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The phytopathogenic bacterium Erwinia chrysanthemi secretes multiple isozymes of plant cell wall disrupting enzymes such as pectate lyase and endoglucanase. We cloned genomic DNA from Erwinia chrysanthemi PY35. One of the E. coli XL1-Blue clones contained a 5.1-kb BamHI fragment and hydrolyzed carboxymethyl cellulose and polygalacturonic acid. By subsequent subcloning, we obtained a 2.9-kb fragment (pPY100) that contained the pel gene responsible for CMCase and pectate lyase activities. The pel gene had an open reading frame (ORF) of 1,278 bp encoding 425 amino acids with a signal peptide of 25 amino acids. Since the deduced amino acid sequence of this protein was very similar to that of PelL of E. chrysanthemi EC16, we concluded that it belonged to the pectate lyase family EC 4.2.2.2, and we designated it PelL1. Sequencing showed that the PeIL1 protein contains 400 amino acids and has a calculated pI of 7.15 and a molecular mass of 42,925 Da. The molecular mass of PelL1 protein expressed in E. coli XL1-Blue, as analyzed by SDS-PAGE, appeared to be 43 kDa. The optimum pH for its enzymatic activity was 9, and the optimum temperature was about 40 decreased C.

Bacteria secrete specific extracellular signaling molecules that increase in concentration with cell density. In a process known as quorum sensing, bacteria regulate their behavior in response to such molecules.1 Quorum sensing attracts attention as a promising anti-pathogenic drug target rather than anti-bacterial, notably preventing the emergence of drag-resistant bacteria.2 The ComX pheromone3 is a signaling oligopeptide that stimulates natural genetic competence controlled by quorum sensing in Bacillus subtilis.4 In the presence of the ComX pheromone, the membrane-located receptor histidine kinase ComP autophosphorylates and donates phosphate via a two-component-system to activate competence gene expression.5 Previous studies indicated that the ComX pheromone is posttranslationally modified by the addition of an isoprenoid to a tryptophan residue.6,7 Posttranslational isoprenoidal modification on the cystein residue8 is widely observed in many important proteins such as the Ras oncoproteins, which plays a crucial role in human tumor and the isoprenoidal modification is essential for the Ras functions.9 Therefore, the posttranslational isoprenoidal modification is an attractive target for cancer therapy, but on the tryptophan residue, including other amino acid residues except cystein, is unprecedented. Recently the ComXRO-E-2 pheromone 1 from B. subtilis strain RO-E-2,6 was shown to be a hexapeptide possessing a modified tryptophan residue with a geranyl group. This novel modification resulted in the formation of a tricyclic structure (Figure 1).10 Fig 1 Chemical structure of ComXRO-E-2 pheromone Since further studies are required to elucidate the details of the function through the interaction between the ComX pheromone and ComP, various ComXRO-E-2 analogs were prepared using solid phase peptide synthesis.10–13 The biological activities of these peptides as well as of ComXRO-E-2 pheromone were investigated using β-galactosidase assays.6,10–12,14 These data were used to draw the dose response curves. The biological activities of these peptides were represented by two values both normalized to the activity of the ComXRO-E-2 pheromone (Table 1). The first value presents the concentration of each peptide, needed to obtain the same β-galactosidase activity as that obtained with the ComXRO-E-2 pheromone at EC50. The second is the maximum activity as a percentage of that obtained with the ComXRO-E-2 pheromone. Table 1 Biological activities of ComXRO-E-2 analogs Although N-terminal truncated [2–6]ComXRO-E-2 and [3–6]ComXRO-E-2 showed significant biological activities as previously reported,12 [4–6]ComXRO-E-2 lost all activity (entry 4). The C-terminal glutamate residue was partially dispensable like the N-terminal glycine. In contrast, deletion of the glutamic acid and glutamate residues C-terminal to tryptophan dramatically decreased the activity (entry 5–8). These results indicated that for activity, either the modified tryptophan must reside at an internal position, or that contacts of the ComP receptor with the glutamic acid residue are important. A minimal active core within ComXRO-E-2 appears to consist of the tripeptide, [3–5]ComXRO-E-2 (entry 9). Elongation of ComXRO-E-2 pheromone by the addition of alanine at either the N- or C-terminus did not affect the activity (entry 10,11). The roles of individual amino acid side chains were investigated substitution of each residue except the modified tryptophan with alanine. Surprisingly, none were absolutely essential for biological activity, although alanine substitution of 3 phenylalanins and 6 glutamate decreased the activity substantially (entry 12–16). Earlier work on the structure-activity-relationships of tremerogen A-10,15 which is the sex pheromone of basidiomycetous yeasts containing a C-terminal farnesyl modified cysteine methyl ester, revealed that removal of the C-terminus methyl ester or N-terminal residues decreased biological activity16 in contrast to the present results with the ComXRO-E-2 pheromone, which showed that only tripeptide, [3–5]ComXRO-E-2, still had considerable activity. These results indicated that the pattern of specific interaction of the ComX pheromone with its receptor are unique and different from that of the S-isoprenoidal peptides. Furthermore, the precise structure of modified tryptophan residue was essential for the biological activity, because synthetic ComXRO-E-2 peptides, containing a geranyltryptophan residue with a geranyl group replacing a tryptophanyl proton10 or with additional stereoisomers at the modified tryptophan residue,11,12 showed no biological activities. Although the farnesyl group on tremerogen A-10 was replaceable by lipophilic long chains,16 the role of the geranyl moiety in biological activity and in determining pherotype specificity is not yet known. Into investigate this question, we are synthesizing analogs of ComXRO-E-2 with other side chains replacing the geranyl moiety. In summary, various ComXRO-E-2 analogs were synthesized and their biological activities were studied to investigate structure-activity-relationships. These results showed that the minimal active unit was the tripeptide, [3–5]ComXRO-E-2, and all residues except the modified tryptophan residue were replaceable by alanine without total loss of activity.

The importance of PPARγ (peroxisome proliferator-activated receptor γ) in gastric cancer (GC) is unclear. We investigated the role of PPARγ in GC cell lines and an animal model, and its prognostic significance of PPARγ in GC patients. We controlled PPARγ and galectin-9 expression by using siRNAs and lentiviral constructs. Interaction between PPARγ and galectin-9 was evaluated using luciferase and chromatin immunoprecipitation assays. PPARγ expression in GCs was determined by immunohistochemical staining of tissue microarrays and survival analysis was done. Overexpression of PPARγ was accompanied by increased galectin-9. Enhanced PPARγ or galectin-9 expression increased E-cadherin expression; decreased expression of N-cadherin, fibronectin, snail, twist and slug and reduced cell invasion and migration. PPARγ bound to the galectin-9 promoter region. Galectin-9 activity increased in PPARγ-overexpressing cells but decreased in PPARγ siRNA-treated cells. In a zebrafish xenograft model, the number of migrated cancer cells and number of fish with AGS cells in the tail vein were reduced in PPARγ-overexpressing GC cells. PPARγ was expressed in 462 of the 688 patients (69.2%) with GC. In 306 patients with intestinal-type GC, those with PPARγ-positive tumors had lower overall and cancer-specific mortalities than those with PPARγ-negative tumors. PPARγ expression was an independent prognostic factor for overall and GC-specific mortality in patients with intestinal-type GC (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.81). PPARγ inhibits cell invasion, migration and epithelial-mesenchymal transition through upregulation of galectin-9 in vitro and in vivo.

MicroRNAs (miRNAs) play a critical role in gastric cancer progression and metastasis. This study investigated the role of miRNA-135a in early gastric cancer (EGC) including lymph node (LN) metastasis. We examined the correlation between miRNA-135a expression and clinical outcomes in 59 patients who underwent surgery for EGC. Using gastric cancer cell lines, we performed functional and target gene analyses. miRNA-135a expression was down-regulated in 33.9% of patients. These patients showed a significantly more advanced stage (TNM stage ≥ IB, 35.0% vs. 12.8%, p = 0.045) and higher rate of LN metastasis (30.0% vs. 5.1%, p = 0.014) than those with up-regulation of miRNA-135a expression. In a multivariate analysis, down-regulation of miRNA-135a was an independent risk factor for LN metastasis (adjusted odds ratio, 8.04; 95% confidence interval, 1.08-59.81; p = 0.042). Functional analyses using gastric cancer cell lines showed that miRNA-135a suppressed cell viability, epithelial-mesenchymal transition, cell invasion, and migration. ROCK1 was a target of miRNA-135a and its expression was inversely correlated to that of miRNA-135a. ROCK1 expression was significantly increased in EGC patients with LN metastasis than in those without LN metastasis. Our results confirm the tumor-suppressive role of miRNA-135a, and demonstrate its role in LN metastasis in EGC. miRNA-135a and its target gene ROCK1 may be novel therapeutic and prognostic targets for EGC.

We appreciate Dr Genta for his valuable comments and agree with his perspective on our analysis. The updated Sydney system recommends that glandular atrophy and intestinal metaplasia be graded as absent, mild, moderate or marked. Such grading in this updated system is not a continuous scale, but an ordinal scale. Thus, the data evaluated in the updated Sydney system might not be suitable for comparing means and variances (standard deviations or standard errors of the mean) after conversion into numerical values. Several studies, however, have used means and variances to present changes both before and after Helicobacter pylori eradication. In our study, we similarly analysed our data using numerical analysis. However, to overcome the limitations of the numerical values, we incorporated Figure 3 into our paper, which provides a graphical representation of the distribution of the changes in gastritis severity both before and after H. pylori eradication. We also evaluated our data using a mixed-effects ordinal logistic regression model, which was suggested by Ohkusa et al. The results showed significant decreases in both glandular atrophy and intestinal metaplasia scores of the lesser curvature of the corpus in H. pylori-negative patients compared with those in H. pylori-positive patients, after considering H. pylori status over time (data not shown). Updated Sydney system grading was founded on a relatively objective visual analogue scale, using a graphic model and reducing textual explanation. However, as Dr Genta suggests, grading of such observations is still subject to significant interand intra-observer variabilities, particularly for atrophy. 9 Despite these limitations, this system is currently the mostly widely accepted and used grading system for gastritis. One specialised pathologist’s examination could handle inter-observer variations, but is still subject to intra-observer variabilities. We believe that this dilemma might be resolved in part by a double-blind, randomised trial design.

Background Bleeding after gastrectomy is a less frequent, but fatal complication. Because the pathophysiology and clinical manifestations differ considerably across cases, the exact outcome of postoperative bleeding is unclear. This study aimed to improve management practices for postgastrectomy bleeding by the analysis of risk factors and clinical patterns. Methods From January 2001 to December 2010, 5,739 patients underwent gastrectomy for gastric cancer at the National Cancer Center, Korea. Clinical data from patients with postoperative bleeding were obtained from a prospectively established database, and risk factors for bleeding were analyzed using multivariate binary logistic regression. Results Incidence of the postoperative bleeding was 0.8% ( n = 48) and the subsequent mortality rate was 10% (5/48). Majority of anastomotic bleeding occurred early within 1 day of the operation (5/7; 71%). It was successfully managed with conservative treatment in 3 patients, endoscopic intervention in 2, and relaparotomy in 2. Arterial bleeding occurred in 24 patients, with the main site being the splenic artery (11/24; 46%), and mostly manifested in the delayed period (median, 12 days). Fifteen of them underwent radiologic intervention, and 4 of these patients were referred for operation eventually. The other 9 patients underwent relaparotomy as first-line treatment. Independent risk factors for the bleeding were male (hazard ratio [HR] 2.253; 95% CI, 1.079–4.704), comorbidity (HR, 2.709; 95% CI, 1.440–5.095), previous abdominal operation (HR, 2.785; 95% CI, 1.322–5.867), and palliative surgery (HR, 4.142; 95% CI, 1.443–11.889). Conclusion Postgastrectomy bleeding can be managed properly considering its origin, severity, onset, and the risk factors.

There is no consensus on the optimal method of primary tumor control, determined by preoperative clinical factors, during sentinel node (SN) navigation surgery for early gastric cancer (EGC). In this study, we investigated the accuracy of clinical diagnosis based on preoperative examination in patients with EGC and proposed surgical options for primary tumor control during SN navigation surgery.We analyzed 815 patients with clinical stage IA gastric cancer who underwent gastrectomy at the National Cancer Center in Korea between March 2001 and February 2011. The clinical stage was determined by endoscopy, endoscopic ultrasonography, and abdominal computed tomography.The preoperative assessment of tumor depth and tumor size was accurate in 57.5 and 70.8 % of patients, respectively. Tumor depth and size were underestimated in 8 and 25.3 % of patients. The overall accuracy of histologic diagnosis by endoscopic biopsy was 87.2 %. Of those tumors diagnosed preoperatively as differentiated, 20.5 % revealed mixed histology of undifferentiated type.The recommendation for SN biopsy may be limited to tumors sized 3 cm or smaller to avoid positive lateral margins and to minimize the risk of skip metastases. Endoscopic resection may safely be applied to small mucosal cancers, but other surgical options should be employed for undifferentiated large mucosal lesions, given their tendency for diffuse invasion. Full-thickness resection is preferable for submucosal cancers, to secure clear vertical margins.

Gastric cancer bleeding is not rare complication in patients with advanced gastric cancer (AGC). The aim of this study was to evaluate the efficacy and clinical outcomes of endoscopic therapy (ET) for upper gastrointestinal bleeding (UGIB) from unresectable AGC.Data from 113 patients with UGIB from unresectable AGC who underwent ET at the National Cancer Center, Korea were analyzed retrospectively. Success rates of endoscopic hemostasis, rebleeding rates, mortality at 30 days, and overall survival (OS) rate after initial hemostasis were investigated.The initial hemostasis rate was 92.9% (105/113). Electrocoagulation was the most common method used (92.0%, 104/113), and combination ET was required in 34 patients (30.1%). Rebleeding occurred in 43 patients (41.0%); 3-day and 30-day rebleeding rates were 18.1% and 29.5%, respectively. Multivariate logistic regression analysis showed that transfusion of packed red blood cells ( 5 units) was associated with early rebleeding (≤ 3 days after initial hemostasis) (odd ratio, 4.75; 95% confidential interval, 1.45-15.57; P = 0.010). ET was attempted in 18 patients with rebleeding; hemostasis was achieved in 88.9%. The 30-day mortality rate after initial bleeding event was 15.9%. Median OS after initial hemostasis was 3.2 months. OS was lower for patients with early rebleeding than for those with late rebleeding ( 3 days after initial hemostasis) or without rebleeding (1.0, 3.1, and 4.3 months, respectively; P = 0.004).ET, primarily endoscopic electrocoagulation, achieved a high initial hemostasis rate for UGIB in patients with unresectable AGC. However, rebleeding frequently occurred, and early rebleeding was associated with poor survival.

Perforations are major complications of endoscopic gastric resection, including endoscopic submucosal dissection (ESD), and are generally detected on chest radiography following ESD. We hypothesized that a small amount of free air, defined as “intraperitoneal air,” would not be noted on chest radiography. In this study we aimed to determine how often intraperitoneal air is seen on a computed tomography (CT) scan after ESD and to evaluate the association between clinical factors and intraperitoneal air. A total of 147 patients who underwent ESD for gastric neoplasms were analyzed between September 2009 and September 2010. Patients underwent both chest radiography and noncontrast CT scans. Intraperitoneal air on the CT scan was stratified by the amount of gas as follows: grade I, free air localized along the outside of the gastric wall; grade II, free air in the lesser sac; and grade III, free air in front of the liver. Intraperitoneal air was detected in 56 patients (38.1 %) by an abdominal CT scan, whereas free air was noted in 2 patients (1.4 %) by chest radiography. Most patients with intraperitoneal air (96.4 %, 54/56) were grade I or II and 3.6 % (2/56) were grade III. Abdominal pain was more frequent in the intraperitoneal air group (32.1 %, 18/56) than in the no intraperitoneal air group (17.6 %, 16/91; P = 0.042). Tumor location at the lesser curvature was more frequent in the intraperitoneal air group (66.1 %, 37/56) than in the no intraperitoneal air group (38.5 %, 35/91; P

Splenic artery pseudoaneurysms can be caused by pancreatitis, trauma, or operation. Traditionally, the condition has been managed through surgery; however, nowadays, transcatheter arterial embolization is performed safely and effectively. Nevertheless, several complications of pseudoaneurysm embolization have been reported, including coil migration. Herein, we report a case of migration of the coil into the jejunal lumen after transcatheter arterial embolization of a splenic artery pseudoaneurysm. The migrated coil was successfully removed by performing endoscopic intervention.

Metformin is a first-line anti-diabetic drug that has been widely used in patients with type 2 diabetes. Many population-based epidemiologic studies have shown that metformin treatment is associated with decreased risk for various cancers. Recent epidemiologic studies showed that the use of metformin was associated with a reduction in gastric cancer risk, especially in patients with type 2 diabetes who used metformin for long periods of time (>2∼3 years). Currently, there are no registered clinical trials investigating the anti-cancer effect of metformin in gastric cancer; hence, further well-designed clinical trials are required. Herein, we review the literature regarding the use of metformin for the prevention of gastric cancer.

106 Background: The aim of this study is to compare the long-term outcomes between patients who underwent endoscopic submucosal dissection (ESD) and those who underwent surgery for early gastric cancers (EGCs) turned out to be out-of-indication of ESD. Methods: We retrospectively reviewed database on gastric cancer patient cohort who underwent ESD or surgery from 2004 to 2014. Patients whose lesions revealed to be out-of-indication for endoscopic resection after ESD or surgery were included in the analysis after 1:1 propensity score matching for baseline clinicopathologic characteristics. Overall survival (OS) and gastric cancer recurrence rates were compared between the matched ESD and surgery groups. Results: After propensity score matching, a total of 193 pairs of patients were included, and 126 pairs were ESD with additional operation group and 67 pairs were ESD without additional operation group. OS (5-year OS rates, 89.5% vs. 89.9%; P=.105) and gastric cancer recurrence rates (5-year recurrence rates, 2.6% vs. 1.6%; P=.080) were not different between the ESD and the matched surgery group. In the matched subgroups, ESD with additional operation group had comparable OS and gastric cancer recurrence rates in comparison with matched surgery group. However, ESD without additional operation group had significantly shorter OS (5-year OS rates, 76.8% vs. 86.3%; P=.032) and higher gastric cancer recurrence rates (5-year recurrence rates, 11.9% vs. 0%; P=.002) than matched surgery group. ESD without additional operation was also significant risk factor for overall mortality and gastric cancer recurrence in multivariate analyses. Conclusions: Patients who did not undergo additional operation after ESD for EGCs turned out be the out-of-indication had worse long-term outcomes. Additional operation should be recommended, when EGC was identified to be the out-of-indication after ESD.

Purpose Tumor bleeding is a major complication in inoperable gastric cancer. The study aim was to investigate the effects of proton pump inhibitor (PPI) treatment for the prevention of gastric tumor bleeding. Materials and Methods This study was a prospective double-blind, randomized, placebo-controlled trial. Patients with inoperable gastric cancer were randomly assigned to receive oral lansoprazole (30 mg) or placebo daily. The primary endpoint was the occurrence of tumor bleeding, and the secondary endpoints were transfusion requirement and overall survival (OS). Results This study initially planned to enroll 394 patients, but prematurely ended due to low recruitment rate. Overall, 127 patients were included in the analyses: 64 in the lansoprazole group and 63 in the placebo group. During the median follow-up of 6.4 months, tumor bleeding rates were 7.8% and 9.5%, in the lansoprazole and placebo groups, respectively, with the cumulative bleeding incidence not statistically different between the groups (P=0.515, Gray's test). However, during the initial 4 months, 4 placebo-treated patients developed tumor bleeding, whereas there were no bleeding events in the lansoprazole-treated patients (P=0.041, Gray's test). There was no difference in the proportion of patients who required transfusion between the groups. The OS between the lansoprazole (11.7 months) and the placebo (11.0 months) groups was not statistically different (P=0.610). Study drug-related serious adverse event or bleeding-related death did not occur. Conclusions Treating patients with inoperable gastric cancer with lansoprazole did not significantly reduce the incidence of tumor bleeding. However, further studies are needed to evaluate whether lansoprazole can prevent tumor bleeding during earlier phases of chemotherapy (ClinicalTrial.gov, identifier No. NCT02150447).

Purpose To report our experience of endoscopic botulinum toxin injection in patients who experienced severe delayed gastric emptying after pylorus-preserving gastrectomy (PPG). Materials and methods We reviewed the medical records of 6 patients who received the botulinum toxin injection. They presented with severe delayed gastric emptying in the early postoperative period. Endoscopic botulinum toxin was administered as 4 injections of 25-50 IU into each of the 4 quadrants of the prepyloric area. Results All botulinum toxin injections were successful without any complications, enabling 5 patients to tolerate soft solid diets and one to tolerate a soft fluid diet within 10 days. The endoscopic criteria of 4 patients improved. Symptom recurrence caused 2 patients to undergo repeat injections that were successful. The median follow-up period was 27 months, and all patients could ingest normal regular diets at the last follow-up. Conclusions Endoscopic botulinum toxin injection is a feasible treatment option for early delayed gastric emptying after PPG.

Self-expandable metallic stents are used widely to relieve malignant gastric outlet obstruction (GOO). However, restenosis or migration of first stents is a frequent complication. The purpose of this retrospective cohort study was to evaluate the effectiveness of second stents as an approach to manage failure of first stents in patients with malignant GOO. A total of 222 patients with gastric cancer received first stents due to inoperable GOO at National Cancer Center in Korea between January 2008 and June 2011. Monthly follow-up interviews were performed, and second stents (stent-in-stent or stent-after-migration) were inserted in 59 patients by June 2012. Technical and clinical successes and long-term complications were evaluated. The technical and immediate clinical success rates were 98.3 % (58/59) and 91.5 % (54/59), respectively. Patients who received a second stent due to late complications involving the first stent (migration, restenosis, and fracture) showed a higher clinical success rate (95.8 % [46/48]) than patients who received a second stent due to immediate clinical failure of the first stent (72.7 % [8/11], p = 0.04). The immediate clinical success rate of stent-after-migration (100 % [11/11]) was not different from that of stent-in-stent (89.6 % [43/48], p = 1.0). The stent dysfunction rate of stent-after-migration (27.3 % [3/11]) also was similar to that of stent-in-stent (29.2 % [14/48], p = 1.0). The median patencies of stent-in-stent and stent-after-migration were 27.4 and 58.4 weeks, respectively (p = 0.177). There were no significant prognostic factors for patency of second stents. Insertion of a second stent is effective for treating the first-stent failure in gastric cancer patients with GOO, especially if the immediate outcome of the first stent was successful.

Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA) is genomically stable compared to the intestinal type, but the primary driver mutations in DGA are still being defined. Lysine (K) -specific methyltransferase 2C (KMT2C), also known as mixed lineage leukemia 3 (MLL3), is a histone methyltransferase involved in transcriptional coactivation and can be mutated in gastric cancer. The purpose of this study was to determine the frequency of KMT2C mutation in DGA and to elucidate the role of KMT2C in DGA tumorigenesis and progression. Methods: Whole exome sequencing was performed on matched tumor samples of 27 patients with DGA who underwent potentially curative surgical resection. Immunohistochemistry (IHC) was performed for KMT2C protein expression on these same tumors and on an additional 289 tumors from a separate cohort of patients with DGA. KMT2C overexpression in DGA cell lines (MKN-45 and SNU-668) using lentiviral transduction and KMT2C shRNA knockdown in normal gastric epithelial cells were examined in several in vitro assays. Results: Thirty-eight percent of the 27 sequenced DGA specimens harbored somatic mutations in KMT2C. The next most frequent mutation, CDH1, which encodes E-cadherin, was found in 28% of specimens. Patients with KMT2C mutation tended to have worse overall survival (OS) compared to patients without the mutation (p = 0.194). Additional tumor tissue for IHC analysis was only available from 11 of 27 patients. Among this group, patients with tumors expressing KMT2C protein had better OS compared to patients whose tumors did not express KMT2C (p = 0.034). In an external validation set of 289 DGA samples, KMT2C expression again correlated with better OS (p = 0.009). In the DGA cell lines, KMT2C overexpression reduced proliferation by 32-39%, soft agar colony formation by 75-77%, spheroid cell formation by 77-78%, cell migration by 52-60%, and cell invasion by 50-74%. KMT2C overexpression also increased resistance to 5-FU and cisplatin chemotherapy. KMT2C shRNA knockdown in gastric epithelial cells increased proliferation, soft agar colony formation, migration, and invasion by 1.7- to 25-fold. Conclusions: KMT2C is frequently mutated in DGA, and loss of KMT2C protein expression correlates with worse OS. Restoration of KMT2C expression in DGA cell lines reduces cancer stem-like cell and malignant phenotypes. Thus, KMT2C may be a novel therapeutic target for patients with DGA. Citation Format: Soo-Jeong Cho, Changhwan Yoon, Jun Ho Lee, Kevin K. Chang, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon. Diffuse gastric adenocarcinoma often harbors KMT2C mutations resulting in malignant phenotypes and worse overall survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 893.

PURPOSE Increasing evidence suggests that polymorphisms in innate immunity genes are associated with Helicobacter pylori-induced inflammation and may influence susceptibility in developing noncardia gastric cancer. Therefore, we investigate the effect of polymorphisms of innate immunity genes and interactions with environmental factors in the Korean population. MATERIALS AND METHODS We genotyped four polymorphisms of TLR2 (rs1898830), TLR4 (rs10983755 and rs10759932), and CD14 (rs2569190) in a case-control study of 487 noncardia gastric cancer patients and 487 sex- and age-matched healthy controls. Polytomous logistic regression models were used to detect the effects of genetic polymorphisms and environmental factors, which were stratified by the histological type of gastric cancer. RESULTS TLR4 rs10983755 A carriers were found to have higher risk of intestinal-type noncarida gastric cancer than G homozygotes (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.01 to 1.97), but other genetic variants showed no association with the risk of noncardia gastric cancer. Among H. pylori-positive participants, smokers carrying TLR4 rs10983755 A had a higher risk of intestinal-type gastric cancer than nonsmoking TLR4 rs10983755 G homozygotes (OR, 4.28; 95% CI, 2.12 to 8.64). In addition, compared with tap water, other drinking water sources during childhood were found to be associated with the elevated risk of intestinal-type gastric cancer, and these associations were slightly stronger among TLR4 rs10983755 A carriers. CONCLUSION The genetic polymorphisms of innate immunity genes are associated with the development of intestinal-type noncardia gastric cancer and these associations may differ in accordance to an exposure to certain environmental factors.

The purpose of this study was to identify risk factors associated with lymph node (LN) metastasis in early gastric cancer patients who underwent endoscopic resection (ER) and to evaluate the feasibility of minimal LN dissection in these patients. From January 2001 to March 2011, patients who underwent gastrectomy with lymphadenectomy due to the potential risk of LN metastasis after ER were enrolled at National Cancer Center, Korea. The incidence, risk factors, and distribution of LN metastasis were evaluated. Of the 147 enrolled patients, the LN metastasis was identified in 12 patients (8.2 %). The incidence of LN metastasis was not significantly increased in patients with submucosal invasion, lymphovascular invasion, and mixed undifferentiated histology [odds ratio (OR), 5.55, 1.349, and 0.387; 95 % confidence interval (CI), 0.688–43.943, 0.405–4.494, and 0.081–1.84, respectively]. Tumor size more than 2 cm was significantly associated with LN metastasis (OR, 14.056; 95 % CI, 1.76–112.267). The incidence of LN metastasis gradually increased from 3.2 to 20 %, as number of risk factors increased (P = 0.019). LN metastasis was present primarily along the perigastric area in all except two patients (1.4 %) with skip metastasis to extragastric area. Standard surgery with at least D1 + LN dissection must be recommended for patients who proved to have risk factors for LN metastasis after ER, because the potential of skip metastasis is not negligible. Nevertheless, the minimal LN dissection, such as sentinel basin dissection, might be applied cautiously in patients with small-sized tumors after ER.

The best therapeutic modality has not been established for gastric low-grade adenomas or dysplasia (LGD), which can progress to invasive carcinoma despite a low risk. This study aims to investigate the clinical efficacy, safety, and local recurrence after argon plasma coagulation (APC) treatment of gastric LGD compared with endoscopic submucosal dissection (ESD). A total of 320 patients with gastric LGD ≤2.0 cm treated with APC or ESD between 2004 and 2011 were retrospectively analyzed. We compared local recurrence rate, complication rate, procedure time, and admission to hospital between APC and ESD groups. Of the 320 patients, 116 patients were treated with APC and 204 with ESD. During follow-up, local recurrence was more common in the APC group (3.8 %, 4/106) than the ESD group (0.5 %, 1/188; log-rank test P = 0.036). However, all patients with local recurrence (n = 5) were treated by additional APC, and followed up without further recurrences. ESD was complicated by two perforations (1.0 %, 2/204) compared with no perforations in the APC group (0 %, 0/116). Bleeding complications were not different between the APC (1.7 %, 2/116) and ESD (2.0 %, 4/204) groups. Procedure time was shorter in the APC (7.8 ± 5.1 min) than the ESD (53.1 ± 38.1 min) group (P

Purpose Family history of gastric cancer is a major risk factor for the disease. In this study, we investigated the prognoses of patients with gastric cancer with a family history. Patients and Methods We retrospectively reviewed data from 1,273 patients with gastric adenocarcinoma who had undergone gastrectomy between 2001 and 2005 at a tertiary cancer center hospital. A positive family history was defined as a self-reported history of cancer in first- or second-degree relatives. Patients were followed up until December 2009 for death or recurrence. Clinicopathologic characteristics were compared by family history. Kaplan-Meier plots and Cox proportional hazards regressions were applied for disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS). Results Of 1,273 patients, 263 patients (20.6%) had first-degree relatives with a history of gastric cancer. First-degree family history of gastric cancer was associated with better DFS, RFS, and OS (P = .012, .006, and .005, respectively). In patients with stage I or II gastric cancer, first-degree family history was not associated with survival. However, it was associated with a reduced risk of recurrence or mortality in patients with stage III or IV gastric cancer. Compared with patients without a family history, the adjusted hazard ratios for those with a first-degree family history of gastric cancer were 0.49 (95% CI, 0.29 to 0.84) for DFS, 0.51 (95% CI, 0.30 to 0.87) for RFS, and 0.47 (95% CI, 0.26 to 0.84) for OS in patients with stage III or IV gastric cancer. Conclusion A first-degree family history of gastric cancer is associated with improved survival after curative-intent surgery in patients with stage III or IV gastric cancer.

Endoscopy screening in high-risk populations may reduce gastric cancer mortality by detecting cancer earlier. We evaluated the association between the interval between upper gastrointestinal endoscopies and the gastric cancer stage at diagnosis in patients from a region of high prevalence.The study cohort consisted of 2485 patients diagnosed with gastric adenocarcinoma. We evaluated the effect on cancer stage of the interval between the endoscopy that was diagnostic for gastric cancer and the endoscopy preceding it. Patients were stratified into 7 groups: 1-, 2-, 3-, 4-, 5-,5-year intervals and those who were never screened.The risk of higher cancer stage at diagnosis increased by 23% per increase in interval length (odds ratio = 1.23, 95% confidence interval [CI] = 1.19-1.28). Compared to the never-screened, the odds ratio of having a higher stage of cancer decreased gradually from 0.53 (95% CI = 0.41-0.69) in the5-year interval group to 0.31 (95% CI = 0.24-0.40) in the 1-year interval group. Compared to the 1-year interval group, the risk of advanced gastric cancer was increased in the 4- and 5-year, but not the 2- and 3-year, interval groups. However, patients with a family history of gastric cancer were more likely to have a higher stage at diagnosis if they had a 3-year interval rather than a 1-year interval.A significant benefit in cancer stage at diagnosis was observed in all interval groups compared to never-screened. Endoscopy intervals of 3 years or less showed similar benefits, but family members of gastric cancer patients may benefit from intervals of under 3 years.

Laparoscopically assisted total gastrectomy (LATG) is technically difficult. Robot surgery has theoretical advantages such as increased degrees of freedom of instruments and a three-dimensional view. The current study aimed to determine whether a robot-assisted total gastrectomy (RATG) has a real benefit over LATG in terms of surgical and oncologic outcomes. A single-center case–control study was conducted. The study included 36 patients who underwent RATG and 65 patients who underwent LATG at the National Cancer Center in Korea between February 2009 and May 2011. No patients were excluded from the analysis within the study period. Clinicopathologic data, operative data, postoperative morbidity, and pathologic data were analyzed by Student’s t-tests and Chi-square tests, as indicated. The mean age of the patients was 53.9 ± 11.7 years in the RATG group and 56.9 ± 12.3 years in the LATG group (P = 0.236). The mean BMI was 23.2 ± 2.5 kg/m2 in the RATG group and 23.6 ± 3.4 kg/m2 in the LATG group (P = 0.494). The mean postoperative hospital stay was 8.8 ± 3.3 days in the RATG group and 10.3 ± 10.8 days in the LATG group (P = 0.416). The mean operative time was 305.8 ± 115.8 min in the RATG group and 210.2 ± 57.7 min in the LATG group (P

Helicobacter pylori infection is a risk factor for gastric cancer. We evaluated whether H. pylori infection and premalignant histological changes are more prevalent in siblings of young gastric cancer patients.Young (age ≤ 40) gastric cancer patients (n = 185), their young siblings (n = 130), and young control participants (n = 287) were recruited. H. pylori infection and histological changes were assessed using the updated Sydney system in biopsy specimens from three regions. We analyzed the association of H. pylori infection and histological changes with gastric cancer using logistic regression analysis. The H. pylori infection rate was significantly higher in young cancer patients than their siblings (odds ratio [OR]= 2.42, P = 0.001) or control participants (OR = 3.60, P0.001). In H. pylori-infected subjects, corpus gastritis and premalignant changes of the corpus lesser curvature (LCv) were also more prevalent in patients than in siblings or controls. In terms of the antrum, intestinal metaplasia was more prevalent in H. pylori-infected patients than in siblings or controls, while atrophy was not affected. Siblings also had a higher H. pylori infection rate (OR = 1.60, P = 0.046) and higher prevalence of intestinal metaplasia at the corpus LCv (OR = 2.88, P =0.027) than control participants.Even in young adults, H. pylori infection is a risk factor for gastric cancer. Young adults with histological findings including corpus predominant gastritis, corpus atrophy, or intestinal metaplasia are at increased risk. Since young siblings share risk factors, screening and treatment should be considered for these family members.

A tumor thrombus in the portal vein originating from gastric cancer is a rare condition. Little is known about the development of portal vein tumor thrombus (PVTT) and its effect on the survival of gastric cancer patients.PVTT originating from gastric cancer was identified retrospectively with computed tomography in 51 patients, from January 2002 to June 2007. PVTT was classified by metastatic routes as follows: lymph node (LN), hepatic mass, and hematogenous type. The median survival from PVTT, and the factors affecting the survival of gastric cancer patients with PVTT were analyzed.The median survival of gastric cancer patients with PVTT (N = 51) was 5.4 months. The median survival was compared according to clinical characteristics, and multivariate analysis proved that female and hepatic mass type were independent risk factors for poor prognosis. The characteristics of the hepatic mass type were old age, higher proportion of tumors located in the upper-third of the stomach, and liver metastasis, compared to the LN or the hematogeneous type.PVTT originating from gastric cancer was a poor prognostic factor and the median survival from PVTT was different according to several clinical factors.

Aims The authors aimed to compare the surgical performance and the short-term clinical outcomes of robotic assisted laparoscopic distal gastrectomy (RADG) with laparoscopy-assisted distal gastrectomy (LADG) in distal gastric cancer patients. Method From April 2009 to August 2010, 62 patients underwent LADG and 30 patients underwent RADG for preoperative stage I distal gastric cancer by one surgeon at the National Cancer Center, Korea. Surgical performance was measured using lymph node (LN) dissection time and number of retrieved LNs, which were viewed as surrogates of technical ease and oncologic quality. Results In clinicopathologic characteristics, mean age, depth of invasion and stage were significantly different between the LADG and RADG group. Mean dissection time at each LN station was greater in the RADG group, but no significant intergroup difference was found for numbers of retrieved LNs. Furthermore, proximal resection margins were smaller, and hospital costs were higher in the RADG group. In terms of the RADG learning curve, mean LN dissection time was smaller in the late RADG group ( n = 15) than in the early RADG group ( n = 15) for 4sb/4d, 5, 7-12a stations, but numbers of retrieved LNs per station were similar. Conclusion With the exception of operating time and cost, the numbers of retrieved LNs and the short-term clinical outcomes of RADG were found to be comparable to those of LADG, despite the surgeon's familiarity with LADG and lack of RADG experience. Further studies are needed to evaluate objectively ergonomic comfort and to quantify the patient benefits conferred by robotic surgery.

Although gastric cancer (GC) and duodenal ulcer (DU) are both strongly associated with Helicobacter pylori infection, a DU is negatively associated with the risk of GC. The aim of the study is to evaluate histologic risk factors for GC among patients with a DU.A total of 541 consecutive patients with GC were prospectively evaluated for the presence of a DU. Control patients with only a DU (n = 89) were recruited from health screening population. Histologic grading was assessed using the updated Sydney system for six gastric biopsies from three regions. GC risk among patients with a DU was evaluated using logistic regression analysis.Among patients with GC, 7.6% (41/541) had a concomitant DU or an ulcer scar. Corpus-predominant/pangastritis were more frequently found in concomitant GC patients with a DU (90%) than in patients with a DU alone (62%) (p = .001). In patients with a DU, moderate-severe chronic inflammation at the lesser and greater curvatures of corpus was associated with GC risk (OR, 3.70; 95% CI, 1.46-9.36, and OR, 7.72; 95% CI, 3.18-18.7, respectively). Additionally, moderate-severe intestinal metaplasia (IM) at the antrum and corpus lesser curvature was associated with GC risk (OR, 7.52; 95% CI, 3.06-18.5, and OR, 9.25, 95% CI, 2.39-35.8, respectively).A DU is not rare in patients with GC in a high-risk region of GC. Patients with a DU with chronic corpus gastritis and IM have an increased risk of GC, thus those patients should be followed up for GC development.

The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms.Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks.Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6).The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

Self-expandable metallic stents (SEMSs) provide effective palliation for inoperable malignant gastric outlet obstruction (GOO). The objective of this study was to evaluate the effectiveness of SEMSs in patients with recurrent gastric cancer after radical gastrectomy. We retrospectively analyzed data from patients with gastric cancer who underwent endoscopic SEMS placement. The patients had obstructive symptoms due to recurrent gastric cancer after curative-intent subtotal or total gastrectomies. Technical and clinical success rates of stent placement were evaluated and clinical outcomes were compared according to operation types. A total of 15 patients underwent total gastrectomies with esophagojejunostomies and Roux-en-Y reconstructions, 8 underwent subtotal gastrectomies with Billroth I reconstructions, and 12 underwent subtotal gastrectomies with Billroth II reconstructions. Four patients in the Billroth II group received stents in afferent and efferent loops, so a total of 39 stents were placed. Technical success was achieved with 92% (36/39) of stents, and clinical success occurred with 90% (35/39) of stents, with no significant differences among surgery groups or between stent types (covered vs. uncovered). The GOO score (preprocedure: 0.45 ± 0.62) increased by 1 week (2.06 ± 0.51, p

To evaluate the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC) according to tumor subtype in Korea.H. pylori status was determined serologically using the enzyme-linked immunosorbent assay. In total, 2,819 patients with GC and 562 healthy controls were studied. A logistic regression method was used after adjusting for possible confounders.The prevalence of H. pylori infection was significantly higher in the GC patients (84.7%) than in the controls (66.7%) (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.46-3.97). The adjusted OR was significantly higher in H. pylori-infected patients aged60 years (OR, 4.69; 95% CI, 3.44-6.38) than in those aged ≥60 years (OR, 1.48; 95% CI, 0.88-2.46; p0.001). Subgroup analyses revealed no differences in seroprevalence between early gastric cancer (84.8%; OR, 3.01; 95% CI, 2.27-4.01) and advanced gastric cancer (84.6%; OR, 2.94; 95% CI, 2.24-3.85), cardia cancer (83.8%; OR, 2.98; 95% CI, 2.16-4.02) and noncardia cancer (84.8%; OR, 3.17; 95% CI, 2.48-4.04), and differentiated carcinoma (82.7%; OR, 2.99; 95% CI, 2.21-4.04) and undifferentiated carcinoma (86.8%; OR, 3.05; 95% CI, 2.32-4.00).The seroprevalence of H. pylori was higher in GC patients than in healthy controls, especially in younger patients. H. pylori infection is associated with GC, regardless of the tumor location, stage, or differentiation.

Background Self-expandable metallic stents (SEMSs) provide effective palliation of malignant pyloric obstruction in patients with inoperable gastric cancer. Objective To compare the effectiveness and side effects of covered and uncovered SEMSs for the palliation of malignant pyloric obstruction. Design Prospective, randomized, single-center study. Setting Tertiary-care cancer center hospital. Patients This study involved 80 patients with pyloric obstruction related to inoperable gastric cancer. Intervention Covered or uncovered SEMS placement. Main Outcome Measurements Technical and clinical success rates as well as the patency rate at 8 weeks after placement. Results Both groups had a technical success rate of 100% with no immediate complications. Both groups also had comparable clinical success rates (covered SEMS, 95% [38 of 40] and uncovered SEMS, 90% [36 of 40], P = .68) and 8-week patency rates (covered SEMS, 61.3% [19 of 31] and uncovered SEMS, 61.1% [22 of 36], P > .99). Stent migration within 8 weeks was more common in the covered SEMS group (25.8% [8 of 31]) than in the uncovered SEMS group (2.8% [1 of 36], P = .009), whereas re-stenosis because of tumor ingrowth was more common in the uncovered SEMS group (25.0% [9 of 36] vs 0% [0 of 31] in the covered SEMS group, P = .003). Overall patient survival and stent patency did not differ between groups ( P = .27 and 0.61 by log-rank test, respectively). Limitations The study population was limited to gastric cancer patients, and stent designs were changed in the midst of the study period. Conclusion Both the covered and uncovered SEMSs are effective and have comparable 8-week patency in patients with malignant pyloric obstruction, despite different patterns of late stent failure.

Only a few surgeons with much experience of laparoscopic surgery perform laparoscopy-assisted total gastrectomy (LATG), because of its technical difficulty and concern about subsequent complications. The aim of this study was to evaluate the technical feasibility and safety of LATG as compared with laparoscopy-assisted distal gastrectomy (LADG) in gastric cancer.From January 2002 to December 2007, LADG was performed in 473 patients and LATG in 67 patients at the Korean National Cancer Center. Surgical procedures and short-term surgical outcomes of LATG were analyzed.D2 lymph node dissection was performed in 35 LATG (52.2%) cases and in 274 LADG (57.9%) cases (P = 0.378). Mean blood losses during operation were 156.8 +/- 158.0 ml and 190.7 +/- 176.2 ml, respectively (P = 0.114). The open conversion rate for LATG was higher than LADG without significance (4.3% vs. 1.7%, P = 0.153). Complications occurred in 18 LATG cases (26.9%) and 38 LADG cases (8.0%) (P0.001). The most common postoperative complication of LATG was anastomotic stricture after esophagojejunostomy.LATG is a technically feasible procedure as compared with LADG. However, its postoperative complication rate is higher than that of LADG, especially that of anastomotic stricture. A more effective anastomotic method during LATG is required to prevent stricture.

Endoscopic submucosal dissection (ESD) of tumor in the upper part of the stomach is technically difficult and has a high complication rate. We compared the feasibility and safety of ESD for metachronous tumor found in the remnant stomach after distal gastrectomy with ESD for tumor in the upper third of the intact stomach. We retrospectively compared clinical outcome and safety of 13 lesions (11 early gastric cancers (EGCs) and 2 dysplasias) in the remnant stomach and 30 lesions (28 EGCs and 2 dysplasias) in the upper third of the intact stomach. All patients were treated with ESD at a cancer center hospital. En bloc resection rates were 100% (13/13) for remnant gastric tumor and 87% (26/30) for upper-third tumor (p = 0.30). En bloc resection rates with tumor-free margins (R0 resection) were 92% (12/13) for remnant gastric tumor and 73% (22/30) for upper-third tumor (p = 0.24). Curative resection rates were 85% (11/13) for remnant gastric tumor and 67% (20/30) for upper-third tumor (p = 0.29). Median procedure duration for ESD was 68 min (range 32–233 min) in the remnant stomach and 78 min (range 45–261 min) in the intact stomach (p = 0.49). One case of perforation and one of delayed bleeding occurred in the upper-third tumor group, whereas none occurred in the remnant tumor group. Local recurrence was found in no patients in the remnant gastric tumor group but in one patient in the upper-third tumor group. ESD for metachronous remnant gastric tumor was feasible and safe in comparison with ESD for tumor in the upper third of the intact stomach.

Background/Aims: Lymph node metastasis is the most important point to consider when deciding on the modality of resection in patients with early gastric cancer. This study was conducted to evaluate the learning curve for identification of sentinel lymph nodes in patients with gastric cancer. Methods: The investigators included the results from 2 prospective series of sentinel lymph node mapping. Cumulative sum (CUSUM) analysis was performed to assess the learning curves for identification of sentinel lymph nodes at CUSUM target success rates of 95%. Results: One surgeon performed 135 sentinel lymph node mappings for 2 prospective series. The success rate exceeded 90%. The learning period for gastric cancer sentinel node mapping was calculated to be 26 cases for achieving a 95% success rate. Multiple logistic regression analysis for successful detection of sentinel nodes showed that surgical experience of sentinel lymph node mapping was an independent factor for successful detection of sentinel nodes. Conclusions: This study suggests that the learning period for identification of sentinel lymph nodes in gastric cancer would be 26 cases. In clinical trials for gastric cancer with sentinel lymph node mapping, the learning curve should be considered to minimize bias due to surgical factors.

The technical difficulty of lymph node dissection in laparoscopy-assisted distal gastrectomy (LADG) remains a barrier for extending the indication for this modality and limits its widespread clinical practice. The aim of this study was to evaluate our institutional guidelines for LADG, limiting the indications for this modality to only clinical stage T1N0 or T1N1 gastric cancer.From January 2002 to October 2006, a total of 294 cases of LADG and 664 cases of open distal gastrectomy (ODG) for clinical T1N0 or T1N1 gastric cancer were performed at the National Cancer Center, Korea. The two groups' clinicopathologic characteristics, surgical outcome, morbidity, and survival were compared.The mean operating time for the LADG group was significantly longer than that for the ODG group (265.8 +/- 56.3 vs. 171.4 +/- 43.1 minutes, P.001). The mean number of retrieved lymph nodes in the LADG group was higher than that of the ODG group (39.5 +/- 14.7 vs. 37.2 +/- 12.9, P = .017). The postoperative hospital stay was shorter in the LADG group (8.0 +/- 3.3 vs. 10.5 +/- 4.1 days, P.001). The complications rate was lower for the LADG group than that for the ODG group (6.8% vs. 11.3%, P = .032). The overall survival rate was not significantly different between the two groups (P = .880).Before considering expanding the indications for LADG, developing a carefully thought-out guideline and conducting an audit are mandatory.

We performed a retrospective study to evaluate the efficacy of cetuximab plus chemotherapy in metastatic gastric cancer (MGC) patients previously treated with chemotherapy and to investigate potential predictors of treatment efficacy in those patients. Thirty-two patients with MGC were included in this study. Cetuximab was delivered, often combined with irinotecan-based chemotherapy. Thirty patients were analyzed for K-ras mutations via direct sequencing of the tumor DNA. Patients were heavily pretreated with a median number of three previous lines of palliative chemotherapy (56% of the patients were refractory to all of the following drugs: fluoropyrimidines, cisplatin, irinotecan, oxaliplatin, and docetaxel) and 53% of the patients displayed poor performance status. Of 28 response-assessable patients, the overall response rate to cetuximab plus chemotherapy was 3.6% [95% confidence interval (CI) 0–10.5%] and the disease control rate was 28.6%. The median progression-free survival (PFS) was 1.7 months (95% CI 1.3–2.1 months), and the median overall survival (OS) was 3.2 months (95% CI 1.4–5.0 months). Multivariate analyses revealed that skin rash and performance status were significantly associated with PFS and OS. The presence of a K-ras mutation (13.3%) was not associated with either PFS or OS. Our study suggests that MGC patients with good performance status and skin rash benefit most from salvage cetuximab combined with chemotherapy, even in heavily pretreated status.

Background and Objectives The factors associated with successful sentinel node biopsy (SNB) are limited in gastric cancer despite a wide range of sensitivities reported. This study was performed to identify the factors associated with detection failure and SNB false-negativity in gastric cancer. Methods SNB was performed on 156 gastric cancer patients from May 2002 to April 2007 at the Korean National Cancer Center during three consecutive prospective trials. Indications for SNB were determined preoperatively in cT1-2N0 patients. Dissected SNs and non-SNs after D2 lymphadenectomy were pathologically evaluated for metastasis. Clinical, pathological, and technical factors were analyzed for detection failure and false-negativity. Results SNs were detected in 147 patients (94.2%) and the median number of SNs detected per patient was 3 (1–12). Twenty-five of 37 with nodal metastasis were diagnosed by SNB (sensitivity, 67.6%). Surgeon's inexperience (≤30 procedures) and a male patient gender were significantly associated with detection failure (P = 0.014 and 0.031, respectively). A small number of SNs (≤ 3) was found to be significantly associated with false-negativity (P = 0.027). Conclusions SNB requires experience for successful detection and should be performed cautiously in male patients. Harvesting of more than three SNs is warranted to reduce false-negatives when diagnosing nodal metastasis. J. Surg. Oncol. 2009;99: 137–142. © 2008 Wiley-Liss, Inc.

Background and Aim: Previously, we showed that treatment with celecoxib significantly reduced the number of viable gastric cancer cells, in a dose- and time-dependent manner. However, the specific anti-cancer effects of celecoxib on gastric cancer cells have not been clarified. The present in vitro study was carried out to investigate the mechanism involved in the anti-gastric cancer effects of celecoxib. Methods: 3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out after treating AGS cells (human gastric cancer cell line, ATCC CRL 1739) with celecoxib or indomethacin, and the effect of prostaglandin E2 or LY294002 (PI3K inhibitor) was evaluated. Western blot analysis of tAkt (total Akt), pAkt (phosphorylated Akt), pGSK3β (phosphorylated glycogen synthase kinase-3β), pFKHR (phosphorylated forkhead transcriptional factor), and caspase-9 was carried out at various concentrations (0, 5, 10, 25, or 50 µmol/L) of celecoxib or indomethacin-treatment for 24 or 48 h in AGS cells. Results: Celecoxib- or LY294002-induced cell death was found to occur in a dose-dependent manner in AGS cells, and these decreases were slightly recovered by the addition of PGE2 (25 or 50 µmol/L). The expression of pAkt but not tAkt was lower in the celecoxib treated-AGS cells and the response was dose dependent (P

Statins, HMG-CoA reductase inhibitors could be associated with the risk reduction of colorectal cancer. We previously demonstrated that simvastatin inhibits NF-kappaB signaling in human intestinal epithelial cells and ameliorates acute murine colitis. The aim of our study was to evaluate the effects of simvastatin on the apoptotic pathways related to NF-kappaB signaling in colon cancer cells, and on anticancer effects in 2 different animal models. We treated cell lines (COLO 205 and HCT 116) with simvastatin or vehicle and determined apoptosis by cell cycle analysis, Annexin V-FITC staining, caspase-3 activity assay and confocal microscopy. We assessed the expression of antiapoptotic factors by RT-PCR and Western blotting. In the colitis-associated colon cancer (CAC) model, we induced colonic tumors in C57/BL6 mice by azoxymethane and dextran sulfate sodium administration, and evaluated simvastatin's effect on tumor growth. In the xenograft model, we evaluated its effect on the inoculated tumor growth. In both cell lines, simvastatin caused dose- and time-dependent cell death. Annexin V staining significantly increased after simvastatin treatment. It augmented caspase-3 activity and downregulated the expression of Bcl-2, Bcl-xL, cIAP1 and cFLIP. In the CAC model, simvastatin significantly reduced tumor development. In the xenograft model, tumors from animals treated with simvastatin had smaller volumes, larger necrotic areas, lower expression of VEGF and higher apoptotic scores. In conclusion, simvastatin inhibited colon cancer development by induction of apoptosis and suppression of angiogenesis. These results suggest that simvastatin could be a potential chemopreventive and therapeutic agent of CAC as well as de novo colon cancer.

Phlegmonous gastritis is a rare and rapidly progressive bacterial infection of the stomach wall, with a high mortality rate. Antibiotics with or without surgical treatment are required for treatment. We present a case in which phlegmonous gastritis occurred during the diagnostic evaluation of early gastric cancer. The patient showed improvement after antibiotic treatment, but attempted endoscopic submucosal dissection failed because of submucosal pus. We immediately applied argon plasma coagulation since surgical resection was also considered a high-risk procedure because of the submucosal pus and multiple comorbidities. However, there was local recurrence two years later, and the patient underwent subtotal gastrectomy with lymph node dissection. Considering the risk of incomplete treatment immediately after recovery from phlegmonous gastritis and that recurrent disease can be more difficult to manage, delaying treatment and evaluation until after complete recovery of PG might be a better option in this particular clinical situation.

Purpose Early gastric cancer cases that are estimated to meet indications for treatment before endoscopic submucosal resection are often revealed to be out-of-indication after the treatment. We investigated the short-term treatment outcomes in patients with early gastric cancer according to the pretreatment clinical endoscopic submucosal resection indications. Materials and Methods We retrospectively reviewed the medical records of patients with early gastric cancer that met the pretreatment endoscopic submucosal resection indications, from 2004 to 2011. Curative resection rate and proportion of out-of-indication cases were compared according to the pre-endoscopic submucosal resection indications. Pre-endoscopic submucosal resection factors associated with out-of-indication in the final pathological examination were analyzed. Results Of 756 cases, 660 had absolute and 96 had expanded pre-endoscopic submucosal resection indications. The curative resection rate was significantly lower in the patients with expanded indications (64.6%) than in those with absolute indications (81.7%; P65 years, tumor size of >2 cm, tumor location in the upper-third segment of the stomach, and undifferentiated histological type in pre-endoscopic submucosal resection evaluations were significant risk factors for out-of-indication after endoscopic submucosal resection. Conclusions Non-curative resection due to out-of-indication occurred in approximately one-third of the early gastric cancer cases that clinically met the expanded indications before endoscopic submucosal resection. The possibility of additional surgery should be emphasized for patients with early gastric cancers that clinically meet the expanded indications.

Background and Aim: The risk of hepatocellular carcinoma (HCC) is known to be age dependent; the influence of age on prognosis is, however, controversial. The aim of this study was to compare the tumor characteristics and survival rates of young and old HCC patients, with respect to tumor stage. Methods: We reviewed the clinical data and survival times of 71 young HCC patients from 1987 to 2003 and compared these with those of their older counterparts (n = 239). Patients were categorized into three age groups: group A, age