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Tsuburaya A.,Yokohama City University | Yoshida K.,Gifu University | Yoshino S.,Yamaguchi University | Takahashi M.,Yokohama Municipal Citizens Hospital | And 14 more authors.
The Lancet Oncology | Year: 2014

Background: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. Methods: We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m2 per day), S-1 only (80 mg/m2 per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m2) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. Findings: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). Interpretation: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. Funding: Epidemiological and Clinical Research Information Network. © 2014 Elsevier Ltd.

Shoji T.,Osaka City University | Masakane I.,Yabuki Shima Clinic | Watanabe Y.,Kasugai Municipal Hospital | Iseki K.,University of Ryukyus | Tsubakihara Y.,Osaka General Medical Center
Clinical Journal of the American Society of Nephrology | Year: 2011

Summary Background and objectives Dialysis patients show "reverse causality" between serum cholesterol and mortality. No previous studies clearly separated the risk of incident cardiovascular disease (CVD) and the risk of death or fatality after such events. We tested a hypothesis that dyslipidemia increases the risk of incident atherosclerotic CVD and that protein energy wasting (PEW) increases the risk of fatality after CVD events in hemodialysis patients. Design, setting, participants, & measurements This was an observational cohort study in 45,390 hemodialysis patients without previous history of myocardial infarction (MI), cerebral infarction (CI), or cerebral bleeding (CB) at the end of 2003, extracted from a nationwide dialysis registry in Japan. Outcome measures were new onsets of MI, CI, CB, and death in 1 year. Results The incidence rates of MI, CI, and CB were 1.43, 2.53, and 1.01 per 100 person-years, and death rates after these events were 0.23, 0.21, and 0.29 per 100 person-years, respectively. By multivariate logistic regression analysis, incident MI was positively associated with non-HDL cholesterol (non-HDL-C) and inversely with HDL cholesterol (HDL-C). Incident CI was positively associated with non-HDL-C, whereas CB was not significantly associated with these lipid parameters. Among the patients who had new MI, CI, and/or CB, death risk was not associated with HDL-C or non-HDL-C, but with higher age, lower body mass index, and higher C-reactive protein levels. Conclusions In this hemodialysis cohort, dyslipidemia was associated with increased risk of incident atherosclerotic CVD, and protein energy wasting/inflammation with increased risk of death after CVD events. © 2011 by the American Society of Nephrology.

Choi Y.L.,Jichi Medical University | Choi Y.L.,Tokyo Medical University | Soda M.,Jichi Medical University | Yamashita Y.,Jichi Medical University | And 14 more authors.
New England Journal of Medicine | Year: 2010

The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.) Copyright © 2010 Massachusetts Medical Society.

Tajiri H.,Osaka General Medical Center | Tanaka H.,Aichi Cancer Center Research Institute | Brooks S.,State University of New York at Buffalo | Takano T.,Osaka General Medical Center
Cancer Causes and Control | Year: 2011

Objective A nation-wide prevention program utilizing passive-active immunoprophylaxis for high-risk babies against maternal HBV transmission was introduced in Japan in January of 1986. The prevention program was expected to eradicate HBV-related hepatocellular carcinoma (HCC). The aim of this study was to evaluate the effect of this selective prevention program against maternal HBV transmission on the occurrence of HBV-related HCC. Methods We reviewed the annual reports from a nationwide survey of childhood solid tumors that was reported in the Journal of the Japanese Society of Pediatric Surgeons during the 28 years period from 1981 to 2008. The number of HCC cases were grouped for every 5-year period with an additional period of the past 3 years and compared with those of hepatoblastoma. Results The reported number of children with hepatoblastoma in each period was constant during the 28 years study period. In contrast, both the number of patients with HBV-related HCC and the ratio of HBV-related HCC to hepatoblastoma gradually decreased over the study period, with a significant drop in the last two periods ranging from 2001 to 2008 (p<0.001). Conclusion The prevention program against maternal HBV infection of infants born to HBV carrier mothers may have decreased the occurrence of HBV-related HCC in childhood. © Springer Science+Business Media B.V. 2010.

Takemoto N.,Suita Municipal Hospital | Horii A.,Suita Municipal Hospital | Horii A.,Osaka University | Sakata Y.,Osaka General Medical Center | Inohara H.,Osaka University
Otology and Neurotology | Year: 2011

Objective: To search for prognostic predictors and reexamine the usefulness of electroneurography (ENoG) in predicting the prognosis of peripheral facial palsy using statistical methods. Study Design: Prospective study. Setting: Tertiary referral center. Patients: Consecutive 142 patients with Bell's palsy and 26 with Ramsay Hunt syndrome treated with steroid plus antiviral agents. Interventions: Multivariate analysis was used to identify which factors, including Yanagihara grading score and ENoG, predict better recovery. Receiver operating characteristic (ROC) curves were constructed for ENoG and grading score. The cumulative recovery rate by ENoG was calculated using Kaplan-Meier analysis. Recovery was defined as the improvement of grading score to 36 points or more (full score, 40) without synkinesis. Results: Multivariate analysis revealed that Ramsay Hunt syndrome, the worst grading score and ENoG were the significant prognostic predictors. The area under the ROC curve for ENoG was broader than those for grading score, indicating that ENoG was superior to grading score in terms of accuracy for prognosis prediction. The ROC curve revealed that more than 85% degeneration on ENoG had the best specificity (77.8%) and sensitivity (71.4%) to predict nonrecovery. When ENoG was subjected to the analysis of cumulative recovery rate using Kaplan-Meier plots, patients with more than 85% degeneration on ENoG had significantly poorer prognosis. Conclusion: ENoG was the most effective factor for prediction of the prognosis of peripheral facial palsy, and more than 85% degeneration had the best specificity and sensitivity to predict nonrecovery. © 2011, Otology & Neurotology, Inc.

Hagihira S.,Osaka University | Takashina M.,The Surgical Center | Mori T.,Osaka General Medical Center | Mashimo T.,Osaka University
Anesthesia and Analgesia | Year: 2012

Background: We previously reported that electroencephalographic (EEG) bicoherence, the degree of phase coupling among the frequency components of a signal, showed 2 peaks during isoflurane anesthesia. Hayashi et al. (Br J Anaesth 2007;99:389-95) also revealed that the peak frequency of bicoherence around 10 Hz increased when ketamine was added. Because nitrous oxide (N2O) and ketamine share several common features, they are often treated as the same category of anesthetic. Here, we investigated the effect of N2O on EEG bicoherence and other EEG derivatives during isoflurane anesthesia. Methods: Twenty patients (aged 34-72 years, ASA physical status I and II) of either gender who underwent elective laparoscopic surgery were included. Raw EEG data, along with EEG-derived parameters, were recorded using an A-1050 Bispectral Index (BIS) monitor and our self-authored Bispectral Analyzer for BIS software. We compared 2 peaks of EEG bicoherence (pBIC-low, around 4 Hz; and pBIC-high, around 10 Hz), as well as BIS and spectral edge frequency 95% (SEF95). Anesthesia was induced with 3 mg • kg thiopental and 3 μg • kg fentanyl. After tracheal intubation, anesthesia was maintained with isoflurane (expired concentration at 1.0%), oxygen, and nitrogen. Fentanyl was added and maintained at an estimated effect-site concentration of >1.5 ng • mL. We obtained baseline data 1 hour after induction of anesthesia, then 70% N2O was added for 30 minutes. Results: Before N2O, pBIC-low and pBIC-high were 49.3% ± 8.3% and 42.4% ± 11.0%. Ten minutes after starting N2O, pBIC-high decreased to 14.9% ± 5.9% (P < 0.001), and it was statistically significantly lower throughout the N2O period. Meanwhile, pBIC-low transiently decreased to 37.2% ± 12.8% (P = 0.01) during the early phase of N2O administration. Before N2O, BIS and SEF95 were 43.2 ± 4.9 and 13.1 ± 2.0 Hz, respectively. Both BIS and SEF95 slightly but statistically significantly decreased during N2O administration. Fifteen minutes after starting N2O, BIS and SEF95 were 35.7 ± 6.2 (P < 0.001) and 8.6 ± 1.8 Hz (P < 0.001) and they decreased more when large δ waves emerged. Fifteen minutes after stopping N2O, BIS, SEF95, as well as pBIC-low and pBIC-high returned to pre-N2O values. Conclusion: Dissimilar to the effect of ketamine, N2O significantly decreases pBIC-high during isoflurane anesthesia. © 2012 International Anesthesia Research Society.

Nishikawa K.,Osaka General Medical Center
Gan to kagaku ryoho. Cancer & chemotherapy | Year: 2013

We report the case of a patient with paclitaxel (PTX) -resistant recurrent gastric cancer who was effectively treated with S-1 plus docetaxel( DOC). A 62-year-old woman underwent total gastrectomy for Stage IV advanced gastric cancer (type 4, por 2>sig, pT4a (SE), pN3a, pP1, CY1) in 2009. Although S-1 was administered as first-line chemotherapy, recurrent peritoneal metastasis was diagnosed 22 months after surgery. S-1 plus irinotecan (CPT-11) was administered as second-line chemotherapy, and this was followed by weekly PTX (80 mg/m2) as third-line chemotherapy. However, computed tomography (CT) showed increased ascites and peritoneal wall thickening in the pelvis. As the tumor proved resistant to PTX, making the treatment ineffective, S-1( 80 mg/m2, day 1-14, q3w) plus DOC( 40 mg/m2, day 1, q3w) was initiated. Two months later, the ascites and peritoneal wall thickening in the pelvis disappeared. Twelve months after initiation of S-1 plus DOC chemotherapy, no sign of recurrence has been noted.

Takano T.,Osaka General Medical Center | Tajiri H.,Osaka General Medical Center | Kashiwagi Y.,Tokyo Medical University | Kimura S.,Osaka General Medical Center | Kawashima H.,Tokyo Medical University
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2011

We report the systemic cytokine and chemokine response in children with the 2009 pandemic influenza A (H1N1) virus infection. In patients with pneumonia, the serum levels of IFN-γ and IL-5 were significantly higher than those in patients without pneumonia. This tendency was also present for IL-6, IL-8, IL-10, IL-13, and MCP-1 in patients with pneumonia. Among patients with pneumonia, the levels of MCP-1 were significantly higher in the group of patients with pneumonia with severe respiratory failure than patients with mild pneumonia. © 2010 The Author(s).

Sakaguchi Y.,Osaka University | Fujii N.,Hyogo Prefectural Nishinomiya Hospital | Shoji T.,Osaka General Medical Center | Hayashi T.,Osaka General Medical Center | And 2 more authors.
Kidney International | Year: 2014

Although previous studies in the general population showed that hypomagnesemia is a risk for cardiovascular diseases (CVD), the impact of magnesium on the prognosis of patients on hemodialysis has been poorly investigated. To gain information on this we conducted a nationwide registry-based cohort study of 142,555 hemodialysis patients to determine whether hypomagnesemia is an independent risk for increased mortality in this population. Study outcomes were 1-year all-cause and cause-specific mortality with baseline serum magnesium levels categorized into sextiles. During follow-up, a total of 11,454 deaths occurred, of which 4774 had a CVD cause. In a fully adjusted model, there was a J-shaped association between serum magnesium and the odds ratio of all-cause mortality from the lowest to highest sextile, with significantly higher mortality in sextiles 1-3 and 6. Similar associations were found between magnesium and both CVD and non-CVD mortality. The proportion of patients with a baseline intact parathyroid hormone level under 50 pg/ml was significantly higher in the highest sextile; however, after excluding these patients, the CVD mortality risk in the highest sextile was attenuated. Thus, hypomagnesemia was significantly associated with an increased risk of mortality in hemodialysis patients. Interventional studies are needed to clarify whether magnesium supplementation is beneficial for improving patient prognosis © 2013 International Society of Nephrology.

Kawada J.,Osaka General Medical Center
Gan to kagaku ryoho. Cancer & chemotherapy | Year: 2012

There is no standard second line regimen for metastatic or recurrent esophageal cancer. We investigated the feasibility of combination chemotherapy with Docetaxel (DOC) and Nedaplatin (CDGP) as a second-line regimen for metastatic or recurrent esophageal cancer. Patients received DOC (60 mg/m2 intravenously) on day 1 and subsequently CDGP(70 mg/m2 intravenously) on day 1 of each 4-week period thereafter. We analyzed the toxicity and efficacy in 9 patients treated with combination chemotherapy with DOC and CDGP. The observed Grade 3-4 toxicities were neutropenia and anemia. Three patients had stable disease and 6 patients had progressive disease. The median progression free survival and overall survival were 4.3 and 8.1 months, respectively. Combination chemotherapy with DOC and CDGP is considered a feasible second line regimen for metastatic or recurrent esophageal cancer.

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