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ObjectiveTo date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.DesignThe primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.ResultsFrom the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction pConclusionUsing machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.Trial registration numberUMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)

Whole-exome sequencing (WES) can detect not only single-nucleotide variants in causal genes, but also pathogenic copy-number variations using several methods. However, there may be overlooked pathogenic variations in the out of target genome regions of WES analysis (e.g., promoters), leaving many patients undiagnosed. Whole-genome sequencing (WGS) can potentially analyze such regions. We applied long-read nanopore WGS and our recently developed analysis pipeline "dnarrange" to a patient who was undiagnosed by trio-based WES analysis, and identified a heterozygous 97-kb deletion partially involving 5'-untranslated exons of MBD5, which was outside the WES target regions. The phenotype of the patient, a 32-year-old male, was consistent with haploinsufficiency of MBD5. The transcript level of MBD5 in the patient's lymphoblastoid cells was reduced. We therefore concluded that the partial MBD5 deletion is the culprit for this patient. Furthermore, we found other rare structural variations (SVs) in this patient, i.e., a large inversion and a retrotransposon insertion, which were not seen in 33 controls. Although we considered that they are benign SVs, this finding suggests that our pipeline using long-read WGS is useful for investigating various types of potentially pathogenic SVs. In conclusion, we identified a 97-kb deletion, which causes haploinsufficiency of MBD5 in a patient with neurodevelopmental disorder, demonstrating that long-read WGS is a powerful technique to discover pathogenic SVs.

Background Second-line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Patients receiving SLC are categorized into two disease status groups: tumour progression after first-line chemotherapy and early recurrence after adjuvant chemotherapy. Differences between these groups have not yet been clarified. Patients and methods A total of 163 eligible patients registered in the randomized phase III TRICS trial evaluating SLC for patients with AGC was classified into the progressive disease (PD) group (n = 55) or the early relapse (ER) group (n = 108). We compared overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). Results The ER group had a lower median age than the PD group (66 vs. 72 years; P = 0.016), performance status (PS) 0 was more frequently seen in the ER group (87% vs. 71%; P = 0.012). The adjusted median OS was 13.7 months in the ER group and 13.6 months in the PD group (IPTW hazard ratio [HR]: 1.023; P = 0.854). The adjusted median PFS was 4.9 months in the ER group and 4.4 months in the PD group (IPTW HR: 0.707; P = 0.004). ORR was significantly better in the ER group than the PD group (21.3% vs. 4.9%; P = 0.020). No significant differences were observed in the incidence of adverse events. Conclusions ER was associated with improved PFS and better ORR than PD, although no difference in survival was demonstrated. From the viewpoint of treatment outcome, it seems appropriate to treat patients with ER in the same way as patients with PD. Clinical trial registration UMIN 000002571.

Perioperative treatment for locally advanced gastric cancer has been inconsistent between Japan and the Western countries. In Japan, D2 gastrectomy followed by adjuvant chemotherapy is regarded as standard treatment, while neoadjuvant or perioperative chemotherapy is considered to be a standard in the Western countries. Stomach Cancer Study Group of Japan Clinical Oncology Group (JCOG) has conducted many perioperative chemotherapy trials. After the publishing of positive results of ACTS-GC trial, stage-specific adjuvant chemotherapy protocols are planned. JCOG1104 was conducted as to demonstrate the non-inferiority of four courses of S-1 to standard eight courses of S-1, because the efficacy of S-1 appears to be sufficient in stage II. The trial failed to demonstrate the non-inferiority of four courses of S-1. S-1 for 1 year is still recognized to be a standard for stage II gastric cancer. For stage III, studies with more intensive treatments were planned as the efficacy of S-1 monotherapy seems to be insufficient. As in the Western countries, JCOG planned the perioperative chemotherapy. However, the clinical staging is a serious issue to select optimal patients for perioperative chemotherapy. JCOG conducted a prospective cohort study to evaluate the validity of clinical staging in JCOG1302A. From the results of this study, cT3-4 and cN1–3 are selected as optimal candidate for perioperative chemotherapy. JCOG1509 was conducted to demonstrate the superiority of perioperative chemotherapy to adjuvant chemotherapy in these cohorts. Perioperative chemotherapy for marginally resectable tumours such as linitis plastica or extensive nodal disease and special type of cancer like HER2 positive are also conducted.

Aim Gastric cancer is the second leading cause of cancer death worldwide. Surgery is the mainstay treatment for gastric cancer. There are no prediction models that examine the severity of postoperative morbidity. Herein, we constructed prediction models that analyze the risk for postoperative morbidity based on severity. Methods Perioperative data were retrieved from the National Clinical Database in patients who underwent elective gastric cancer resection between 2011 and 2012 in Japan. Severity of postoperative complications was determined by Clavien‐Dindo classification. Patients were randomly divided into two groups, the development set and the validation set. Logistic regression analysis was used to build prediction models. Calibration powers of the models were assessed by a calibration plot in which linearity between the observed and predicted event rates in 10 risk bands was assessed by the Pearson R 2 statistic. Results We obtained 154 278 patients for the analysis. Prediction models were constructed for grade ≥2, grade ≥3, grade ≥4, and grade 5 in the development set (n = 77 423). Calibration plots of these models showed significant linearity in the validation set (n = 76 855): R 2 = 0.995 for grade ≥2, R 2 = 0.997 for grade ≥3, R 2 = 0.998 for grade ≥4, and R 2 = 0.997 for grade 5 (all: P

Gastric cancer with extensive lymph node metastasis is commonly regarded as unresectable, while preoperative chemotherapy followed by gastrectomy has been tested since 2000 in JCOG (JCOG0001 and JCOG0405). The survivals were quite different between the trials despite the similar eligibility criteria. The aim of this study was to investigate if survival is still better in JCOG0405 after adjusting baseline factors and if there is any subset of patients who benefit more from either treatment. Eligibility criteria for both trials included histologically proven gastric adenocarcinoma; bulky nodal involvement around the celiac artery and its major branches (bulky N) and/or para-aortic lymph node (PAN); cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Patients received two or three cycles of preoperative chemotherapy of irinotecan plus cisplatin in JCOG0001, or S-1 plus cisplatin in JCOG0405, followed by D3 gastrectomy. Multivariable analysis for overall survival adjusting baseline and treatment factors was performed with the Cox regression model. After adjusting baseline factors, S-1 plus cisplatin was superior to irinotecan plus cisplatin for overall survival (HR = 0.39: 95% CI 0.22–0.67). The 5-year overall survival was poor for patients with bulky N+/PAN+ (19.2%) compared with bulky N+/PAN− (50.7%) or bulky N−/PAN+ (43.5%). S-1 plus cisplatin was shown to be a favorable preoperative treatment for gastric cancer with extensive lymph node metastasis by multivariable analysis, while poor prognosis in patients having both bulky N+ and PAN+ may necessitate further treatment improvement.

Biomarkers for selecting gastric cancer (GC) patients likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy were searched for using samples of patients recruited into SAMIT, a phase III randomized controlled trial. Total RNA was extracted from 556 GC patients and the expression of 105 genes were quantified using real-time PCR. Genes predicting positive effects of sequential paclitaxel on overall survival (OS), disease-free survival (DFS), or cumulative incidence of relapse were identified based on p-values associated with the interaction between the biomarker and sequential paclitaxel or monotherapy group. Low VSNL1 and CD44v expression predicted the positive effects of sequential paclitaxel in all above three endpoints. In the patient subgroup with combined low expression of both genes, sequential paclitaxel therapy was associated with a significantly improved OS (hazard ratio [HR] = 0.48 [95% confidence interval (CI), 0.30–0.78]; p

BACKGROUND Stable coronary artery disease is caused by a variable combination of organic coronary stenosis and functional coronary abnormalities, such as coronary artery spasm. Thus, we examined the clinical importance of comorbid significant coronary stenosis and coronary spasm. METHODS AND RESULTS We enrolled 236 consecutive patients with suspected angina who underwent acetylcholine provocation testing for coronary spasm and fractional flow reserve (FFR) measurement. Among them, 175 patients were diagnosed as having vasospastic angina (VSA), whereas the remaining 61 had no VSA (non‐VSA group). The patients with VSA were further divided into the following 3 groups based on angiography and FFR: no organic stenosis (≤50% luminal stenosis; VSA‐alone group, n=110), insignificant stenosis of FFR>0.80 (high‐FFR group, n=36), and significant stenosis of FFR≤0.80 (low‐FFR group, n=29). The incidence of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, urgent percutaneous coronary intervention, and hospitalization attributed to unstable angina was evaluated. All patients with VSA received calcium channel blockers, and 28 patients (95%) in the low‐FFR group underwent a planned percutaneous coronary intervention. During a median follow‐up period of 656 days, although the incidence of major adverse cardiovascular events was low and comparable among non‐VSA, VSA‐alone, and high‐FFR groups, the low‐FFR group had an extremely poor prognosis (non‐VSA group, 1.6%; VSA‐alone group, 3.6%; high‐FFR group, 5.6%; low‐FFR group, 27.6%) ( P CONCLUSIONS These results indicate that patients with VSA with significant coronary stenosis represent a high‐risk population despite current guideline‐recommended therapies, suggesting the importance of routine coronary functional testing in this population.

Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection. Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS). Age was a significant prognostic factor in addition to tumor stages both in “surgery alone” and “adjuvant” groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1–2 than in T3–4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio [HR]s: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1–2, N2–3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1–2 N1–3 groups were between 0.29 and 0.45. For T3–4 N0–1 group, S-1 was likely to be effective, not significant. Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1–2 tumors with lymph node metastasis.

Postoperative intra-abdominal infectious complication (PIIC) after gastrectomy for gastric cancer worsens in-hospital death or long-term survival. However, the methodology for PIIC preoperative risk assessment remains unestablished. We aimed to develop a preoperative risk model for postgastrectomy PIIC. We collected 183,936 patients’ data on distal or total gastrectomy performed in 2013–2016 for gastric cancer from the Japanese National Clinical Database and divided into development (2013–2015; n = 140,558) and validation (2016; n = 43,378) cohort. The primary outcome was the incidence of PIIC. The risk model for PIIC was developed using 18 preoperative factors: age, sex, body mass index, activities of daily living, 12 comorbidity types, gastric cancer stage, and surgical procedure in the development cohort. Secondarily, we developed another model based on the new scoring system for clinical use using selected factors. The overall incidence of PIIC was 4.7%, including 2.6%, 1.7%, and 1.3% in anastomotic leakage, pancreatic fistula, and intra-abdominal abscess, respectively. Among the 18 preoperative factors, male [odds ratio, (OR) 1.92], obesity (OR, 1.52–1.96), peripheral vascular disease (OR, 1.55), steroid use (OR, 1.83), and total gastrectomy (OR, 1.89) strongly correlated with PIIC incidence. The entire model using the 18 factors had good discrimination and calibration in the validation cohort. We selected eight relevant factors to create a simple scoring system, using which we categorized the patients into three risk groups, which showed good calibration. Using nationwide clinical practice data, we created a preoperative risk model for postgastrectomy PIIC for gastric cancer.

Background: We hypothesized that the relative proportion of tumor (PoT) at the luminal surface can predict gastric cancer (GC) patient survival.Methods: We measured the luminal PoT in resection specimens from 231 GC patients with stage II/III disease who had surgery at the Kanagawa Cancer Center, Yokohama, Japan. Tissue microarrays were used to assess the extent of immune cell infiltration by CD45 immunohistochemistry. Results were related to histopathological features and patient overall survival (OS).Results: PoT was significantly lower in diffuse-type (30%) compared to intestinaltype GC (41 %) , P = 0.03. Patients with low PoT intestinal-type GC survived significantly longer than patients with high PoT intestinal-type GC (5 years OS: 78% vs 47%, P = 0.0112). Low PoT was an independent favorable prognostic factor in multivariate analysis in intestinal-type GC. Low PoT was correlated with high content of CD45-positive immune cells (P = 0.035). There was no relationship between PoT and survival in diffuse-type GC.Conclusions: This is the first study to identify a subgroup of patients with stage II/III intestinal-type GC at high risk of recurrence by measuring PoT at the luminal surface. The relationship between PoT and immune cell content provides an initial insight into potential underlying biological mechanisms.

Background Benchmarking of long-term surgical outcomes has rarely been attempted. We previously devised a prediction model for assessing the outcome of late survival after surgery, termed the Estimation of Postoperative Overall Survival for Gastric Cancer (EPOS-GC). This study was undertaken to validate EPOS-GC in an external data set. Methods A retrospective cohort study was conducted in 11 cancer care hospitals in Japan, analyzing a consecutive series of patients who underwent elective gastric cancer resection between April 2007 and March 2009. EPOS-GC consists of three tumor-related variables and three physiological variables. The primary endpoint was postoperative overall survival. The observed-to-expected (O/E) ratio of 5-year survival rates was defined as a metric of quality of care. The sample size for O/E was determined as 42. Results We included 2045 patients for analysis. The median (95% confidence interval) follow-up time was 5.1 (1.2–6.8) years for censored patients. Although EPOS-GC demonstrated a good discriminative power (Harrell's C-index, 95% confidence interval: 0.80, 0.79–0.83), the calibration plot revealed that EPOS-GC underestimated 5-year survival rates in the high-risk group. Therefore, we recalibrated the model with Cox's regression analysis. The recalibrated EPOS-GC showed a good calibration, preserving the high discriminative power (C-index, 95% confidence interval: 0.80, 0.78–0.82). The O/E among hospitals according to the recalibrated EPOS-GC ranged between 0.87 and 1.27. The O/E correlated with hospital volumes (Spearman's correlation = 0.76, n = 11, p = .006). Conclusion EPOS-GC with recalibration can convey risk-adjusted quality assurance regarding late survival following gastric cancer resection.

In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294). HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety. Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6–5.1), which was longer than the 2-month protocol-specified threshold (p

Background: The current pooled analysis evaluated the efficacy of Hangeshashinto (TJ-14) in the prevention and/or treatment of chemotherapy-induced oral mucositis (COM) in gastric cancer and colorectal cancer using two prospective, multi-institutional, randomized, double-blind, placebo-controlled phase II trials. Patients and Methods: HANGESHA-G and HANGESHA-C randomly assigned patients with gastric cancer or colorectal cancer who developed moderate to severe COM (grade ≥1) during any cycle of chemotherapy to receive either TJ-14 or a placebo as a double-blind trial. The patients received a placebo or TJ-14 for four to six weeks, according to the chemotherapy regimen, from the start of their next course of chemotherapy. The primary endpoint was the incidence of grade ≥2 COM in the protocol treatment course, and the secondary endpoints were the time to disappearance of COM and the incidence of adverse events. Results: The pooled population included 181 patients. The incidence of grade ≥2 COM in the TJ-14 group was 55.7% (49 patients), while that in the placebo group was 53.8% (50 patients); there was no significant difference between the two groups (p=0.796). The median time to remission of grade ≥2 COM to grade

Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs.Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy.Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance.Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.

Background The prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear. Patients and methods In this 2×2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m 2 for 21 d with 1 week rest)/cisplatin (60 mg/m 2 at day 8) or PC (80 and 25 mg/m 2 , respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS). Results Between October 2009 and July 2011, 83 patients received 2 courses of SC (n = 21), 4 courses of SC (n = 20), 2 courses of PC (n = 21) and 4 courses of PC (n = 21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses. Conclusions Two courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer. Clinical trial number UMIN-000002595.

The functional assessment of cancer therapy-gastric (FACT-Ga) questionnaire was designed to evaluate quality of life (QOL) in patients with gastric cancer. We aimed to explore the reliability and validity of FACT-Ga in Japanese patients, and assess the sensitivity of the gastric cancer subscale for detecting changes in cancer-related variables over time. The Japanese version of FACT-Ga was used, and data were obtained from Japanese patients who participated in either of two clinical trials: treatment for advanced or recurrent gastric cancer with ascites (advanced-GC group), or adjuvant chemotherapy after curative resection of gastric cancer (adjuvant group). Psychometric data including data used to determine reliability, internal consistency, and clinical validity were analyzed. Clinical validity was evaluated by comparing subscale scores for patients in the two groups, and by comparing subscale scores for patients with different performance status scores. Correlation between gastric cancer subscale scores and gastric cancer-related variables was also examined. In addition, sensitivity of the gastric cancer subscale to changes in ascites volume, abdominal girth, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) was examined by evaluating their correlation in the advanced-GC group. We collected data on 156 patients (62 advanced-GC group patients and 94 adjuvant group patients). Response rates for the subscales were over 80 % at most time points for both the groups. Cronbach’s coefficient alpha revealed good internal consistency for each subscale. At baseline, the adjuvant group had higher QOL scores than the advanced-GC group (P

Objectives The aim of this study was to examine which component of drug-eluting stents (DES) plays a major role in enhanced coronary vasoconstricting responses after DES implantation in pigs. Background Recent studies have reported unremitting angina due to vasomotion abnormalities even after successful DES implantation. However, it remains to be elucidated which component of DES (metal stent, polymer coating, or antiproliferative drug) is responsible for DES-induced coronary hyperconstricting responses. Methods We developed poly- dl -lactic acid and polycaprolactone (PDLLA-PCL) copolymer technology with higher biocompatibility that is resorbed within 3 months. Four types of coronary stents were made: 1) a stent with polylactic acid (PLA) polymer coating containing antiproliferative drug (P1+D+); 2) a stent with PLA polymer coating alone without any drug (P1+D–); 3) a stent with novel PDLLA-PCL polymer coating alone (P2+D–); and 4) a bare metal stent (P–D–). The 4 stents were randomly deployed in the left anterior descending and left circumflex coronary arteries in 12 pigs. Results After 1 month, coronary vasoconstriction by intracoronary serotonin was enhanced at P1+D+ and P1+D– stent edges compared with P2+D– and P–D– stent edges and was prevented by a specific Rho-kinase (a central molecule of coronary spasm) inhibitor, hydroxyfasudil. Immunostainings showed that inflammatory changes and Rho-kinase activation were significantly enhanced at P1+D+ and P1+D– sites compared with P2+D– and P–D– sites. There were significant positive correlations between the extent of inflammation or Rho-kinase expression/activation and that of coronary vasoconstriction. Conclusions These results indicate the important roles of PLA polymer coating in DES-induced coronary vasoconstricting responses through inflammatory changes and Rho-kinase activation in pigs in vivo, which are ameliorated by PDLLA-PCL copolymers.

Background The findings of COMPASS, a randomized phase II study, suggested that the regimens and courses of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) did not affect the pathological response. However, pathological complete response was achieved in 10% patients who received four courses of either S-1/cisplatin or paclitaxel/cisplatin. We hypothesized that if relevant biomarkers could be used to predict the suitable NAC regimen before treatment initiation, further improvements could be ensured in the outcomes of locally advanced GC. Materials and methods mRNA extraction, real-time polymerase chain reaction, and immunohistochemical analyses were performed using endoscopic biopsy specimens of primary tumors, collected prior to NAC, to determine the clinically relevant biomarkers. Results TIMP1, DSG2, RRM1, MUC2, EGFR, ZDHHC14, and CLDN18.2 were identified as biomarker candidates, since their expression was significantly associated with the pathological responses to each NAC regimen. Furthermore, TIMP1 and DSG2 were identified as predictive biomarkers of the pathological response to each NAC regimen. Conclusions The effective prediction of the pathological response to NAC regimens in locally advanced GC using biomarkers identified from endoscopic biopsy specimens indicates the possibility of personalizing NAC based on biomarker analysis.

Many patients with gastric cancer relapse during or early after adjuvant chemotherapy. The standard treatment for early relapse patients is a second-line chemotherapy (SLC) based on irinotecan, taxanes, or a platinum-based chemotherapy. The platinum-containing biweekly irinotecan plus cisplatin (IRI/CDDP) combination was assumed to be promising in several reports of clinical trials as SLC. TRICS trial, a randomized phase III study of IRI/CDDP vs. IRI in platinum-naive gastric cancers refractory to S-1 monotherapy, revealed that both irinotecan-based chemotherapies were effective and well tolerated. This study analyzed 108 patients in the TRICS trial who experienced early relapse. Patients receiving IRI/CDDP (IRI, 60 mg/m2; CDDP, 30 mg/m2, q2w) versus IRI (150 mg/m2, q2w) were compared regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. The OS was 14.0 (95% confidence interval [CI]: 11.0–21.2) and 14.0 (95% CI: 10.7–16.5) months for IRI/CDDP and IRI, respectively (hazard ratio [HR]: 0.782; 95% CI: 0.515–1.188, P = 0.249). No significant differences were observed for PFS (5.0 vs. 4.5 months, respectively; HR: 0.802; 95% CI: 0.543–1.185, P = 0.268) or ORR (19.6% [95% CI: 9.4–33.9%] vs. 23.3% [95% CI: 11.8–38.6%], respectively). The incidence of grade 3–4 anemia was higher for IRI/CDDP than for IRI (20% vs. 0%, respectively; P = 0.0006). Our study showed no significant survival differences between IRI/CDDP and IRI in platinum-naive patients who relapsed during or within 6 months after S-1 adjuvant therapy; therefore, IRI may be a good option in this population. UMIN 000002571.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1mut) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1mut from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment., Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.

Background Capecitabine plus cisplatin (XP) is a standard global regimen, while S-1 plus cisplatin (SP) is a Japanese standard for first-line treatment of advanced gastric cancer (AGC). We conducted a phase II trial comparing XP with SP for patients with AGC to confirm whether these regimens can be used as controls in a phase III study and to explore whether histological subtypes favour XP or SP. Patients and methods Eligible patients were randomised to receive either S-1 40 mg/m2 for 21 days plus cisplatin 60 mg/m2 (q5w) or capecitabine 1000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w). The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), overall response rate (ORR) and safety. Results In 110 eligible patients, 24-week PFS was higher in both groups (SP 50.9%, XP 43.5%) than the protocol-specified threshold of 40%. The median PFS for SP versus XP was 5.6 and 5.1 months (hazard ratio [HR], 1.126; p = 0.5626); OS was 13.5 and 12.6 months (HR, 0.942; p = 0.7769) and the ORR was 42.4% and 69.4% (p = 0.0237), respectively. The most common grade ≥3 adverse events with SP/XP were anaemia (16%/20%), neutropenia (9%/18%) and anorexia (18%/13%). Subgroup analysis by histological classification showed no statistical difference between treatments. Conclusions XP and SP are comparable and can be recommended as control arms in a phase III study for AGC. Histological subtypes were not sensitive markers for the selection of XP or SP. Clinical trial registration NCT00140624 .

Objective: To establish the gene copy number status of receptor tyrosine kinase (RTK) and downstream signaling (DSS) genes genes in primary gastric cancer (primGC) and matched lymph node metastases (LNmet). Background: Evidence suggests that coamplification between RTKs and DSSs and conversion between primGC and LNmet are associated with resistance to targeted therapy. Methods: DNA from 237 Japanese primGC and 103 matched LNmet was analyzed using a newly developed multiplex ligation-dependent probe amplification (MLPA) probemix to investigate RTK (EGFR, HER2, FGFR2, and MET) and DSS (PIK3CA, KRAS, MYC, and CCNE1) gene copy number status. Results were compared between primGC and LNmet and related to clinicopathological data including survival. Results: A total of 150 (63%) primGC had either RTK or DSS amplification. DSS coamplification was more frequent than RTK coamplification in primGC and LNmets. Moreover, 70 (30%) GC showed a disconcordant RTK and/or DSS gene copy number status between primGC and LNmet, most common was negative conversion for DSS genes (n=40 GC). The presence of RTK amplification in primGC was related to poorer survival in univariate analysis (P=0.04). Conclusions: This is the first and most comprehensive study in gastric cancer investigating the concordance between gene copy number status of targetable RTKs and downstream signaling oncogenes in primGC and LNmets. Future studies need to establish whether the relative high frequency of RTK and DSS coamplification and/or the relative high rate of negative conversion in LNmet can potentially explain recent failures of RTK targeted therapy in gastric cancer patients.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

BACKGROUND In the current era of primary percutaneous coronary intervention (PCI), some patients with acute myocardial infarction (AMI) still do not undergo primary PCI. METHODS AND RESULTS To examine the clinical characteristics of AMI patients who did not undergo primary PCI, we analyzed patients enrolled between 2002 and 2010 in the MIYAGI-AMI Registry Study, in which all AMI patients in the Miyagi prefecture have been prospectively registered. Among a total of 8,640 patients, 1,879 (21.7%) did not undergo primary PCI and their in-hospital mortality was significantly worse compared with those who did (21.4% vs. 6.4%, P

BACKGROUND The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P

Objective Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

Coronary artery spasm plays important roles in the pathogenesis of a wide range of ischemic heart disease. Recent studies have demonstrated that coronary spasm is frequently noted in Caucasians as in Asians [(1)][1]. We previously demonstrated that vascular smooth muscle cell hypercontraction

Recent gastric cancer clinical trials have aimed to establish the efficacy of combination therapy over monotherapy, however, the role for genomic biomarkers in these trials has remained largely unexplored. Here, using the NanoString expression platform, we analyzed 105 gastric tumors from a randomized phase III Japanese clinical trial (GC0301/TOP002) testing the efficacy of irinotecan plus S-1(IRI-S) versus S-1 therapy. We found that previously established proliferative subtype signatures, were associated with older patients (>65 years) and liver metastasis while mesenchymal subtype signatures were associated with younger patients (≤65 years) and peritoneal metastasis. Genes associated with tumor microenvironment (CD4, CD14, ADAMTS1, CCL5, CXCL12, CCL19), therapeutic implications (DPYD) and oncogenic signaling (Wnt5A, PTRF) were significantly associated with patient age, histology, tumor status, measurable lesions and metastasis. We identified Wnt5A downregulation as a candidate predictor of improved progression free survival (>8 weeks) in S-1 but not in IRI-S treatment. Although statistical significance was not achieved, mesenchymal subtype showed a trend for treatment interaction with IRI-S for efficacy. These findings highlight promising genomic markers that could be useful predictors of chemotherapy efficacy for better prognosis and survival outcome in gastric cancer.

Background Recent studies suggested that perivascular components, such as perivascular adipose tissue (PVAT) and adventitial vasa vasorum (VV), play an important role as a source of various inflammatory mediators in cardiovascular disease. Objectives The authors tested their hypothesis that coronary artery spasm is associated with perivascular inflammation in patients with vasospastic angina (VSA) using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). Methods This study prospectively examined 27 consecutive VSA patients with acetylcholine-induced diffuse spasm in the left anterior descending artery (LAD) and 13 subjects with suspected angina but without organic coronary lesions or coronary spasm. Using CT coronary angiography and electrocardiogram-gated 18F-FDG PET/CT, coronary PVAT volume and coronary perivascular FDG uptake in the LAD were examined. In addition, adventitial VV formation in the LAD was examined with optical coherence tomography, and Rho-kinase activity was measured in circulating leukocytes. Results Patient characteristics were comparable between the 2 groups. CT coronary angiography and ECG-gated 18F-FDG PET/CT showed that coronary PVAT volume and coronary perivascular FDG uptake significantly increased in the VSA group compared with the non-VSA group. Furthermore, optical coherence tomography showed that adventitial VV formation significantly increased in the VSA group compared with the non-VSA group, as did Rho-kinase activity. Importantly, during the follow-up period with medical treatment, both coronary perivascular FDG uptake and Rho-kinase activity significantly decreased in the VSA group. Conclusions These results provide the first evidence that coronary spasm is associated with inflammation of coronary adventitia and PVAT, where 18F-FDG PET/CT could be useful for disease activity assessment. (Morphological and Functional Change of Coronary Perivascular Adipose Tissue in Vasospastic Angina [ADIPO-VSA Trial]; UMIN000016675 )

Background Myocardial bridge (MB) is a myocardial bundle through which coronary segment tunnels and could compress coronary arteries causing myocardial ischemia. However, the characteristic structural findings of MB remain to be fully elucidated. Recently, we demonstrated that optical coherence tomography (OCT) enables us to visualize adventitial vasa vasorum (VV) formation in humans. In this study, we examined adventitial VV formation at the coronary segment with MB in humans using OCT. Methods We examined 15 consecutive patients with suspected angina pectoris and MB in the left anterior descending (LAD) coronary arteries but no angiographic coronary stenosis. MB was detected on coronary angiography as a segment with milking effect. We performed intracoronary OCT imaging along the entire LAD. Morphometric analysis was performed at MB and proximal/distal segments at every 1mm. Results OCT examination showed the absence of adventitial VV formation at MB in the LAD, while VV was clearly noted at both the proximal and distal reference segments. Adventitial VV area was significantly less at MB compared with the proximal or distal references. Conclusions These results with OCT imaging indicate that coronary segments with MB lack adventitial VV formation in humans, suggesting that MB could influence morphological and functional changes of the coronary artery.

Aims Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P

BACKGROUND We are now facing rapid population aging in Japan, which will affect the actual situation of cardiovascular diseases. However, age-specific trends in the incidence and mortality of acute myocardial infarction (AMI) in Japan remain to be elucidated.Methods and Results:We enrolled a total of 27,220 AMI patients (male/female 19,818/7,402) in our Miyagi AMI Registry during the past 30 years. We divided them into 4 age groups (≤59, 60-69, 70-79 and ≥80 years) and examined the temporal trends in the incidence and in-hospital mortality of AMI during 3 decades (1985-1994, 1995-2004 and 2005-2014). Throughout the entire period, the incidence of AMI steadily increased in the younger group (≤59 years in both sexes), while in the elderly groups (≥70 years in both sexes), the incidence significantly decreased during the last decade (all P

Summary 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/m 2 per day), S-1 only (80 mg/m 2 per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m 2 ) 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; p non-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.

Duchenne muscular dystrophy (DMD) is strongly associated with a unique form of dilated cardiomyopathy. Cardiac complications are the leading cause of death in DMD; thus, longitudinal assessments and early intervention for cardiac dysfunction are necessary to improve prognosis. Two-dimensional echocardiography, which is routinely used for cardiac assessment, has some limitations for quantitative analyses in DMD patients with thoracic deformities and regional wall motion abnormalities in the left ventricle. Recently, real-time three-dimensional echocardiography has emerged as a feasible tool for cardiac assessment in various cardiac diseases. The aim of this study was to examine the utility of this technology in DMD. We evaluated left ventricular ejection fraction (LVEF), a major parameter of left ventricular function, in 17 male DMD patients. LVEF values measured by real-time three-dimensional echocardiography were compared with those determined by two established nuclear cardiology methods: "the first-pass method of radionuclide angiocardiography" and "quantitative electrocardiogram-gated single-photon emission computed tomography". A good correlation was observed for LVEF values, particularly between real-time three-dimensional echocardiography and "the first-pass method of radionuclide angiocardiography" (r=0.90, p

Background Locally advanced gastric cancer with extensive regional and/or para-aortic lymph node (PAN) metastases is typically unresectable and associated with poor outcomes. This study investigated the safety and efficacy of S-1 plus cisplatin followed by extended surgery with PAN dissection for gastric cancer with extensive lymph node metastasis. Methods Patients with gastric cancer with bulky lymph node metastasis along the coeliac artery and its branches and/or PAN metastasis received two or three 28-day cycles of S-1 plus cisplatin, followed by gastrectomy with D2 plus PAN dissection. The primary endpoint was the percentage of complete resections with clear margins in the primary tumour (R0 resection). A target sample size of 50 with one-sided α of 0·105 and β of approximately 0·2 corresponded to an expected R0 rate of 65 per cent and a threshold of 50 per cent. Results Between February 2005 and June 2007, 53 patients were enrolled, of whom 51 were eligible. The R0 resection rate was 82 per cent. Clinical and pathological response rates were 65 and 51 per cent respectively. The 3- and 5-year overall survival rates were 59 and 53 per cent respectively. During chemotherapy, grade 3/4 neutropenia occurred in 19 per cent and grade 3/4 non-haematological adverse events in 15·4 per cent. The incidence of grade 3/4 adverse events related to surgery was 12 per cent. There were no reoperations or treatment-related deaths. Conclusion For locally advanced gastric cancer with extensive lymph node metastasis, 4-weekly S-1 plus cisplatin followed by surgery including PAN dissection was safe and effective for some patients. Further investigation of this treatment strategy is warranted.

Accuracy of the radiologic diagnosis of gastric cancer staging after neoadjuvant chemotherapy remains unclear.Patients enrolled in the COMPASS trial, a randomized phase II study comparing two and four courses of S-1 plus cisplatin and paclitaxel and cisplatin followed by gastrectomy, were examined. The radiologic stage was determined by using thin-slice computed tomography (CT) or multidetector low CT by following Habermann's method.A total of 75 patients registered in the COMPASS study who underwent surgical resection were examined in this study. The radiologic T and pathologic T stages were not significantly correlated (p = 0.221). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 42.7, 10.7, and 46.7%, respectively. When patients were stratified according to the pathologic response of the primary tumor, the correlation was not significant in either the responders (n = 32, p = 0.410) or the nonresponders (n = 43, p = 0.742). The radiologic accuracy was 37.5% in the responders and 42.7% in the nonresponders. The radiologic N and pathologic N stages were significantly correlated (p = 0.000). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 44, 29.3, and 26.7%, respectively. When stratifying the patients with measurable lymph nodes according only to the radiologic response, the correlation was significant in the nonresponders (n = 23, p = 0.035) but not in the responders (n = 28, p = 0.634). The radiologic accuracy was 39.3% in the responders and 52.1% in the nonresponders.Restaging using CT after neoadjuvant chemotherapy for gastric cancer is considered to be inaccurate and unreliable. In particular, the radiologic T-staging determined after neoadjuvant chemotherapy should not be considered in clinical decision-making.

BACKGROUND Although emergency care of acute myocardial infarction (AMI) could theoretically be improved through improved patient delay, this notion remains to be confirmed. Additionally, the influence of large earthquakes on the emergency care of AMI cases remains to be elucidated. The Great East Japan Earthquake (March 11, 2011) has enabled us to address these issues. METHODS AND RESULTS We analyzed the data from 2008 to 2011 (n=3,937) in the Miyagi AMI Registry Study. In-hospital mortality was significantly lower in 2011 as compared with the previous 3 years (7.3% vs. 10.5%, P

The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation.

Neoadjuvant chemotherapy may improve outcomes in gastric cancer. Tumor responses can be evaluated with RECIST, Japanese Classification of Gastric Carcinoma (JCGC), and histological criteria. These approaches have not yet been compared.We analyzed two phase II trials of neoadjuvant chemotherapy using S-1 plus cisplatin. JCOG0210 included patients with linitis plastica and large ulcero-invasive tumors, whereas JCOG0405 comprised those with para-aortic or bulky lymph node metastases. Radiologic evaluations were conducted using RECIST in JCOG0405 and JCGC criteria in JCOG0210, because the latter included many patients without measurable lesions. A histological responder was defined as a patient in whom one third or more of the tumor was affected. The hazard ratios (HR) for death between responders and non-responders and response rate differences between short- and long-term survivors were estimated.In JCOG0210 (n = 49), HR was 0.54 in JCGC responders (P = 0.059) and 0.40 in histological responders (P = 0.005). The difference in response rates between short- and long-term survivors using histological criteria (34 %, P = 0.023) was greater than that using JCGC criteria (24 %, P = 0.15). In JCOG0405 (n = 51), HR was 0.67 in RECIST responders (P = 0.35) and 0.39 in histological responders (P = 0.030). In short- and long-term survivors, respectively, RECIST response rates were 62 and 67 % (P = 0.77), whereas histological response rates were 33 and 63 % (P = 0.048).Histological criteria showed higher response assessment validity than RECIST or JCGC criteria and yielded the best surrogate endpoint for overall survival.

Paclitaxel–cisplatin (TC) combination is effective and well tolerated in patients with unresectable gastric cancer. We investigated the efficacy and safety of TC for locally advanced gastric cancers in a neoadjuvant setting. Patients received 2–4 courses of paclitaxel (80 mg/m2) and cisplatin (25 mg/m2) on days 1, 8, and 15 in a 4-weekly schedule, followed by radical gastrectomy. Primary endpoint was the pathological response rate: percentage of tumors in which one-third or more parts were affected. All 52 patients enrolled were eligible. Thirty-six (69.7 %) patients completed two or more courses of chemotherapy. Forty-three patients (82.7 %) underwent surgery, 33 (63.5 %) had R0 resection, and there was no treatment-related death. The pathological response was 34.6 % (95 % CI 22.0–49.1) for all registered patients; the null hypothesis of tumor response ≤10 % was rejected (p

Background and Objectives We conducted a phase II study to evaluate the safety and efficacy of preoperative chemotherapy with S-1 + cisplatin followed by gastrectomy in patients with linitis plastica (type 4) or large ulcero-invasive-type (type 3) gastric cancer. Methods Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or type 3. Patients received two 28-day courses of preoperative chemotherapy of S-1 (80–120 mg/body, p.o., days 1–21) and cisplatin (CDDP; 60 mg/m2, i.v., day 8). Primary endpoints were completion of protocol treatment and incidence of treatment-related death (TRD). Results Among the 49 eligible patients with the median age of 61 years, 36 completed the protocol treatment comprising two courses of preoperative chemotherapy and R0/1 resection (73.5% completion, 80% CI, 63.7–81.7%). One TRD was observed during the first course of chemotherapy. Median survival and 3-year overall survival were 17.3 months and 24.5%, respectively. Conclusions Preoperative chemotherapy with S-1 + CDDP followed by gastrectomy is a safe and promising treatment for type 4 and large type 3 gastric cancers. Based on the results of this study, we are now conducting a phase III study (JCOG0501) to confirm the superiority of this treatment. J. Surg. Oncol. 2013;107:741–745. © 2013 Wiley Periodicals, Inc.

Background: Oxidative stress induces secretion of cyclophilin A (CyPA) from vascular smooth muscle cells and it plays a crucial role in the pathogenesis of atherosclerosis in mice. Therefore, we tested our hypothesis that plasma CyPA levels are increased in patients with coronary artery diseases (CAD). Methods and Results: In 320 consecutive patients undergoing coronary angiography, we examined the relationship between plasma CyPA levels and the severity of CAD. We measured plasma CyPA by an immunoassay based on the sandwich technique. Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it (P