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REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients.Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo.The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age.In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.

Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens.In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343.Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57-12·37) in the nivolumab group and 8·59 months (5·65-11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60-6·37) in the nivolumab group and 4·14 months (3·42-4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51-0·78; p0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7-32·0) with nivolumab and 10·9% (6·2-17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines.Ono Pharmaceutical and Bristol-Myers Squibb.

Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte–associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy. Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS). Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61–5.16 vs. 4.90 months, 95% CI, 3.45–6.54, HR = 1.44; 80% CI, 1.09–1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5–18.9) and 12.1 months (95% CI, 9.3–not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients. Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671–8. ©2017 AACR.

Importance REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). Objective To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. Design, Settings, and Participants Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). Interventions Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. Main Outcomes and Measures Overall survival (OS), defined as time from randomization to death from any cause. Results In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment–emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. Conclusions and Relevance In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more. Trial Registration clinicaltrials.gov Identifier:NCT01140347

This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival.Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone.Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival.Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.

PURPOSE The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy-gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)-in patients with advanced pancreatic cancer. MATERIALS AND METHODS There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks and capecitabine 850 mg/m(2) twice daily for 2 weeks followed by 1 week's rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated. RESULTS The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2. CONCLUSION GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment.

Although gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to those in western countries. However, there are currently no Korean multidisciplinary guidelines for gastric cancer. Experts from related societies developed guidelines de novo to meet Korean circumstances and requirements, including 23 recommendation statements for diagnosis (n=9) and treatment (n=14) based on relevant key questions. The quality of the evidence was rated according to the GRADE evidence evaluation framework: the evidence levels were based on a systematic review of the literature, and the recommendation grades were classified as either strong or weak. The applicability of the guidelines was considered to meet patients' view and preferences in the context of Korea. The topics of the guidelines cover diagnostic modalities (endoscopy, endoscopic ultrasound, and radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, and radiotherapy), and pathologic evaluation. An external review of the guidelines was conducted during the finalization phase.

Unlike previous piezoelectric energy harvesters that generate electrical energy from a magnetic field according to the magnetic strength or magnetostrictive material, the proposed method achieves significant power enhancement using directional optimization of magnetization. This method can serve as a ubiquitous autonomous energy source that converts a magnetic field into usable electrical energy in a wireless sensor network for an (Industrial) Internet of Things (IIoT). The key approach in the proposed model is to increase of the Lorentz force by vertically adjusting the magnetic flux direction of a power cable and the magnetic direction of a tip magnet. In the simulation, a 3592 times higher y-axis Lorentz force was obtained in the vertical pole array, which resulted in about a 1.6 times higher output voltage. Then, we experimentally compared the electrical output performance of six different types of pole array according to the size and direction of the tip magnet. In a one-tip magnet (10 × 10 × 10 mm3), the output power values were 2.34 mW (Vertical) and 1.23 mW (Horizontal) at 8 kΩ matching impedance. For two-tip magnets (20 × 10 × 10 mm3), the output power values of the harvester were 39.2 mW (Planar-Vertical), 18.4 mW (Orthogonal-Vertical), 8.64 mW (Planar-Horizontal), and 0.05 mW (Orthogonal-Horizontal) at 5 kΩ matching impedance. It was found that the power generation differed by 2.13 to 784 times. With this method of power enhancement using multi-disciplinary research, we successfully constructed autonomous IoT and IIoT sensor systems for smart homes, smart buildings and smart factories.

Purpose Cisplatin plus 5-fluorouracil has been globally accepted as a standard regimen for the treatment for advanced gastric cancer. However, cisplatin has several disadvantages, including renal toxicity and the need for admission. S-1 plus cisplatin has become a standard treatment for advanced gastric cancer in East Asia. This phase III study was designed to evaluate the potential benefits of adding docetaxel to S-1 without a platinum compound in patients with advanced gastric cancer. Methods Patients were randomly assigned to receive docetaxel plus S-1 or S-1 alone. The docetaxel plus S-1 group received docetaxel on day 1 and oral S-1 on days 1–14 of a 21-day cycle. The S-1 alone group received oral S-1 on days 1–28 of a 42-day cycle. The primary end point was overall survival. Results Of the 639 patients enrolled, 635 were eligible for analysis. The median overall survival was 12.5 months in the docetaxel plus S-1 group and 10.8 months in the S-1 alone group (p = 0.032). The median progression-free survival was 5.3 months in the docetaxel plus S-1 group and 4.2 months in the S-1 alone group (p = 0.001). As for adverse events, neutropenia was more frequent in the docetaxel plus S-1 group, but remained manageable. Conclusion As first-line treatment for advanced gastric cancer, docetaxel plus S-1 significantly improves median overall and progression-free survival as compared with S-1 alone. (ClinicalTrials.gov number: NCT00287768).

The BRAF mutation has been shown to be associated with aggressive clinicopathologic characteristics of papillary thyroid cancer (PTC). However, several studies that analyzed hundreds of patients have not demonstrated any correlation. The objective of this study was to investigate the relationship of the BRAF mutation with clinicopathologic factors in a large group of homogenous PTC patients.We collected data of PTC patients who received curative resection of the thyroid gland and who had undergone BRAF mutation tests of their thyroid cancer tissue. Minor variant PTCs and mixed-type thyroid cancers were excluded in this analysis. Clinicopathologic characteristics, including age, sex, BRAF mutation, tumor histology, size, extrathyroidal extension, tumor margin, lymph node metastasis, multifocality, stage, and associated thyroid disease, were collected. The relationship of the BRAF mutation with clinicopathologic factors was analyzed in each homogenous histologic PTC.There were 3130 PTC patients who met the criteria, and these patients were divided into three major histologic groups: conventional PTC (n = 2947), diffuse sclerosing variant PTC (n = 98), and follicular variant PTC (n = 85). The BRAF mutation was variably detected in 75.3%, 61%, and 40% of patients, respectively. In conventional PTC cases, the BRAF mutation was significantly associated with large tumor size, extrathyroidal extension, and lymph node metastasis. Coexistent chronic lymphocytic thyroiditis was significantly less prevalent in the BRAF mutant group. Age, sex, and tumor margin status were not significantly correlated with the BRAF status. There was no evidence that any clinicopathologic factors were linked with the BRAF mutation status in diffuse sclerosing and follicular variant PTCs.The BRAF mutation was differentially detected in each histologic subtype of PTC and was strongly correlated with pathologic factors, most strongly with no coexistent chronic lymphocytic thyroiditis, in conventional PTC. The BRAF mutation is suggested to be a poor prognostic marker in conventional PTC, and the BRAF mutational analysis may lead to better management for individual PTC patients.

To restore old aqueduct in Korea which is a irrigation bridge to supply water in paddy field area, it is needed to estimate approximate costs of restoration because the basic design for estimation of construction costs is often ruled out in current system. In this paper, estimating models of construction costs were developed on the basis of performance data for restoration of RC aqueduct bridges since 2003. The regression analysis (RA) model and case-based reasoning (CBR) model for the estimation of construction costs were developed respectively. Error rate of simple RA model was lower than that of multiple RA model. CBR model using genetic algorithm (GA) has been applied in the estimation of construction costs. In the model three factors like attribute weight, attribute deviation and rank of case similarity were optimized. Especially, error rate of estimated construction costs decreased since limit ranges of the attribute weights were applied. The results showed that error rates between RA model and CBR models were inconsiderable statistically. It is expected that the proposed estimating method of approximate costs of aqueduct restoration will be utilized to support quick decision making in phased rehabilitation project.

With the purpose of generating a microbial strain for l-ornithine production in Corynebacterium glutamicum, genes involved in the central carbon metabolism were inactivated so as to modulate the intracellular level of NADPH, and to evaluate their effects on l-ornithine production in C. glutamicum. Upon inactivation of the 6-phosphoglucoisomerase gene (pgi) in a C. glutamicum strain, the concomitant increase in intracellular NADPH concentrations from 2.55 to 5.75 mmol g−1 (dry cell weight) was accompanied by reduced growth rate and l-ornithine production, suggesting that l-ornithine production is not solely limited by NADPH availability. In contrast, inactivation of the gluconate kinase gene (gntK) led to a 51.8 % increase in intracellular NADPH concentration, which resulted in a 49.9 % increase in l-ornithine production. These results indicate that excess NADPH is not necessarily rate-limiting, but is required for increased l-ornithine production in C. glutamicum.

Purpose: To evaluate attenuation change of lung nodules and diagnostic performance of CT densitometry for detecting calcification according to tube voltage and current setting in low-dose CT using iterative reconstruction (IR). Material and Methods: CT images of an anthropomorphic phantom containing 14 artificial nodules (7-10 mm) with various mean attenuations (82-402 HU on standard dose) were obtained with 64- and 128-detector-row CT scanners using a standard (120kVp/100mA) and various low-dose settings (80, 100, and 120 kVp; 10-100 mAs) with IR. Mean and standard deviation (SD) of nodule attenuation (HU) were compared according to variation of tube voltages and current settings. As a threshold of 200 HU to determine calcified lesion, diagnostic performance of CT densitometry in low dose techniques was compared with those in standard dose CT. Results: Mean attenuation of nodules increased as the tube voltage decreased and SD increased as the tube voltage and current decreased in both CT scanners (p Conclusion: Although mean attenuation and SD of lung nodules changed variably according to combination of tube current and voltages, densitometry could be applicable for detection of calcification in low dose CT using IR techniques except very low tube current techniques.

Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC.This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used.The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events.Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.

Background The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined. Patients and methods Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71-1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60-3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64-1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45-2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3-5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively. Conclusion The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population. Implications for practice The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.

In order to identify single nucleotide polymorphism and insertion/deletion mutations, we performed whole-genome re-sequencing of the enhanced L-lysine-producing Corynebacterium glutamicum ATCC 21300 strain. In total, 142 single nucleotide polymorphisms and 477 insertion/deletion mutations were identified in the ATCC 21300 strain when compared to 3,434 predicted genes of the wild-type C. glutamicum ATCC 13032 strain. Among them, 110 transitions and 29 transversions of single nucleotide polymorphisms were found from genes of the ATCC 21300 strain. In addition, 11 genes, involved in the L-lysine biosynthetic pathway and central carbohydrate metabolism, contained mutations including single nucleotide polymorphisms and insertions/deletions. Interestingly, RT-PCR analysis of these 11 genes indicated that they were normally expressed in the ATCC 21300 strain. This information of genome-wide gene-associated variations will be useful for genome breeding of C. glutamicum in order to develop an industrial amino acid-producing strain with minimal mutation.

PURPOSE Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. Multimodal treatment involving surgery and chemoradiotherapy has been used to improve the survival of patients. Here, we retrospectively review of treatment outcome of 13 consecutive patients who were treated at a single center. MATERIALS AND METHODS We retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010. Kaplan-Meier survival curve was used to analyze progression-free survival and overall survival of patients. RESULTS The median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patient's condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months). CONCLUSION Patients with anaplastic thyroid cancer showed poor prognosis despite multimodality treatment. Therefore, identification of novel therapeutic targets is warranted to take an effective mode of treatment.

PURPOSE Refractory small-cell lung cancer (SCLC) has a poor prognosis, and current salvage chemotherapy for refractory SCLC, such as CAV (cyclophosphamide, adriamycin, vincristine) or topotecan, has an unsatisfactory outcome, with a response rate and overall survival of less than 10% and 6 months, respectively. This phase II study evaluated the role of topotecan combined with etoposide in SCLC patients that have progressed, or relapsed, within 3 months following completion of the initial chemotherapy. MATERIALS AND METHODS Twenty-seven patients were entered into this study. Eligible patients had an ECOG performance status of less than, or equal to, 2, at least one bidimensionally measurable lesion and adequate end organ function. IV topotecan, 1.0 mg/m2/d for 5 consecutive days, and etoposide, 100 mg/m2/d through days 1 to 3, were administered every 3 weeks until disease progression or undue toxicity. RESULTS The major toxicity was myelosuppression. Grade 3/4 anemia, granulocytopenia, and thrombocy-topenia occurred in 14.2, 34.8, and 27.3% of cycles, respectively. There was no treatment-related death, and other non-hematologic toxicities were generally mild. Four patients achieved partial responses, with a response rate RR of 14.8%. The progression-free survival PFS ranged from 1 to 7 months, with a median of 2.0 months (95% confidence interval 1.22~2.78 months). Twenty-five patients died, with a median overall survival of 5.5 months (ranging from 1 to 21 months, 95% CI 4.32~6.68 months), and the 6-month survival rate was 32.1% (95% confidence interval 14.4~49.8%). CONCLUSION The combination of topotecan and etoposide chemotherapy showed a modest response rate, but failed to prolong survival of refractory SCLC patients compared to topotecan monotherapy.

PURPOSE With the increased use of chemotherapy for non small cell lung cancer (NSCLC), a growing group of patients can now be considered for second-line chemotherapy. However, guidelines for the second line treatment remain to be developed. The objective of this study was to evaluate the efficacy and safety of the gemcitabine and vinorelbine combination therapy in patients with advanced NSCLC, pretreated with taxane and platinum based regimens. Gemcitabine has already demonstrated activity in this patient group, with the combination therapy having been reported to be well tolerated in previous phase I/II studies. MATERIALS AND METHODS Forty two patients with advanced NSCLC (stages III/IV), having received prior taxane and platinum based chemotherapy, with an ECOG performance status (PS) 0~2, and unimpaired hematopoietic and organ function, were treated with vinorelbine, 20 mg/m2, followed by gemcitabine, 1, 000 mg/m2, both administered on days 1, 8 and 15, every 4 weeks. RESULTS Out of the 42 patients enrolled, 41 were evaluable for their response, and all 42 for their toxicity. The patient's characteristics were as follows; median age=60 years (42~73), median PS=1 (range 0~2), a gender ratio 31: 11 males/females, with stages IIIA, IIIB and IV in 3, 14 and 25 cases. The objective responses included a partial response (PR) 8/41 (19.5%), a stable disease 15/41 (36.6%) and a progressive disease 18/41 (43.9%). The median time-to progression (TTP) and survival were 4 months, ranging from 2 to 14 months, and 8 months, ranging from 2 to 17+ months, respectively. Grade 3 neutropenia was seen in 19% of the patient, and there was no grade 4 neutropenia or episodes of febrile neutropenia. No grade 4 thrombocytopenia or other grade 3/4 non-hematological toxicities were observed. CONCLUSION The combination of gemcitabine/vinorelbine is active and well tolerated in patients with advanced NSCLC having failed prior taxane/platinum therapy.

Purpose The aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response. Materials and Methods Fifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study. Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI. Results The median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy. Conclusion It is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles. Development of individualized chemotherapy regimens based on gene expression profiles is warranted.

Purpose This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival. Materials and Methods Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone. Results Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival. Conclusion Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.

In this study, Corynebacterium glutamicum and its derived mutants were used to demonstrate the relationship between proline, glutamate and ornithine. The maximum ornithine production was shown in the culture medium (3295.0 mg/l) when the cells were cultured with 20 mM proline and was 15.5 times higher than in the presence of 1 mM proline. However, glutamate, which known as an intermediate in the process of converting proline to ornithine, did not have any positive effect on ornithine production. This suggests that the conversion of proline to ornithine through glutamate, is not possible in C. glutamicum. Comparative analysis between the wild-type strain, SJC8043 (argF-, argR-) and SJC8064 (argF-, argR- and ocd-), showed that C. glutamicum could regulate ornithine production by ornithine cyclodeaminase (Ocd) under proline-supplemented conditions. Therefore, proline directly caused an increase in the endogenous level of ornithine by Ocd, which would be a primary metabolite in the ornithine biosynthesis pathway.

Two genes involved in central carbon metabolism were inactivated to modulate intracellular glucose 6-phosphate and to evaluate its effects on xanthan production in wild-type Xanthomonas oryzae pv. oryzae. Upon the inactivation of the phosphogluconate dehydratase gene (edd), intracellular glucose 6-phosphate increased from 0.05 to 1.17 mmol/g (dry cell wt). This was accompanied by increased xanthan production of up to 2.55 g/l (culture medium). In contrast, inactivation of 6-phosphogluconate dehydrogenase gene (gndA) did not influence intracellular glucose 6-phosphate nor xanthan production. The intracellular availability of glucose 6-phosphate is proposed as a rate-limiting factor in xanthan production, and it may be possible to increases production of xanthan by modulating the activities of enzymes in central carbon metabolism.

Background Erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) is an oral, epidermal growth factor receptor tyrosine kinase inhibitor that has antitumor activity and good tolerability in non-small cell lung cancer (NSCLC). In particular, higher response rates have been reported in Asian patients than in Western patients. The aim of this study conducted by the Korean Cancer Study Group was to evaluate the efficacy and tolerability of erlotinib monotherapy as a palliative treatment for advanced NSCLC patients in Korea. Patients and Methods Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC including recurrent or metastatic disease, with performance status from 0 to 3, were eligible either if they had received any anticancer treatment except epidermal growth factor receptor inhibitors or if they were unsuitable for chemotherapy because of poor performance status. Enrolled patients were treated with oral erlotinib at a dose of 150 mg daily until disease progression or development of intolerable toxicity. Results A total of 120 patients were enrolled between January 2005 and May 2006. Forty-four patients (36.7%) were female and 72 patients were current or former smoker. Fifty percent of patients had received one prior palliative chemotherapy regimens and 34.2% had two or more prior palliative regimens. The overall tumor response rate was 24.2% (95% confidence interval [CI], 16.8–32.8%) with 4 complete responses and 25 partial responses, and the disease control rate was 56.7%. The favorable clinical variables for tumor response were female ( P = 0.001), never smokers ( P = 0.041), and adenocarcinoma ( P = 0.001). The most common adverse event was skin rash (78% of which grade 3 or 4 skin rash occurred in 13.3% of the patients). With a median follow-up of 23.6 months, the median time to progression was 2.7 months (95% CI, 2.2–3.2), and the median overall survival was 12.9 months (95% CI, 6.9–18.8). By multivariate analysis, female and development of skin rash were significantly associated with longer time to progression and overall survival. Conclusion Erlotinib monotherapy showed significant antitumor activity and an acceptable tolerability profile as a palliative treatment in advanced NSCLC patients in Korea, especially in females, never smokers, and patients with adenocarcinoma histology.

An endonuclease from Xanthomonas oryzae pathovar oryzae (Xoo) KACC10331, XorKII, was recombinantly produced in Escherichia coli by applying the stationary state induction method, which was necessary to prevent the unwanted lysis of E. coli cells. XorKII was purified by immobilized metal affinity chromatography on an FPLC system. The yield was 3.5mg of XorKII per liter of LB medium. The purified recombinant XorKII showed that it recognized and cleaved to the same site as PstI. It behaved as a dimer as evidenced by the size exclusion chromatography. The specific activity of the purified XorKII was determined to be 31,300 U/mg. The enzyme activity was monitored by cleaving lambda DNA or YEp24 plasmid as substrates. The enzyme was the most active at 10mM Tris-HCl pH 7.0, 10 mM MgCl(2), 1mM dithiothreitol at 37 degrees C. XorKII was easily inactivated by heating at 65 degrees C for 5 min, but retained most of the original activity after incubation at 37 degrees C for 24h.

Gemcitabine is the only drug approved for single-agent therapy in advanced pancreatic carcinoma (APC). Gemcitabine-based combination chemotherapy has not yet shown promising results.This multicenter phase II study enrolled previously untreated patients with locally advanced and/or metastatic pancreatic adenocarcinoma. Patients received 1,000 mg/m(2) gemcitabine, 100-min infusion, day 1 and 100 mg/m(2) oxaliplatin, 2-h infusion, day 2; q2w. The primary end point was response rate (RR).Thirteen study centers enrolled 48 eligible patients of which 44 were evaluable. The RR, median overall survival, and median time to progression were 18.2%, 9.4 and 5.6 months, respectively. Sixteen patients (36.4%) experienced clinical benefit. The global quality of life scores improved by 11.71. Grade 3/4 peripheral sensory neuropathy was noted (2.1%), while the most common hematologic toxicity was anemia (grade 3/4, 6.3%).Gemcitabine and oxaliplatin combination chemotherapy showed a promising activity in APC patients and was well tolerated.

Genome sequence analysis of Xanthomonas oryzae pv. oryzae has revealed a cluster of 12 ORFs that are closely related to the gum gene cluster of Xanthomonas campestris pv. campestris. The gum gene cluster of X. oryzae encodes proteins involved in xanthan production; however, there is little experimental evidence supporting this. In this study, biochemical analyses of xanthan produced by a defined set of X. oryzae gum mutant strains allowed us to preliminarily assign functions to most of the gum gene products: biosynthesis of the pentasaccharide repeating unit for GumD, GumM, GumH, GumK, and GumI, xanthan polymerization and transport for GumB, GumC, GumE, and GumJ, and modification of the pentasaccharide repeating unit for GumF, GumG, and GumL. In addition, we found that the exopolysaccharides are essential but not specific for the virulence of X. oryzae.

Biliary tract carcinoma is often diagnosed at an advanced stage, and there is currently no established palliative standard of care. This phase II study investigated the efficacy and safety of combination chemotherapy of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) in biliary tract carcinoma. Patients with unresectable or recurrent biliary tract carcinoma were enrolled, including pretreated and chemotherapy-naive patients. Treatment consisted of intravenous oxaliplatin (100 mg/m 2 , day 1) followed by leucovorin (100 mg/m 2 , day 1) and 5-FU (1000 mg/m 2 , days 1 and 2). Treatment was repeated every 3 weeks. The efficacy and safety of the treatment were determined. Twenty-eight patients were evaluable, and a total of 166 cycles were administered (median five cycles). One complete response (3.6%) and five partial responses (17.9%) were noted, with a response rate of 21.5% [95% confidence interval (Cl): 6.2-36.7], according to Response Evaluation Criteria in Solid Tumors criteria. The median time to progression and overall survival was 3.5 months (95% Cl: 2.7-4.3) and 10.0 months (95% Cl: 7.2-12.8), respectively. The 1 -year survival rate was 17.8%. Grade 3/4 neutropenia and thrombocytopenia were recorded in 18 and 4% of the patients, respectively. No treatment-related death was observed. Oxaliplatin in combination with leucovorin and 5-FU should be considered a feasible chemotherapy regimen for patients with recurrent/ metastatic biliary tract carcinoma.

This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer.We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles.A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent.The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.

The Xanthomonas oryzae pathovar oryzae gum gene cluster is composed of 14 ORFs designated, in sequence, as gumB to M, XOO3167, and gumN. The gum gene cluster constitutes an operon expressed from multiple promoters located upstream of gumB and gumG, respectively. To identify new promoters responsible for the expression of the gum gene cluster, we have conducted a computer-assisted promoter search and identified previously unreported promoter-like sequences upstream of the gumH and gumM genes, respectively. Moreover, the ability of these putative promoters to stimulate the transcription of the downstream genes was demonstrated by RT-PCR analyses using the mutant strains carrying an insertion of the rrnB transcriptional terminator into the gumG, gumH, and gumL gene, respectively.

A method is presented for synthesizing thermo-, acid-stable oligosaccharides (TASO) from sucrose (2.5–4 M) using a dextransucrase prepared from Leuconostoc mesenteroides B-512FMCM. The degree of polymerization (DP) of oligosaccharides synthesized was from 2 to 11. TASO resisted hydrolysis of its glycosidic linkages at 140 °C and pH 6.0 for 1 h. It was stable at pH's ranging from 2 to 4 at 120 °C. These oligosaccharides effectively inhibited the formation of insoluble glucan, the growth and acid production of Streptococcus sobrinus. However, it stimulated the growth of probiotic organisms such as Bifidobaterium sp. TASO potentially can be used as sweeteners for the food and beverages where thermo- and acid-stable properties are required and as potential inhibitors of dental caries.

Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is one of the currently used techniques to identify biomarkers for cancers. This study was planned to establish a system to accurately distinguish gastric cancer patients by using SELDI-TOF-MS. A total of 100 serum samples obtained from 60 individuals with gastric cancer and 40 healthy individuals were screened. Protein expression profiles were expressed on CM10 ProteinChip arrays and analyzed. Peak intensities were analyzed with the Biomarker Wizard software to identify peaks showing significantly different intensities between normal and cancer groups. Classification analysis and construction of decision trees were done with the Biomarker Pattern software 5.0. Seventeen protein peaks showed significant differences between the two groups. The decision tree which gave the highest discrimination included four peaks at mass 5,919, 8,583, 10,286, and 13,758 as splitters. The sensitivity and specificity for classification of the decision tree were 96.7% (58/60) and 97.5% (39/40), respectively. When the protein biomarker pattern was tested on a blinded test set, it yielded a sensitivity of 93.3% (28/30) and a specificity of 90% (18/20). These results suggest that serum protein profiling by the SELDI system may distinguish gastric cancer patients from healthy controls with relatively high sensitivity and specificity.

Background: We conducted a phase II study to assess the efficacy and tolerability of docetaxel and epirubicin as salvage chemotherapy in advanced/metastatic gastric cancer patients with documented progression after 5-fluorouracil/platinum-based combination chemotherapy. Methods: Docetaxel 75 mg/m2 and epirubicin 50 mg/m2 were administered on days 1 and 2, respectively, every 3 weeks. Treatment continued until progression of disease or until a life-threatening adverse event occurred. The primary objectives of this study were to evaluate the safety profile and response rate to this treatment regimen. Results: Thirty-four patients were enrolled in the study. Twenty-six patients had locally advanced or metastatic disease at the time of diagnosis, and 8 patients had recurrent disease after surgical resection of the primary tumor. A total of 157 chemotherapy cycles were administered. Seven (21.8%) patients had a partial response and 12 (37.5%) patients had stable disease. The median time to progression and overall survival were 4.1 and 13.4 months, respectively. Grade III/IV hematologic toxicities included neutropenia in 16 patients (47%) and febrile neutropenia in 8 patients (24%). Nonhematologic toxicities were rare. Conclusion: A combination of chemotherapy with docetaxel and epirubicin showed moderate activity as salvage treatment in advanced/metastatic gastric cancer, especially in patients who had responded to prior chemotherapy.

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.

The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system. Refereed/Peer-reviewed

Purpose Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. Patients and Methods In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m2 per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). Results One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Conclusion Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

We evaluated the relationship between coronary artery disease (CAD) and left ventricular mass (LVM) as measured by cardiac computed tomography (CT) in young adults ≤40 years of age. We retrospectively enrolled 490 consecutive individuals (383 males; mean age, 35.2 ± 4.4 years) who underwent cardiac CT. CAD was defined by the presence of any plaque detected by coronary CT angiography. Left ventricular (LV) function, including LVM, was automatically measured by a dedicated workstation. LVM and LVM index (LVMi) in patients with CT-detected CAD were compared to those of patients without CT-detected CAD. Logistic regression analysis was used to evaluate the relationship between cardiovascular risk factors and CAD. Fifty-five individuals had CT-detected CAD (11.2 %, 53 males). LVM measured by cardiac CT was 126.9 ± 30.0 g for males and 93.6 ± 20.9 g for females. LVM was higher (117.8 ± 30.8 vs. 133.6 ± 33.1 g, P

PURPOSE Gastric cancer is the second leading cause of cancer-related death worldwide. Although surgery is the standard curative treatment for gastric cancer, relapse occurs in a large number of patients, except in the case of early diagnosed gastric cancer. Following previous studies that identified endoplasmic reticulum oxidoreductin 1-α (ERO1L) as a potential marker for gastric cancer, we investigated the functional role of ERO1L in gastric cancer. MATERIALS AND METHODS For validation of microarray data, the mRNA expression level of ERO1L was measured by quantitative real-time reverse transcription polymerase chain reaction in 56 independent stage III gastric cancer patients. Immunohistochemical staining was performed to examine the protein expression level of ERO1L in 231 gastric cancer patients. Correlation between gene expression and cancer prognosis was evaluated. RESULTS Patients with high ERO1L expression had poorer survival than those with low expression (p < 0.01). Functional assays demonstrated that ERO1L knockdown inhibited cell proliferation, migration, invasion, and chemoresistance. In addition, involvement of inactivation of Akt and JNK signaling in molecular mechanisms of ERO1L inhibition was demonstrated. CONCLUSION High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer.

East Asia has higher gastric cancer incidence and mortality rates than other regions. We present a subgroup analysis of East Asians in the positive study RAINBOW.Patients with advanced gastric or gastroesophageal junction adenocarcinoma previously treated with platinum and fluoropyrimidine received ramucirumab 8 mg/kg or placebo on days 1 and 15 plus paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle.Of 665 intention-to-treat patients, 223 were East Asian. Median overall survival was 12.1 months for ramucirumab plus paclitaxel and 10.5 months for placebo plus paclitaxel (hazard ratio: 0.986, 95% confidence interval: 0.727-1.337, P = 0.929). Median progression-free survival was 5.5 months for ramucirumab plus paclitaxel and 2.8 months for placebo plus paclitaxel (hazard ratio: 0.628, 95% confidence interval: 0.473-0.834, P = 0.001). Objective response rates were 34% for ramucirumab plus paclitaxel and 20% for placebo plus paclitaxel. Grade ≥ 3 neutropenia (60% vs 28%) and leukopenia (34% vs 13%) were higher for ramucirumab plus paclitaxel. The rate of febrile neutropenia was low (4% vs 4%). Special interest adverse events included any grade bleeding/hemorrhage (55% vs 25%), proteinuria (27% vs 7%), and hypertension (22% vs 2%).Ramucirumab plus paclitaxel significantly improves progression-free survival and response rate, with prolonged median overall survival and an acceptable safety profile in East Asians with advanced gastric cancer.

Overexpression of the NCgl0462 open reading frame, encoding a class II aminotransferase, was studied in conjunction with other enzymes in L-ornithine biosynthesis in an L-ornithine-producing strain. Expression of the wild-type NCgl0462 open reading frame, which displayed aminotransferase activity, was amplified by placing it under the control of the glyceraldehyde 3-phosphate dehydrogenase gene promoter in the pEK0 plasmid and in the genome. L-Ornithine production in Corynebacterium glutamicum SJC8260 harboring plasmid and the genomic NCgl0462 open reading frame was increased by 8.8 and 21.6%, respectively. In addition, the combined overexpression of the NCgl0462 open reading frame within the genome along with the mutated L-ornithine biosynthesis genes (argCJBD) placed in the pEK0 plasmid in C. glutamicum SJC8260 resulted in significant improvement in L-ornithine production (12.48 g/l for combined overexpression compared with 8.42 g/l for the control). These results suggest that overexpression of the aminotransferase-encoding NCgl0462 open reading frame plays an unequivocal role in the L-ornithine biosynthetic pathway, with overlapping substrate specificity in C. glutamicum.

Objective: Combination of two non-invasive brain stimulation (NBS) modes, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been tried to enhance motor function in stroke patients. We aimed to investigate the changes of motor network after dual-mode NBS using Electroencephalogram (EEG). Methods: Seven subacute ischemic stroke patients (mean age of 60.6 years; 4 males) and 8 healthy controls (mean age of 29.3 years; 4 males) participated. Participants received simultaneous application of 2mA cathodal tDCS over contralesional M1 and 10 Hz rTMS over the ipsilesional M1. Motor function was assessed before and after stimulation by serial reaction time task (SPTT). Eyes-closed resting state EEG was measured for 5 mins using the Neuroprax® EEG system (NeuroConn GmbH, Germany) before and after stimulation, respectively. The EEG signals were preprocessed using the SPM12b (http://www.fil.ion.ucl.ac.uk/spm/). In stroke patients, we flipped EEG signals from affected hemisphere to the left side. We confirmed event-related dynamics of brain oscillations through topography, and connectivity between ipsilesional M1 and contralesional M1 in mu band (8-12Hz) showing resting-state motor neurons over the bilateral M1s. Results: Pre-simulation Event-related desynchronization (ERD) topographic map showed balancing between both hemispheres in heathy controls, however in stroke patients, ipsilesional M1 appeared more ERD, with unbalancing between both hemispheres. After dual-mode NBS, ERD topographic map showed balanced ERD between bilateral hemispheres in both healthy and stroke groups. In other words, stroke patients showed more ERS over the ipsilesional M1 after NBS. Furthermore, in stroke patients, connectivity between ipsilesional M1 (C3) and contralesional M1 (C4) increased after NBS, whereas connectivity between C3 and C4 decreased in healthy controls. Conclusions: These results revealed that there were a balanced ERD and increase of connectivity between bilateral hemispheres after dual-mode NBS in stroke patients. The dual-mode NBS may modulate the pre-existing inter-hemispheric imbalance of both hemispheres in stroke patients.

Genome sequence analysis of Xanthomonas oryzae pv. oryzae KACC10331 provides insight into the X. oryzae gum gene cluster that is composed of 14 open-reading frames (ORFs), designated gumB, -C, -D, -E, -F, -G, -H, -I, -J, -K, -L, -M, XOO3167, and -N. We analyzed the transcriptional linkage of the X. oryzae gum gene cluster by using RT-PCR. Analyses of the gum gene cluster by RT-PCR with the wild-type and mutant strains, which carried a deletion of the promoter-like region upstream of gumB or an insertion of the rrnB transcriptional terminator into the gumF gene, revealed that the ORFs of this gene cluster were transcribed as polycistronic mRNA, from gumB to gumN, and the secondary promoter was located upstream of gumG. Taken together, these results suggest that the genes of this cluster constitute an operon expressed from overlapping transcripts.

Metabolic engineering has been used to improve L-ornithine biosynthesis in Escherichia coli W3110. L-Ornithine production increased from 0.3 to 3.2 mg/g (dry cell weight) when the primary L-ornithine biosynthetic pathway was optimized by disrupting the pathway transcription repressor, thereby increasing the expression of the genes involved in the pathway, and by preventing conversion of L-ornithine into citrulline. When a feedback-resistant N-acetylglutamate synthetase gene (argA214) was placed under the control of the arabinose-inducible promoter, either in the chromosome or on a multicopy plasmid in the cell, the combination of overexpression of argA214 with an argF argI argR triple knockout mutation had an additive effect on L-ornithine production but only when exogenous glutamate was present. When speF (which encodes ornithine decarboxylase) and proB (which encodes gamma-glutamyl kinase) were inactivated to prevent the conversion of L-ornithine to putrescine and to block the biosynthesis of a side branch of L-ornithine, respectively, L-ornithine production was further enhanced approx. 140% from 5.5 to 13.2 mg/g (dry cell weight).

BACKGROUND Biliary tract carcinoma is an aggressive cancer, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A Phase II trial was conducted to study a combination of oral capecitabine and gemcitabine (CapGem) as first-line therapy in patients with advanced and/or metastatic biliary carcinoma. METHODS Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients had histologically or cytologically confirmed, measurable adenocarcinoma and had not received prior therapy with capecitabine or gemcitabine. Treatment consisted of intravenous (i.v.) gemcitabine (1000 mg/m2 on Days 1 and 8) plus oral capecitabine (650 mg/m2 twice daily on Days 1–14) every 3 weeks for up to 6 cycles. Tumor response, survival, and safety were determined. RESULTS A total of 44 patients were evaluable. Primary tumor sites were: intrahepatic (n = 14) and extrahepatic biliary duct (n = 16); gallbladder (n = 7); and ampulla (n = 7). Fourteen (32%) patients had a partial response and 15 (34%) patients had stable disease. Median time to disease progression and overall survival were 6.0 (range, 3.8–8.1) and 14 (range, 11.4–16.6) months, respectively. The 1-year survival rate was 58%. No Grade 4 adverse events were seen. Transient Grade 3 neutropenia/thrombocytopenia and manageable (almost invariably Grade 2) nausea, diarrhea, and hand–foot syndrome were the most common adverse events. CONCLUSIONS CapGem is an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma that offers a convenient home-based therapy. Cancer 2005. © 2005 American Cancer Society.

Capecitabine and gemcitabine are used in the treatment of a variety of solid tumors including pancreatic and biliary tract carcinomas. The authors evaluated survival, response, and toxicity associated with using a combination of capecitabine and gemcitabine to treat patients with unresectable or metastatic gallbladder adenocarcinoma (GBC). Eligible patients had histologically- or cytologically-confirmed GBC, no prior systemic therapy with capecitabine or gemcitabine, Karnofsky Performance Status 70%, serum total bilirubin up to three times normal, and measurable disease. Treatment consisted of gemcitabine 1000 mg/m2 IV on Days 1 and 8 concurrent with administration of capecitabine 1000 mg/m2 PO BID on Days 1 through 14, on a 3-week cycle. Tumor response was assessed by the response evaluation criteria in solid tumors (RECIST criteria) and survival was calculated from initiation of CapGem therapy. A total of 24 patients were enrolled. Median age at the time of diagnosis was 62 years (range, 41-78 years). Fourteen patients had undergone prior surgery. Results showed that eight patients achieved partial response (33%) with an additional 10 patients achieving stable disease (42%). The overall median time to disease progression was 6.0 months (95% CI, 3.8-8.1 months) and overall survival was 16 months (95% CI, 13.8-18.3 months). The one-year survival rate was 58%. No Grade 4 toxicity was seen. Transient Grade 3 neutropenia/ thrombocytopenia and manageable nausea, hand-foot syndrome and anorexia were the most common toxicities. Our study shows that CapGem is an active and well-tolerated chemotherapy regimen in patients with advanced GBC.

See Article on Page 314-321 It has been accepted since the 1990s that palliative chemotherapy can significantly prolong the survival of patients with advanced gastric carcinoma, compared to supportive care alone [1,2]. However, there is controversy over the benefit of salvage therapy past second-line due to the lack of evidence. Recently, there has been renewed interest in salvage chemotherapy after first- and second-line treatments have failed because of the prolonged survival time and relatively low toxicity of agents. Many clinicians consider second-line chemotherapy after failure of first-line chemotherapy for patients with advanced gastric carcinoma [3]. Phase II trials and retrospective analyses have provided evidence that second-line is effective [4]. Recently, randomized phase III trials have strongly indicated that second line or further chemotherapy is more advantageous than supportive care (Table 1). A German trial found that irinotecan monotherapy improved overall survival compared to best supportive care [5]. A Korean trial found that irinotecan or docetaxel monotherapy prolonged overall survival compared to best supportive care and there was no difference in the treatment effect of docetaxel and irinotecan (p = 0.116) [6]. In the 2013 the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium, it was reported that docetaxel [7] and ramucirumab [8] demonstrated clinical benefit over supportive care in two phase III trials. Both agents significantly prolonged overall survival (Table 1). There is ample evidence to support the use of second line treatment in advanced gastric cancer. However, the issue of which regimen is a standard second-line treatment has not been clarified. Table 1 Randomized phase III trials evaluating the advantage of second-line or further chemotherapy over supportive care Little information concerning the survival advantage of third-line chemotherapy is extant. In a Korean phase III trial, the survival benefit in the chemotherapy arm was preserved in the further chemotherapy group (hazard ratio, 0.812; 95% confidence interval [CI], 0.450 to 1.464) (Table 1). Several retrospective studies presented the natural history of advanced gastric cancer with sequential salvage chemotherapy following first-line treatment [4]. The survival prolongation by second- and third-line salvage chemotherapy indicates its feasibility in selected patients. After failure of first-line chemotherapy based on platinum and fluoropyrimidine, irinotecan, or taxane-based regimens have benefited survival and led to the same clinical outcome as salvage chemotherapy in advanced gastric cancer patients [4,6]. Based on the lack of cross-resistance between irinotecan and taxane, both regimens are plausible salvage treatment options. Additionally, it is necessary to select patients for salvage chemotherapy based on survival predictors including performance status, chemotherapy-free interval, response duration, metastatic pattern, tumor burden, and serum carcinoembryonic antigen level [4,6]. Lee and colleagues [9] evaluated the efficacy and toxicity of docetaxel monotherapy, 75 mg/m2 on day 1 every 3 weeks, in advanced gastric cancer patients who did not respond to oxaliplatin with leucovorin and 5-fluorouracil (m-FOLFOX-4), or to irinotecan with leucovorin and 5-fluorouracil (m-FOLFIRI). This retrospective study included thirty three patients and reported an overall response of 15%, time to progression of 2.1 months (95% CI, 1.63 to 2.58), and an overall survival time of 4.7 months (95% CI, 3.20 to 6.20). The results are comparable to previous reports of the efficacy of third-line treatment. This study provides important evidence that docetaxel is a feasible third-line therapy regimen after m-FOLFIRI and m-FOLFOX-4 regimens. A randomized prospective trial could further support this conclusion. Trastuzumab, a molecular target agent, was approved for HER2 amplified gastric cancer patients, and other anti-HER2 agents-including lapatinib-have been evaluated as first- or second-line treatments. Furthermore, studies have been performed to elucidate biomarkers of chemotherapeutic agents and to investigate molecular biological features, including genetic and epigenetic profiles [10]. On the basis of those outcomes, randomized trials of target agents, and molecular biologic markers would facilitate treatment tailored to the individual patient.

To determine whether homology-dependent gene silencing or cosuppression mechanisms underlie copy number control (CNC) of Ty1 retrotransposition, we introduced an active Ty1 element into a naïve strain. Single Ty1 element retrotransposition was elevated in a Ty1-less background, but decreased dramatically when additional elements were present. Transcription from the suppressing Ty1 elements enhanced CNC but translation or reverse transcription was not required. Ty1 CNC occurred with a transcriptionally active Ty2 element, but not with Ty3 or Ty5 elements. CNC also occurred when the suppressing Ty1 elements were transcriptionally silenced, fused to the constitutive PGK1 promoter, or contained a minimal segment of mostly TYA1-gag sequence. Ty1 transcription of a multicopy element expressed from the GAL1 promoter abolished CNC, even when the suppressing element was defective for transposition. Although Ty1 RNA and TyA1-gag protein levels increased with the copy number of expressible elements, a given element's transcript level varied less than twofold regardless of whether the suppressing elements were transcriptionally active or repressed. Furthermore, a decrease in the synthesis of Ty1 cDNA is strongly associated with Ty1 CNC. Together our results suggest that Ty1 cosuppression can occur post-transcriptionally, either prior to or during reverse transcription.