nochioka, ...

Heart and vessels 33, 866-876 2018年

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Actinin-4 protein overexpression as a predictive biomarker in adjuvant chemotherapy for resected lung adenocarcinoma

Shiraishi H, Fujiwara Y, Kakuya T, Tsuta K, Motoi N, Miura N, Watabe Y, Watanabe S-i, Noro R, Nagashima K, Huang W, Yamada T, Asamura H, Ohe Y, Honda K

Biomarkers in Medicine 11 （ 9 ） 721 - 731 2017年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  17520363

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Aim: Although several clinical trials demonstrated the benefits of platinum-combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma. Materials & methods: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups. Results: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter. Conclusion: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients.

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Efficacy and safety of taxane monotherapy in advanced gastric cancer refractory to triplet chemotherapy with docetaxel, cisplatin, and S-1: a multicenter retrospective study

Iizumi S, Takashima A, Narita Y, Tajika M, Muro K, Kawai S, Yasui H, Matsushima T, Takahari D, Nagashima K, Boku N

Cancer Chemotherapy and Pharmacology 80 （ 3 ） 575 - 582 2017年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03445704

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Purpose: Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS. Methods: We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function. Results: A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death. Conclusions: Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.

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Clinical outcomes of resectable esophageal cancer with supraclavicular lymph node metastases treated with curative intent

Honma Y, Hokamura N, Nagashima K, Sudo K, Shoji H, Iwasa S, Takashima A, Kato K, Hamaguchi T, Boku N, Ito Y, Itami J, Koyanagi K, Igaki H, Tachimori Y

Anticancer Research 37 （ 7 ） 3741 - 3749 2017年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02507005

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Background: In the seventh edition of the Union for International Cancer Control (UICC) TNM classification, supraclavicular lymph node (SCLN) in regard to thoracic esophageal cancer (EC) is regarded as a distant organ, therefore, if resectable, SCLN metastasis is considered a candidate for systemic chemotherapy. The purpose of this study was to clarify the survival outcome in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated with curative intent. Patients and Methods: Clinical outcomes in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated by esophagectomy or definitive chemoradiotherapy (dCRT) were retrospectively analyzed. Results: A total of 102 patients were divided in three groups: Surgery with perioperative therapy, n=45; surgery alone, n=19; and dCRT, n=38. Overall, median progression-free survival and median survival time were 9.3 and 26.7 months, respectively. The median survival time was 27.5 months in the group treated with surgery with perioperative treatment, 50.6 months in those treated with surgery alone, and 22 months in the dCRT group. No significant survival difference was seen among the three groupS. Conclusion: Over 30% of patients with resectable M1LYM treated with curative intent achieved long-term survival.

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Irinotecan monotherapy as third-line treatment for advanced gastric cancer refractory to fluoropyrimidines, platinum, and taxanes

Nishimura T, Iwasa S, Nagashima K, Okita N, Takashima A, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Boku N

Gastric Cancer 20 （ 4 ） 655 - 662 2017年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14363291

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Background: Because standard chemotherapy for advanced gastric cancer consists of oral fluoropyrimidines plus platinum as first-line therapy, with paclitaxel plus ramucirumab as the second line, irinotecan is usually positioned as third-line chemotherapy in clinical practice in Japan. Methods: A retrospective evaluation was conducted to determine the efficacy and safety of irinotecan as third-line chemotherapy for advanced gastric cancer in patients refractory or intolerant to fluoropyrimidines, platinum, and taxanes. Results: Between February 2008 and December 2013, 52 patients received third-line irinotecan monotherapy. Among the 32 patients with measurable lesions, 1 patient achieved a confirmed partial response and 6 patients had stable disease. The overall response rate was 3% and the disease control rate was 22%. Median progression-free survival was 2.3 months [95% confidence interval (CI), 1.8–2.8] and median overall survival was 4.0 months (95% CI, 2.6–5.3). The most common adverse events of grade 3 severity or higher were neutropenia (27%), febrile neutropenia (12%), anorexia (12%), and diarrhea (6%). Although no treatment-related deaths occurred, 2 patients (4%) died of disease progression within 30 days after the last administration of irinotecan. Conclusion: Irinotecan monotherapy appears to be tolerated but was shown to have modest activity as third-line chemotherapy for advanced gastric cancer.

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Impact of geographic accessibility on utilization of the annual health check-ups by income level in Japan: A multilevel analysis

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

PLoS ONE 12 （ 5 ） e0177091 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1932-6203

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Although both geographic accessibility and socioeconomic status have been indicated as being important factors for the utilization of health care services, their combined effect has not been evaluated. The aim of this study was to reveal whether an income-dependent difference in the impact of geographic accessibility on the utilization of government-led annual health check-ups exists. Existing data collected and provided by Chiba City Hall were employed and analyzed as a retrospective cohort study. The subjects were 166,966 beneficiaries of National Health Insurance in Chiba City, Japan, aged 40 to 74 years. Of all subjects, 54,748 (32.8%) had an annual health check-up in fiscal year 2012. As an optimal index of geographic accessibility has not been established, five measures were calculated: travel time to the nearest health care facility, density of health care facilities (number facilities within a 30-min walking distance from the district of residence), and three indices based on the two-step floating catchment area method. Three-level logistic regression modeling with random intercepts for household and district of residence was performed. Of the five measures, density of health care facilities was the most compatible according to Akaike's information criterion. Both low density and low income were associated with decreased utilization of the health check-ups. Furthermore, a linear relationship was observed between the density of facilities and utilization of the health check-ups in all income groups and its slope was significantly steeper among subjects with an equivalent income of 0.00 yen than among those with equivalent income of 1.01-2.00 million yen (p = 0.028) or 2.01 million yen or more (p = 0.040). This result indicated that subjects with lower incomes were more susceptible to the effects of geographic accessibility than were those with higher incomes. Thus, better geographic accessibility could increase the health check-up utilization and also decrease the income-related disparity of utilization.

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The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy

Shoji H, Heike Y, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Hamaguchi T

Oncotarget 8 （ 56 ） 95083 - 95094 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1949-2553

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Background: The prognostic significance of peripheral immune status in patients with advanced gastric cancer (AGC) remains unclear. Results: From July 2013 through December 2014, 37 patients were enrolled. Among patients with 25 subsets of immune cells, patients in the high group of granulocytic myeloid-derived suppressor cells (Gr-MDSCs) showed significantly shorter progression-free survival (PFS) than those in the low group (3.98 vs. 8.78 months; hazards ratio (HR), 2.61; p = 0.01). In multivariate analysis, the high Gr-MDSCs value was also associated with shorter PFS (HR, 4.60; 95% confidence interval (CI), 1.79-11.8; p = 0.001). Although significant difference was not found in univariate analysis, the high Gr-MDSCs group was associated with shorter overall survival (OS) (HR, 2.89; 95% CI, 1.23-6.80; p = 0.015) in multivariate analysis. Materials and Methods: In this explorative prospective study, peripheral blood samples were collected from AGC patients before initiating first-line cisplatin-based chemotherapy (S-1 + cisplatin or S-1 + cisplatin + docetaxel). Peripheral blood mononuclear cells were analyzed for 25 immune subsets by multicolor flow cytometry. PFS and OS were compared between the patients divided into high and low (≥ and < median, respectively) groups based on the median value for each immune cell subset. Conclusions: The peripheral immune status of Gr-MDSCs appears to affect the prognosis in AGC. Further research is needed to confirm the clinical value of the level of circulating Gr-MDSCs as a prognostic and/or predictive marker in AGC.

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Quantitative US elastography can be used to quantify mechanical and histologic tendon healing in a rabbit model of Achilles tendon transection

Yamamoto Y, Yamaguchi S, Sasho T, Fukawa T, Akatsu Y, Akagi R, Yamaguchi T, Takahashi K, Nagashima K, Takahashi K

Radiology 283 （ 2 ） 408 - 417 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00338419

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Purpose: To determine the time-dependent change in strain ratios (SRs) at the healing site of an Achilles tendon rupture in a rabbit model of tendon transection and to assess the correlation between SRs and the mechanical and histologic properties of the healing tissue. Materials and Methods: Experimental methods were approved by the institutional animal care and use committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected. The SRs of Achilles tendons were calculated by using compression-based quantitative ultrasonographic elastography measurements obtained 2, 4, 8, and 12 weeks after transection. After in vivo elastography, the left Achilles tendon was harvested for mechanical testing of ultimate load, ultimate stress, elastic modulus, and linear stiffness, and the right tendons were harvested for tissue histologic analysis with the Bonar scale. Timedependent changes in SRs, mechanical parameters, and Bonar scale scores were evaluated by using repeated-measures analysis of variance. The correlation between SRs and each measured variable was evaluated by using the Spearman rank correlation coefficient. Results: Mean SRs and Bonar scale values decreased as a function of time after transection, whereas mechanical parameters increased (P<.001). SR correlated with ultimate stress (r = 0.68, P ,.001,) elastic modulus (r = 0.74, P ,.001), and the Bonar scale (r = 0.87, P ,.001). Conclusion: Quantitative elastography could be a useful method with which to evaluate mechanical and histologic properties of the healing tendon.

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Investigation of optimal weight gain during pregnancy for Japanese Women

Nomura K, Kido M, Tanabe A, Nagashima K, Takenoshita S, Ando K

Scientific Reports 7 （ 1 ） 2569 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2045-2322

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This study aims to compare the US Institute of Medicine (IOM) and Japanese guidelines proposed by the Ministry and the Japan Society for the Study of Obesity on gestational weight gain (GWG), and to explore the optimal GWG range in Japanese women. We investigated 8,152 Japanese women who had full-term singleton babies between 2010 and 2013 at a single center in Tokyo. Logistic regression models showed that GWG below the recommendation of the IOM and Japanese guidelines was similarly associated with an increased risk of light-for-date (LFD), whereas GWG above these guidelines was similarly associated with an increased risk of heavy-for-date (HFD) in pre-pregnancy body mass index categories of underweight (<18.5 kg/m , n = 1559), normal-weight (18.5-24.9 kg/m , n = 4998), overweight (25.0-29.9 kg/m , n = 270), and obese (30 ≤ kg/m , n = 60). The receiver-operating characteristic curve demonstrated that the optimal cutoffs for LFD and HFD were 9.7 and 10.4 kg, respectively in normal-weight mothers. The IOM and Japanese guidelines identified the risk of LFD or HFD equally well. The optimal GWG range in normal-weight women observed in this study was more close to Japanese guideline (i.e., 7-12 kg) compared to the IOM guideline (i.e., 11.5-16 kg). 2 2 2 2

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Income-related inequalities in access to dental care services in Japan

Nishide A, Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

International Journal of Environmental Research and Public Health 14 （ 5 ） 524 2017年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  16617827

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Background: This study aimed to evaluate whether income-related inequalities in access to dental care services exist in Japan. Methods: The subjects included beneficiaries of the National Health Insurance (NHI) in Chiba City, Japan, who had been enrolled from 1 April 2014 to 31 March 2015. The presence or absence of dental visits and number of days spent on dental care services during the year were calculated using insurance claims submitted. Equivalent household income was calculated using individual income data from 1 January to 31 December 2013, declared for taxation. Results: Of the 216,211 enrolled subjects, 50.3% had dental care during the year. Among those with dental visits, the average number of days (standard deviation) spent on dental care services per year was 7.7 (7.1). Low income was associated with a decreased rate of dental care utilization regardless of age and sex. However, there was a significant inverse linear association between the number of days spent on dental care services and income levels for both sexes. Conclusions: There were income-related inequalities in access to dental care services, regardless of the age group or sex, within the Japanese universal health insurance system.

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Circulating anti-coatomer protein complex subunit epsilon (COPE) autoantibodies as a potential biomarker for cardiovascular and cerebrovascular events in patients with obstructive sleep apnea

Matsumura T, Terada J, Kinoshita T, Sakurai Y, Yahaba M, Ema R, Amata A, Sakao S, Nagashima K, Tatsumi K, Hiwasa T

Journal of Clinical Sleep Medicine 13 （ 3 ） 393 - 400 2017年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15509389

　概要を見る

Study Objectives: Although moderate to severe obstructive sleep apnea (OSA) is an independent risk factor for severe arteriosclerotic diseases such as cardiovascular disease (CVD) and stroke, the development of atherosclerosis-related diseases cannot yet be predicted in patients with OSA. In a pilot study, we identified autoantibodies against the coatomer protein complex, subunit epsilon [circulating anti-coatomer protein complex subunit epsilon autoantibody (COPE-Ab)], a cytosolic complex that mediates protein transport in the Golgi compartment, as a potential novel biomarker of atherosclerosis. This study aimed to evaluate whether COPE-Ab levels had an association with cardiovascular and cerebrovascular events in patients with OSA. Methods: Eighty-two adult patients with a diagnosis of OSA via polysomnography and 64 healthy donors were studied. Serum COPE-Ab levels were measured using an amplified luminescence proximity homogeneous assay. Then, clinical factors related to atherosclerosis were evaluated with respect to COPE-Ab levels. Results: Significant differences in COPE-Ab levels were observed in terms of OSA severity. COPE-Ab levels were significantly higher in patients with OSA and also CVD and/or stroke, hypertension, and a high body mass index. Univariate and multivariate logistic regression analyses of patients with OSA identified elevated COPE-Ab level as a significant predictor of CVD and/or stroke. Conclusions: An elevated COPE-Ab level may be a potential predictor of the risks of cardiovascular and cerebrovascular events in patients with OSA. Therefore, patients with higher COPE-Ab levels may require more careful and intensive treatment. Commentary: A commentary on this article appears in this issue on page 361.

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A prospective, multi-center, randomized phase II study to evaluate the efficacy and safety of eculizumab in patients with Guillain-Barré syndrome (GBS): Japanese Eculizumab Trial for GBS (JET-GBS)

Yamaguchi N, Misawa S, Sato Y, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kohara N, Hirata K, Nishiyama K, Yabe I, Kaida K-I, Suzuki N, Nodera H, Tsuji S, Koike H, Kira J-I, Hanaoka H, Kusunoki S, Kuwabara S

JMIR Research Protocols 5 （ 4 ） e210 2016年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1929-0748

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BACKGROUND: Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy that causes acute flaccid paralysis. Immunoglobulin and plasma exchange are established treatments for GBS; however, a substantial number of patients, particularly those with severe disease, have poor recovery and residual deficits. Recent studies suggest that complement activation plays a pivotal role in GBS-associated axonal degeneration, and eculizumab is a humanized monoclonal antibody that specifically binds to complement component 5 and potently inhibits complement activation. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, for treatment of GBS. METHODS: The Japanese Eculizumab Trial for GBS (JET-GBS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 33 GBS patients unable to walk independently within 2 weeks from symptom onset (Hughes functional grade 3-5) were randomized at a 2:1 ratio to receive either intravenous eculizumab (900 mg/day) or placebo once weekly for 4 weeks, followed by 20 weeks of follow-up. The primary endpoint for efficacy is the proportion of patients who regain their ability to walk without aid at 4 weeks after the first dose of the study treatment, while primary safety outcomes are the incidence of adverse events and serious adverse events during the trial. RESULTS: Enrollment for the trial began in August 2015. This trial is still ongoing. All participants have been enrolled, and follow-up will be completed in October 2016. CONCLUSIONS: This study is the first to investigate the efficacy and safety of eculizumab for GBS. In case of a positive result, we will plan a phase III trial to investigate this issue in a larger number of patients. CLINICALTRIAL: UMIN Clinical Trials Registry UMIN 000018171; https:/upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function= brows&action=brows&type=summary&language=J&recptno=R000020978 (Archived by WebCite at http://www.webcitation.org/ 6lTiG8ltG). Clinical Trials.gov NCT02493725; https://clinicaltrials.gov/ct2/show/NCT02493725 (Archived by WebCite at http://www.webcitation.org/6lVJZXKSL).

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Comparison of drug use between clinical practice and regulatory approval: results in older Japanese patients with rheumatoid arthritis, diabetes, high blood pressure, or depression

Tanemura N, Uyama Y, Nagashima K, Suzuki T, Asahina Y, Kobayashi Y, Iyo M, Yokote K, Hanaoka H

Therapeutic Innovation and Regulatory Science 50 （ 6 ） 743 - 750 2016年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  21684790

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Background: In this study, differences in older patients between drug use as reported in clinical practice and in clinical trials for regulatory approval were examined. Methods: Electronic medical record (EMR) data such as patient background (age, sex), concomitant drugs, data on laboratory tests, and prescribed doses of drugs from outpatients with rheumatoid arthritis, diabetes, high blood pressure, or depression at Chiba University Hospital were obtained for the period from January 2003 to December 2012. These data were compared with data from relevant clinical trials for regulatory approval in order to examine differences in drug use. Results: There were 5134 eligible patients. The prescribed doses of drugs were lower than the standard approved doses for depression and rheumatoid arthritis but were generally within the approved dose range for type 2 diabetes mellitus and hypertension. When comparing the characteristics of older patients taking tacrolimus, 5.6% to 17.0% of those would not be able to participate in clinical trials because of liver or renal abnormality, and the incidence rates of some adverse drug events (ADEs) differed significantly between clinical practice and clinical trials. Conclusions: Appropriate doses of drugs for older patients may differ from approved doses in certain diseases. Complex situations such as a lot of polypharmacy, comorbidity, and functional impairment in older patients in clinical practice make it difficult to evaluate safety based on data from clinical trials. In the future, utilization of a database created from the EMR of older patients should be considered for assessment of drug safety in older patients in clinical practice.

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Efficacy of intravenous nicorandil for fractional flow reserve assessment: study protocol for a crossover randomised trial

Nishi T, Kitahara H, Fujimoto Y, Nakayama T, Sugimoto K, Nagashima K, Hanaoka H, Kobayashi Y

BMJ Open 6 （ 11 ） e012737 2016年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2044-6055

　概要を見る

Introduction: Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. Intravenous administration of nicorandil can be applicable for fractional flow reserve (FFR) measurement as a hyperaemic agent and a possible alternative to adenosine. However, the effectiveness of intravenous nicorandil infusion for FFR measurement is largely unclear. Methods and analysis: This crossover randomised study is being performed to investigate the efficacy of intravenous administration of nicorandil for FFR measurement. Patients with an intermediate coronary artery stenosis who satisfy the eligibility criteria undergo FFR measurement with a consecutive randomised order of patient-blind infusions of continuous intravenous administration of adenosine and a single bolus intravenous administration of nicorandil. The primary end point of the study is the agreement between the FFR values obtained by the intravenous nicorandil and those obtained by the intravenous adenosine. Recruitment of this trial started in November 2015 and will end in March 2017, or until a total of 50 participants have been recruited. Ethics and dissemination: The protocol was approved by the Institutional Review Board at Chiba University Hospital. Study findings will be published in peer-reviewed journals.

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Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial

Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S-i, Kohara N, Kanda T, Kira J-i, Hanaoka H, Kuwabara S, for the Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group

The Lancet Neurology 15 （ 11 ） 1129 - 1137 2016年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  14744422

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Background Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome. Methods We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age ≥20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179. Findings Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0·39 (SD 0·34) in the thalidomide group compared with −0·02 (0·54) in the placebo group (adjusted mean difference 0·41, 95% CI 0·02–0·80; p=0·04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0·006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease. Interpretation Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk. Funding Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals. 2

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Comparison of panitumumab plus irinotecan and cetuximab plus irinotecan for KRAS wild-type metastatic colorectal cancer

Yamaguchi T, Iwasa S, Nagashima K, Ikezawa N, Hamaguchi T, Shoji H, Honma Y, Takashima A, Okita N, Kato K, Yamada Y, Shimada Y

Anticancer Research 36 （ 7 ） 3531 - 3536 2016年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02507005

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Background/Aim: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan. Patients and Methods: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan. Results: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab. Conclusion: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer

Sasaki Y, Akasu T, Saito N, Kojima H, Matsuda K, Nakamori S, Komori K, Amagai K, Yamaguchi T, Ohue M, Nagashima K, Yamada Y

Cancer Science 107 （ 7 ） 1006 - 1012 2016年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13479032

　概要を見る

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur–uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

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Pretreatment immune status correlates with progression-free survival in chemotherapy-treated metastatic colorectal cancer patients

Tada K, Kitano S, Shoji H, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Yamada Y, Katayama N, Boku N, Heike Y, Hamaguchi T

Cancer Immunology Research 4 （ 7 ） 592 - 599 2016年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  23266066

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It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (TEM), were measured by multicolor-flow cytometry.Wedivided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4 TEM, or low CD8 TEM quantities had significantly shorter progression-free survival (P = 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n =21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n = 19, 47.5%; P < 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5-34.2; P < 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemotherapy.

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Utility of prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with nucleos(t)ide analogues

Tawada A, Chiba T, Saito T, Ogasawara S, Suzuki E, Ooka Y, Arai M, Kanda T, Shinozaki M, Goto N, Nagashima K, Yokosuka O

Oncology 90 （ 4 ） 199 - 208 2016年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00302414

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Objective: The utility of risk scores to predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogue (NA) remains to be elucidated. Methods: CU-HCC (The Chinese University of Hong Kong-HCC) and GAG-HCC (Guide with Age, Gender, HBV DNA, Core promoter mutations and Cirrhosis) scores of 225 Japanese patients treated with NAs for at least 2 years were calculated before and 2 years after the NA treatment. According to the cutoff values, the patients were categorized into high-score or low-score groups. Results: Sixteen of 225 patients developed HCC. Patients with a high score before the NA treatment showed a significantly higher HCC incidence than those with a low score using both score models (p < 0.001). Time-dependent receiver operating characteristic analyses based on scores before and 2 years after the NA treatment showed that both models exhibited moderate accuracy in predicting HCC development. The HCC incidence was significantly lower in the patients whose scores decreased below the cutoff values in response to the NA treatment than in those whose scores remained high using both models (p < 0.01). Conclusions: The predictive performance of the CU-HCC and GAG-HCC scores in the CHB patients treated with NAs is comparable to that in the NA-naive patients. The patients with sustained high scores after the NA treatment showed a higher incidence of HCC development.

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Income related inequality of health care access in Japan: a retrospective cohort study

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

PLoS ONE 11 （ 3 ） e0151690 2016年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1932-6203

　概要を見る

The purpose of this retrospective cohort study was to analyze the association between income level and health care access in Japan. Data from a total of 222,259 subjects (age range, 0-74 years) who submitted National Health Insurance claims in Chiba City from April 2012 to March 2014 and who declared income for the tax period from January 1 to December 31,2012 were integrated and analyzed. The generalized estimating equation, in which household was defined as a cluster, was used to evaluate the association between equivalent income and utilization and duration of hospitalization and outpatient care services. A significant positive linear association was observed between income level and outpatient visit rates among all age groups of both sexes; however, a significantly higher rate and longer period of hospitalization, and longer outpatient care, were observed among certain lower income subgroups. To control for decreased income due to hospitalization, subjects hospitalized during the previous year were excluded, and the data was then reanalyzed. Significant inverse associations remained in the hospitalization rate among 40-59-year-old men and 60-69-year-old women, and in duration of hospitalization among 40-59 and 60-69-year-olds of both sexes and 70-74-year-old women. These results suggest that low-income individuals in Japan have poorer access to outpatient care and more serious health conditions than their higher income counterparts.

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The impact of heptavalent pneumococcal conjugate vaccine on the incidence of childhood community-acquired pneumonia and bacteriologically confirmed pneumococcal pneumonia in Japan

Naito S, Tanaka J, Nagashima K, Chang B, Hishiki H, Takahashi Y, Oikawa J, Nagasawa K, Shimojo N, Ishiwada N

Epidemiology & Infection 144 （ 3 ） 494 - 506 2016年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09502688

　概要を見る

Heptavalent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2010. We investigated the impact of PCV7 on childhood community-acquired pneumonia (CAP) and pneumococcal pneumonia (PP). Children aged <5 years living in Chiba city, Japan, who were admitted to hospitals were enrolled to estimate the incidence of CAP based on the mid-year population. PP was determined by the presence of Streptococcus pneumoniae in cultured blood and/or sputum samples of CAP patients. The incidence of CAP and S. pneumoniae isolated from PP patients was compared before (April 2008-March 2009) and after (April 2012-March 2013) the introduction of PCV7 immunization. The annual incidence of CAP was reduced [incidence rate ratio 0·81, 95% confidence interval (CI) 0·73-0·90]. When comparing post-vaccine with pre-vaccine periods, the odds ratio for PP incidence was 0·60 (95% CI 0·39-0·93, P = 0·024). PCV7-covered serotypes markedly decreased (66·6% in pre-vaccine vs. 15·6% in post-vaccine, P < 0·01), and serotypes 6C, 15A, 15C and 19A increased. Multidrug-resistant international clones in the pre-vaccine period (Spain -2/ST90, Taiwan -14/ST236) decreased, while Sweden -25/ST63 was the dominant clone in the post-vaccine period. A significant reduction in the incidence of both CAP hospitalizations and culture-confirmed PP of vaccine serotypes was observed at 2 years after PCV7 vaccination. 6B 19F 15A

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Quantitative ultrasound elastography with an acoustic coupler for Achilles tendon elasticity: measurement repeatability and normative values

Yamamoto Y, Yamaguchi S, Sasho T, Fukawa T, Akatsu Y, Nagashima K, Takahashi K

Journal of Ultrasound in Medicine 35 （ 1 ） 159 - 166 2016年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02784297

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Objectives-The purposes of this study were to measure intraobserver and interobserver repeatability of quantitative elastography using an acoustic coupler for the Achilles tendon, to compare elastographic values among different age groups, and to assess the correlation between quantitative and conventional qualitative measurements. Methods-One hundred asymptomatic Achilles tendons of 50 volunteers were examined. For quantitative elastography, the strain value of the tendon was divided by that of the acoustic coupler with a known Young modulus, and the strain ratio was calculated. B-mode image assessment and qualitative elastography were also performed. Intraobserver repeatability and interobserver repeatability of strain ratio measurements were calculated. The strain ratios were compared among age groups by the Kruskal-Wallis test. Additionally, strain ratios for each B-mode grade and qualitative elastographic grade were compared by the Wilcoxon signed rank test. Results-Intraobserver repeatability intraclass correlation coefficient (1, 3) values were 0.87 and 0.93, respectively. The correlation coefficient between the observers' measurements was 0.61. The strain ratio for the 30s age group was 0.27, which was significantly lower than the values for the other age groups (P < .001). Although 97 of 100 tendons were normal on B-mode evaluations, 36 of the 97 tendons were degenerated on qualitative elastography and also had higher strain ratio values than normal tendons. Conclusions-Quantitative elastography using an acoustic coupler is a reproducible technique for measuring the elasticity of the Achilles tendon. It may detect early tendon degeneration that is not depicted on B-mode imaging.

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Study protocol for a phase III multicentre, randomised, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin A in patients with severe Kawasaki disease (KAICA Trial)

Aoyagi R, Hamada H, Sato Y, Suzuki H, Onouchi Y, Ebata R, Nagashima K, Terauchi M, Terai M, Hanaoka H, Hata A, on behalf of the KAICA Trial investigators

BMJ Open 5 （ 12 ） e009562 2015年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2044-6055

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Introduction: Kawasaki disease (KD) is an acute, selflimited vasculitis of unknown aetiology that predominantly affects infants and young children. We hypothesise that cyclosporin A (CsA) may be effective in treating KD by regulating the Ca2+/NFAT signalling pathway. This trial compares the current standard therapy of intravenous immunoglobulin (IVIG) and the combined IVIG+CsA therapy in paediatric patients with severe KD. Methods and analysis: This trial is a phase III, multicentre, randomised, open-label, blinded-end point trial that evaluates the efficacy and safety of IVIG+CsA therapy. Patients with severe KD who satisfy the eligibility criteria are randomised (1:1) to receive either CsA (5 mg/kg/day for 5 days; Neoral) plus high-dose IVIG (2 g/kg for 24 h and aspirin 30 mg/kg/day), or high-dose IVIG alone (2 g/kg for 24 h and aspirin 30 mg/kg/day). The primary end point is the frequency of occurrence of coronary artery abnormalities during the trial period. An independent end point review committee will be in charge of the trial assessment. Ethics and dissemination: The protocol was approved by the Institutional Review Board of each institution. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, in Japan. The trial is currently on-going and is scheduled to finish in April 2017. The findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number: JMA-IIA00174; Preresults.

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Validity assessment of self-reported medication use by comparing to pharmacy insurance claims

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

BMJ Open 5 （ 11 ） e009490 2015年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2044-6055

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Objectives: In Japan, an annual health check-up and health promotion guidance programme was established in 2008 in accordance with the Act on Assurance of Medical Care for the Elderly. A self-reported questionnaire on medication use is a required item in this programme and has been used widely, but its validity has not been assessed. The aim of this study was to evaluate the validity of this questionnaire by comparing self-reported usage to pharmacy insurance claims. Setting: This is a population-based validation study. Self-reported medication use for hypertension, diabetes and dyslipidaemia is the evaluated measurement. Data on pharmacy insurance claims are used as a reference standard. Participants: Participants were 54 712 beneficiaries of the National Health Insurance of Chiba City. Primary and secondary outcome measures: Sensitivity, specificity and κ statistics of the self-reported medication-use questionnaire for predicting actual prescriptions during 1 month (that of the checkup) and 3 months (that of the check-up and the previous 2 months) were calculated. Results: Sensitivity and specificity scores of questionnaire data for predicting insurance claims covering 3 months were, respectively, 92.4% (95% CI 91.9 to 92.8) and 86.4% (95% CI 86.0 to 86.7) for hypertension, 82.6% (95% CI 81.1 to 84.0) and 98.5% (95% CI 98.4 to 98.6) for diabetes, and 86.2% (95% CI 85.5 to 86.8) and 91.0% (95% CI 90.8 to 91.3) for dyslipidaemia. Corresponding κ statistics were 70.9% (95% CI 70.1 to 71.7), 77.1% (95% CI 76.2 to 77.9) and 69.8% (95% CI 68.9 to 70.6). The specificity was significantly higher for questionnaire data covering 3 months compared with data covering 1 month for all 3 conditions. Conclusions: Self-reported questionnaire data on medication use had sufficiently high validity for further analyses. Item responses showed close agreement with actual prescriptions, particularly those covering 3 months.

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S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: A pooled analysis of four phase II studies

Iwasa S., Nagashima K., Yamaguchi T., Matsumoto H., Ichikawa Y., Goto A., Yasui H., Kato K., Okita N.T., Shimada Y., Yamada Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology）  76 （ 3 ） 605 - 614 2015年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03445704

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Purpose: S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens. Methods: We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX. Results: Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65 % in SIR/SIRB vs. 52 % in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX. Conclusions: S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

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Predictive power of a body shape index for development of diabetes, hypertension, and dyslipidemia in Japanese adults: a retrospective cohort study

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

PLoS One 10 （ 6 ） e0128972 2015年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1932-6203

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Background/Objectives Recently, a body shape index (ABSI) was reported to predict all-cause mortality independently of body mass index (BMI) in Americans. This study aimed to evaluate whether ABSI is applicable to Japanese adults as a predictor for development of diabetes, hypertension, and dyslipidemia. Subjects/Methods We evaluated the predictive power of ABSI in a retrospective cohort study using annual health examination data from Chiba City Hall in Japan, for the period 2008 to 2012. Subjects included 37,581 without diabetes, 23,090 without hypertension, and 20,776 without dyslipidemia at baseline who were monitored for disease incidence for 4 years. We examined the associations of standardized ABSI, BMI, and waist circumference (WC) at baseline with disease incidence by logistic regression analyses. Furthermore, we conducted a casematched study using the propensity score matching method. Results Elevated BMI, WC, and ABSI increased the risks of diabetes and dyslipidemia [BMI-diabetes: odds ratio (OR) = 1.26, 95% confidence interval (95%CI) = 1.20-1.32; BMI-dyslipidemia: OR = 1.15, 95%CI = 1.12-1.19; WC-diabetes: OR = 1.24, 95%CI = 1.18-1.31; WC-dyslipidemia: OR = 1.15, 95%CI = 1.11-1.19; ABSI-diabetes: OR = 1.06, 95%CI = 1.01 -1.11; ABSI-dyslipidemia: OR = 1.04, 95%CI = 1.01-1.07]. Elevated BMI and WC, but not higher ABSI, also increased the risk of hypertension [BMI: OR = 1.32, 95%CI = 1.27-1.37; WC: OR = 1.22, 95%CI = 1.18-1.26; ABSI: OR = 1.00, 95%CI = 0.97-1.02]. Areas under the curve (AUCs) in regression models with ABSI were significantly smaller than in models with BMI or WC for all three diseases. In case-matched subgroups, the power of ABSI was weaker than that of BMI and WC for predicting the incidence of diabetes, hypertension, and dyslipidemia. Conclusions Compared with BMI or WC, ABSI was not a better predictor of diabetes, hypertension, and dyslipidemia in Japanese adults.

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Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer

Takahashi N., Yamada Y., Furuta K., Nagashima K., Kubo A., Sasaki Y., Shoji H., Honma Y., Iwasa S., Okita N., Takashima A., Kato K., Hamaguchi T., Shimada Y.

Cancer Science （Cancer Science）  106 （ 5 ） 604 - 610 2015年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13479032

　概要を見る

Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild-type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients.

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Bevacizumab and postoperative wound complications in patients with liver metastases of colorectal cancer

Utsumi H, Honma Y, Nagashima K, Iwasa S, Takashima A, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Kishi Y, Nara S, Esaki M, Shimada K

Anticancer Research 35 （ 4 ） 2255 - 2261 2015年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02507005

　概要を見る

Aim: The present study investigated whether bevacizumab (BV) is associated with postoperative wound complications (PWCs). Patients and Methods: We retrospectively analyzed patients undergoing surgery for liver metastases of colorectal cancer at our Institution. Patients were divided into 3 groups according to the preoperative treatment: chemotherapy with BV (group A), chemotherapy without BV (group B) and no chemotherapy (group C). Results: Between February 2003 and September 2012, 297 patients underwent 373 surgeries. Groups A, B and C consisted of 23, 62 and 288 patients, respectively. PWCs occurred in 29 patients (7.8%). In multivariate analysis, there were no differences in PWCs among the groups (C vs. B:P=0.739; C vs. A: P=0.110). Conversely, lower serum albumin levels (<3.5g/dl vs. ≥3.5g/dl: p=0.030) and synchronous colorectal resection (no vs. yes; p<0.001) remained significant risk factors of developing PWCs. Conclusion: Chemotherapy with or without BV did not influence the risk of PWCs.

A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy

Nagashima K, Yanai T, Iwasa S, Ohyanagi F, Kasai T, Minato K, Sakai H, Sakamoto C, Takeda K, Harada D, Goto K, Yamamoto N

Japanese Journal of Clinical Oncology 45 （ 2 ） 229 - 231 2015年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03682811

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A randomized Phase II dose-finding trial comparing olanzapine 10 mg with olanzapine 5 mg for patients receiving highly emetogenic chemotherapy with cisplatin was started in June 2014. The purpose of the trial is to evaluate the efficacy and safety of the two olanzapine doses and to determine which is more promising as a test arm for comparison with the current standard antiemetic care (a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone) in a subsequent Phase III trial. Patients receiving cisplatin-containing regimens will be randomized to the olanzapine 10 or 5 mg arm. A total of 150 patients will be accumulated from nine institutions over 2 years. The primary endpoint is complete response defined as no emetic episodes and no use of rescue medications in the delayed (24-120 h) phase. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000014214.

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A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy

Shirakawa T., Kato K., Nagashima K., Nishikawa A., Sawada R., Takahashi N., Shoji H., Sasaki Y., Honma Y., Iwasa S., Takashima A., Okita N., Hamaguchi T., Yamada Y., Shimada Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology）  74 （ 6 ） 1207 - 1215 2014年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03445704

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Introduction: Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer, and taxanes have shown efficacy after FP-based chemotherapy, but there is no standard regimen for second-line chemotherapy (SLC). We retrospectively investigated the clinical features of taxane therapy in SLC for esophageal squamous cell carcinoma (ESCC). Methods: The selection criteria were pathologically proven ESCC; advanced or recurrent disease previously treated with FP at our hospital; performance status (PS) 0-2; and adequate organ function. Docetaxel (DTX) was administered 3-weekly at 70 mg/m². Paclitaxel (PTX) was administered at 100 mg/m² weekly for 6 weeks, with 1 week's rest. Results: The analysis covered 163 patients from August 2006 to June 2012. Median age was 64 years (range 37-83: DTX group 132 patients and PTX group 31). Progression-free survival and median overall survival (OS) were 2.3 and 6.1 months, respectively, with PTX and 2.3 and 5.3 months with DTX. Response rates were 20.7 % for PTX and 5.9 % for DTX. The rate of grades 3-4 neutropenia was higher with DTX (32.6 %) than with PTX (16.1 %). Grade 3 febrile neutropenia was seen in 6.1 % of DTX recipients but in no PTX group. According to multivariate analyses of OS, PS 2, number of metastatic sites 2, and CRP 1 mg/dL were independent predictors of poor prognosis. Conclusions: PTX and DTX were both effective in SLC for ESCC, but their toxicity profiles differed. In terms of febrile neutropenia, PTX seems more appropriate.

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Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection

Shoji H., Yamada Y., Taniguchi H., Nagashima K., Okita N., Takashima A., Honma Y., Iwasa S., Kato K., Hamaguchi T., Shimada Y.

Cancer Science （Cancer Science）  105 （ 8 ） 1002 - 1007 2014年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13479032

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c-MET is implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the association between c-MET expression and tumor recurrence in CRC patients after curative liver resection, and to evaluate concordance in c-MET expression and various mutations of KRAS, BRAF and PIK3CA between primary CRC and paired liver metastases. A cohort of patients was tested for c-MET immunoreactivity (i.e. immunohistochemistry [IHC]) and KRAS, BRAF and PIK3CA mutations. Analyses were performed both on primary tumors and paired liver metastases, and the association between IHC and mutations results were assessed. A total of 108 patients were eligible. A total of 53% of patients underwent simultaneous resection of primary tumors and metastases, and the others underwent metachronous resection. Levels of concordance between primary tumors and metastases were 65.7%, 87.7%, 100% and 95.2% for c-MET, KRAS, BRAF and PIK3CA, respectively. High levels of c-MET expression (c-MET-high) in the primary tumors were observed in 52% of patients. Relapse-free survival was significantly shorter for patients with c-MET-high primary tumors (9.7 months) than for those with c-MET-low primary tumors (21.1 months) (P = 0.013). These results suggest that a high level of genetic concordance in KRAS, BRAF and PIK3CA between primary tumors and liver metastases, and c-MET-high in the primary tumors were associated with shorter relapse-free survival after hepatic metastasectomy. A high expression of c-MET in primary tumors was associated with worse RFS for patients who had undergone curative hepatectomy. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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Lack of association of proteinuria and clinical outcome in patients treated with bevacizumab for metastatic colorectal cancer

Iwasa S, Nakajima TE, Nagashima K, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y

Anticancer Research 33 （ 1 ） 309 - 316 2013年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  02507005

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Background: Although bevacizumab-related hypertension has been reported as a predictive marker of therapy efficacy, an association between proteinuria and efficacy has not been reported. Patients and Methods: Eighty-two consecutive patients with metastatic colorectal cancer treated with bevacizumab as first-line treatment between July 2007 and April 2009 were examined. Results: Seventy-one patients were included in the analysis set. Proteinuria occurred in 29 patients: Grade 1 in 15 patients and grade 2 in 14 patients; no grade 3 or higher proteinuria was observed. The response rate did not increase with the severity of proteinuria (p=0.307). The median progressionfree survival was 17.8 months in cases with grade 2 proteinuria, 16.0 months in those with grade 1 proteinuria, and 10.4 months in those with grade 0 proteinuria (p=0.030). In multivariate analysis with a time-dependent adjustment, there was no correlation between severity of proteinuria and survival. Conclusion: Bevacizumab-related proteinuria was not a predictive marker for patients with colorectal cancer treated with first-line bevacizumab.

Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial

Horita Y, Yamada Y, Kato K, Hirashima Y, Akiyoshi K, Nagashima K, Nakajima TE, Hamaguchi T, Shimada Y

International Journal of Clinical Oncology 17 （ 6 ） 604 - 609 2012年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13419625

　概要を見る

Objective: FOLFIRI is a standard chemotherapy regimen for the treatment of metastatic colorectal cancer. Although some studies have shown its efficacy in combination with bevacizumab as first-line chemotherapy, there are no data to support FOLFIRI plus bevacizumab as second-line chemotherapy in patients with this form of cancer. The aim of this study was to evaluate the efficacy and safety of FOLFIRI and bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer. Methods: Eligible patients were ≥20 years old, previously treated (except with irinotecan [CPT-11] and bevacizumab), with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate organ function. Twenty-five eligible patients received FOLFIRI with bevacizumab at a dose of 10 mg/kg given intravenously on day 1. All therapy was administered every 2 weeks until disease progression. The primary endpoint was the response rate. Results: Twenty-five patients were enrolled between February 2008 and March 2009. The median age was 62 (range 38-73) years, the male/female distribution was 20/5, 16 patients had performance status 0 and 9 had performance status 1, and the proportion of patients who were oxaliplatin pretreated/untreated was 16/9. The overall response rate was 32% (90% confidence interval [CI]: 17.0-50.4%), with 8 patients showing partial responses, 15 with stable disease, and 2 with disease progression. Median progression-free survival was 11.6 months (95% CI: 6.9-16.4). Median overall survival was 21.4 months (95% CI: 12.0-30.8). The grade 3/4 adverse events with treatment were neutropenia (64%), leukopenia (16%), diarrhea (8%), anorexia (8%), and febrile neutropenia (8%). The bevacizumab-related grade 3/4 adverse event was hypertension, which was observed in 12% of patients. Conclusions: The FOLFIRI plus bevacizumab regimen is an active, well-tolerated second-line chemotherapy treatment for patients with metastatic colorectal cancer. © 2011 Japan Society of Clinical Oncology.

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A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer

Okita NT, Esaki T, Baba E, Sakai D, Tokunaga S, Takiuchi H, Mizunuma N, Nagashima K, Kato K

Investigational New Drugs 30 （ 5 ） 2026 - 2031 2012年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01676997

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Summary: Currently, no prospective data exists to support a stop-and-go modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n=1; partial response, n=23; stable disease, n=21; progression, n=1; and not evaluated, n=4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients. © 2011 Springer Science+Business Media, LLC.

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Study designs and statistical analyses for biomarker research

Gosho M, Nagashima K, Sato Y

Sensors 12 （ 7 ） 8966 - 8986 2012年06月

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A distinct regulatory role of Th17 cytokines IL-17A and IL-17F in chemokine secretion from lung microvascular endothelial cells

Fujie H, Niu K, Ohba M, Tomioka Y, Kitazawa H, Nagashima K, Ohrui T, Numasaki M

Inflammation （Inflammation）  35 （ 3 ） 1119 - 1131 2012年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03603997

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Th17 cytokines IL-17A and IL-17F play a critical role in the activation and recruitment of neutrophils at airway inflammation mainly through the induction of CXC chemokines in the lungs. Vascular endothelial cells belong to the category of major CXC chemokine-producing cells. However, until now, the precise role of Th17 cytokines in CXC chemokine secretion in lung microvascular endothelial cells (LMVECs) has not been fully elucidated. In this study, we examined the biological effects of Th17 cytokines IL-17A and IL-17F on CXCL1, CXCL5, and CXCL8 release in LMVECs. Both IL-17 receptor A (IL-17RA) and IL-17RC are expressed on the surface of LMVECs. In contrast to IL-17F, IL-17A significantly upregulated CXCL1 mRNA expression and protein release, whereas both IL-17A and IL-17F did not have the ability to induce CXCL5 and CXCL8 secretion in LMVECs. IL-17A and IL-17F displayed positive regulatory effects on IL-1β- induced CXCL1, CXCL5, and CXCL8 secretion. On the other hand, IL-17A enhanced the upregulating effect of TNF-α on CXCL1, CXCL5, and CXCL8 release, whereas IL-17F had a negative regulatory effect on TNF-α-mediated secretion. Th2 cytokines IL-4 and IL-13 showed an inhibitory effect on IL-1β plus IL-17A-induced CXCL1, CXCL5, and CXCL8 secretion, but displayed a positive regulatory effect on TNF-α plus IL-17A-induced secretion. These results provide evidence that Th17 cytokines IL-17A and IL-17F have a distinct regulatory role in CXCL1, CXCL5, and CXCL8 expression in LMVECs stimulated either with IL-1β or with TNF-α. Our findings also suggest that CXC chemokine secretion in LMVECs may be complicatedly regulated by Th17 cytokines, Th2 cytokines, and macrophage-associated cytokines in pathological conditions such as bronchial asthma. © 2011 Springer Science+Business Media, LLC.

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Nucleostemin and TWIST as predictive markers for recurrence after neoadjuvant chemotherapy for esophageal carcinoma

Nakajima TE, Yoshida H, Okamoto N, Nagashima K, Taniguchi H, Yamada Y, Shimoda T, Masutomi K

Cancer Science 103 （ 2 ） 233 - 238 2012年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13479032

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We recently demonstrated that overexpression of the nucleolar GTP-binding protein nucleostemin drives the fraction of genetically-defined tumor cells that exhibit markers and tumorigenic properties of tumor initiating cells. More specifically, cells that constitutively express elevated levels of nucleostemin exhibit increased TWIST expression; expression of genes that induced pluripotent stem cells; enhanced radioresistance; tumor formation, even when small numbers of cells are implanted; and an increased propensity to metastasize. An immunohistochemical analysis of cancer stem cell markers, such as nucleostemin and TWIST has not been conducted in surgically-resected esophageal squamous cell carcinomas after neoadjuvant chemotherapy. In the present study, we examined the expression of CD133, CD44, nucleostemin, guanine nucleotide-binding protein-like 3-like, and TWIST by immunohistochemistry in a series of 54 surgically-resected specimens of esophageal squamous cell carcinomas after neoadjuvant chemotherapy. We identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were significantly correlated with poor relapse-free survival. Together, these observations imply nucleostemin and TWIST as the predictive markers for postoperative recurrence. © 2011 Japanese Cancer Association.

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フェンタニル貼付剤の粘着性に関する検討―貼付試験と粘着性による評価―

大島新司, 間祐太朗, 長島健悟, 田中享, 佐野元彦, 太田昌一郎, 細谷治, 安野伸浩, 從二和彦

日本緩和医療薬学雑誌 5   7 - 13 2012年01月

研究論文（学術雑誌）, 共著, 査読有り

A modified maximum contrast method for unequal sample sizes in pharmacogenomic studies

Nagashima K, Sato Y, Hamada C

Statistical Applications in Genetics and Molecular Biology 10 （ 1 ） Article 41 2011年09月

研究論文（学術雑誌）, 共著, 査読有り

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Characteristics and outcomes of patients with advanced gastric cancer who declined to participate in a randomized clinical chemotherapy trial

Tanai C, Nakajima TE, Nagashima K, Kato K, Hamaguchi T, Yamada Y, Muro K, Shirao K, Kunitoh H, Matsumura Y, Yamamoto S, Shimada Y

Journal of Oncology Practice 7 （ 3 ） 148 - 153 2011年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15547477

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Purpose: There is insufficient data to verify whether participation in clinical trials in itself can lead to better clinical outcomes. We have analyzed the characteristics and outcomes of patients who declined to participate in a randomized trial in comparison with those who participated in the trial. Patients and Methods: A randomized trial for naive advanced gastric cancer was offered to 286 patients. The trial investigated the superiority of irinotecan plus cisplatin and the noninferiority of S-1 compared with continuous fluorouracil infusion. We retrospectively reviewed the characteristics and outcomes for both participants and nonparticipants in this trial. Results: Of the 286 patients, 98 (34%) declined to participate in the trial. The rate of declining was significantly higher amongyounger patients (P = .003), and it varied significantly between attending physicians (range, 23% to 58%; P = .004). There were no other significant correlations between rate of declining and patient characteristics. No significant differences were observed in the clinical outcomes between the participants and nonparticipants, for whom the median survival times were 367 versus 347 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 1.21 (95% CI, 0.91 to 1.60). No interaction was observed between participation and the various regimens. Conclusion: There was no difference in clinical outcomes between participants and nonparticipants. However, the patient's age and the doctor-patient relationship may have an effect on patient accrual to randomized trials. Copyright © 2011 by American Society of Clinical Oncology.

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Progression-free survival in first-line chemotherapy is a prognostic factor in second-line chemotherapy in patients with advanced gastric cancer

Hashimoto K, Takashima A, Nagashima K, Okazaki S, Nakajima TE, Kato K, Hamaguchi T, Yamada Y, Shimada Y

Journal of Cancer Research and Clinical Oncology 136 （ 7 ） 1059 - 1064 2010年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  01715216

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Purpose: First-line chemotherapy (Cx-1) in advanced gastric cancer (AGC) provides survival benefit. However, it is unclear who should proceed to second-line chemotherapy (Cx-2). Methods: We reviewed patients who received Cx-2 for AGC following progressive disease after Cx-1 from 2000 to 2005 at the National Cancer Center Hospital, Tokyo. To evaluate the prognostic factors in Cx-2, Cox regression multivariate analysis was performed. Results: Of 995 patients who received Cx-1 in this study period, 466 met the eligibility criteria. The median progression-free survival in Cx-1 (PFS-1) was 133 days. The median survival time from the date of starting second-line chemotherapy (MST-2) was 207 days. Multivariate analysis revealed that the factors affecting short survival time in Cx-2 were poor performance status (>2), low serum albumin level (<3.5 mg/dL), elevated C-reactive protein level (>1.0 mg/dL), patients with bone, liver or peritoneal metastasis, and patients without previous gastrectomy (p < 0.01). PFS-1 was an independent prognostic factor for survival (PFS-1 <120, MST-2 133 days, PFS-1 >120, MST-2 258 days, hazard ratio 0.71, 95% confidence interval 0.58-0.86, p < 0.01). The Cx-2 regimen (irinotecan vs. taxane) did not correlate with survival. Conclusion: PFS-1 is one of the prognostic factors of Cx-2 in patients with AGC. © 2010 Springer-Verlag.

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A new statistical screening approach for finding pharmacokinetics-related genes in genome-wide studies

Sato Y, Laird NM, Nagashima K, Kato R, Hamano T, Yafune A, Kaniwa N, Saito Y, Sugiyama E, Kim S-R, Furuse J, Ishii H, Ueno H, Okusaka T, Saijo N, Sawada J-i, Yoshida T

The Pharmacogenomics Journal 9 （ 2 ） 137 - 146 2009年04月

研究論文（学術雑誌）, 共著, 査読有り

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