Primary Gastric Cancer Patients Research Articles

Long non-coding RNA NEAT1 decreases the chemosensitivity of gastric cancer cells via regulating P-glycoprotein expression

Drug resistance remains to be one of the major challenges in clinical treatment of gastric cancer (GC). Accumulating evidences have highlighted the involvement of long non-coding RNA (lncRNA) in carcinogenesis, chemoresistance, and metastasis. NEAT1, a recently identified lncRNA, was identified as an oncogene to regulate carcinogenesis. This present study aimed to investigate the role of NEAT1 in the drug resistance in GC. Our study found that NEAT1 expression was significantly upregulated in relapsed GC patients and cisplatin (CDDP)-resistant cell lines compared with primary GC patients and parental GC cell lines. NEAT1 upregulation was largely companied with the induction of P-gp. Overexpression of NEAT1 significantly increased the expression of several drug-resistance proteins, thereby compromising the sensitivity of GC cells to CDDP. In contrast, NEAT1 knockdown by RNAi did the opposite. Therefore, lncRNA NEAT1 is an important modulator for drug resistance of GC via promoting the expression of P-gp and other associated proteins.

662P - Gastrectomy after response to intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology

Background: The prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology (CY1) remains poor in spite of recent progress in systemic chemotherapy. We developed several regimens combining intraperitoneal (IP) and systemic chemotherapy, and evaluated the safety and efficacy in clinical trials. Gastrectomy after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate this multidisciplinary treatment strategy. Methods: This study enrolled 158 primary P1 or CY1 gastric cancer patients treated with IP paclitaxel or docetaxel with systemic chemotherapy at the University of Tokyo Hospital between 2005 and 2015. Gastrectomy was performed when peritoneal cytology turned negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. Combination chemotherapy was restarted after surgery and repeated with appropriate dose reduction. Results: Ninety-one patients were chemo-naïve, and 67 patients had received standard systemic chemotherapy at the previous hospitals before the initiation of IP chemotherapy. Gastrectomy was performed in 94 (P1 85, P0CY1 9) of 158 (P1 147, P0CY1 11) patients after response to chemotherapy. R0 resection was achieved in 61 of 94 patients (65%). Postoperative complications included anastomotic leakage in 3 patients and pancreatic fistula in 2 patients, which were cured conservatively. The median survival time (MST) of 94 patients with gastrectomy was 31.3 months (95% confidence interval [CI] 26.1-39.3 months) from the initiation of IP chemotherapy and 35.8 months (95% CI 28.5-40.1 months) from the diagnosis of gastric cancer. Relapse or progression was observed in 78 of 94 patients with a median time of 17.9 months (95% CI 15.0-24.2 months). The first site of recurrence or progression was the peritoneum in 61 patients and the other site in 28 patients (both in 11 patients). The MST of 64 patients without gastrectomy was 12.3 months (95% CI 10.0-13.9 months). Conclusions: Gastrectomy after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients. Legal entity responsible for the study: The University of Tokyo Funding: Japan Agency for Medical Research and Development Disclosure: All authors have declared no conflicts of interest.

D-dimer is an essential accompaniment of circulating tumor cells in gastric cancer

BackgroundFibrinogen (FIB) is an important source of fibrin, which plays a crucial role in circulating tumor cells (CTCs) extravasation and distant metastasis development. We hypothesize it’s stable final product, plasma D-dimer, may be associated with CTCs appearance and can reflect the metastatic phenotype in cancer patients.MethodsWe first verified our hypothesis in different murine gastric cancer metastasis models in vivo, plasma D-dimer and fibrinogen as well as its degradation products were directly examined in three metastasis immune-deficient mouse models and in controls. Next, we gathered and analyzed the result of plasma D-dimer levels and CTCs numbers in 41 advanced primary gastric cancer (GC) patients. A follow-up study was conducted in these patients.ResultsIn three in vivo murine metastasis models, plasma D-dimer levels were extremely elevated in a hematogenous and intraperitoneal murine model of metastasis compared with a subcutaneous tumor model and the control group, supporting our previous hypothesis. While in 41 GC patients, the result displayed that plasma D-dimer levels were remarkably increased in patients with distant metastases, especially in visceral metastases patients. Additionally, linear association was shown between D-dimer level and CTCs numbers (R2 = 0.688, p < 0.001), additionally, plasma D-dimer represent a better survival predictor than CTCs.ConclusionsPlasma D-dimer is an essential accompaniment of CTCs in GC that is easy to measure and lower in cost, and can be used in the detection of hematogenous metastasis.

Surgery after intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology findings.

Despite recent progress in systemic chemotherapy, the prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology findings (CY1) is still poor. We developed a regimen combining intraperitoneal (IP) paclitaxel (PTX) with S-1 and PTX, which can produce notable efficacy with regard to peritoneal lesions. Surgery after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate the safety and efficacy. This study enrolled 100 primary P1 or CY1 gastric cancer patients treated with IP PTX plus S-1 and PTX at the University of Tokyo Hospital between 2005 and 2011. Radical gastrectomy was performed when peritoneal cytology findings became negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. The same chemotherapy regimen was restarted after surgery and repeated with appropriate dose reduction. Gastrectomy was performed in 64 (P1 56, P0CY1 8) of 100 (P1 90, P0CY1 10) patients. R0 resection was achieved in 44 patients (69%). The median survival time was 30.5months [95% confidence interval (CI) 23.6-37.7months] from the initiation of intraperitoneal chemotherapy and 34.6months (95% CI 26.8-39.4months) from the diagnosis of gastric cancer. Postoperative complications included anastomotic leakage and pancreatic fistula, each in two patients, which were cured conservatively. There were no treatment-related deaths. The median survival time of the 36 patients who did not undergo surgery was 14.3months (95% CI 10.0-17.8months). Surgery after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients.

Impact of preoperative sarcopenia on recurrecnce in gastric cancer surgery.

120 Background: Our previous study clarified that morbidity was a negative prognostic factor and sarcopenia defined by of the handgrip strength was a risk factor for the morbidity in gastric cancer surgery. Sarcopenia was reportedly a negative prognostic factor in colorectal cancer, hepatocellular carcinoma and malignant melanoma. This study aimed to evaluate impact of preoperative sarcopenia on recurrence-free survival (RFS) in gastric cancer surgery. Methods: Between May 2011 and June 2013, 256 consecutive primary gastric cancer patients who underwent curative surgery were retrospectively examined. Patients who received neoadjuvant chemotherapy or were diagnosed with pathological stage IV were excluded. Preoperative skeletal muscle mass was evaluated by bioelectrical impedance analysis and was expressed as skeletal muscle index or SMI (muscle mass/height2) by adjusting absolute muscle mass with height. Preoperative muscle function was measured by hand grip strength (HGS). Each cutoff value was determined as the gender-specific lowest 20% of the distribution of each measurement. Univariate and multivariate analyses were preformed to identify risk factors for RFS using a Cox proportional hazards model. Results: Median age (range) was 66 years (37-85 years). Male to female ratio was 168:88. Median follow-up period was 33.4 months. Pathological stage was I in 160, II in 48 and III in 48 patients. Univariate analysis showed that age, adjuvant chemotherapy, pT, pN, histological type, tumor size, total gastrectomy, low SMI and low HGS were significant risk factors for RFS. Multi-variate Cox’s proportional hazard analyses demonstrated that pT (HR 2.76, p = 0.0001), pN (HR 1.375, p = 0.037), histological type (HR 3.46, p = 0.014), low SMI (HR2.17, p = 0.036) were the significant risk factors for RFS. The three-year RFS was 89.1% in the patients with high SMI and 73.2% in those with low SMI (p = 0.007). Conclusions: Low SMI was an independent risk factor for RFS in Stage I-III gastric cancer. Low HGS, a risk factor for morbidity shown in our previous study, was not a risk independent factor for RFS. Preoperative sarcopenia as the short- and long-term outcomes has a value to be tested in the future prospective studies in gastric cancer surgery.

Abstract 4769: CHFR methylation is an independent prognostic marker of poor prognosis in gastric cancer

Abstract Introduction : Although primary gastric cancer (PGC) is the leading cause of cancer-related death in Asia, remnant gastric cancer (RGC), a cancer deloping after a subtotal gastrectomy in the part of the stomach not excised, is rare but equally lethal. In PGC, aberrant gene methylation has been reported to be correlated with carcinogenesis and development. However, few reports describe the process of molecular carcinogenesis in RGC. CHFR is a mitotic checkpoint- and tumor suppressor gene in a diverse number of solid malignancies. CHFR is most frequently inactivated by promoter CpG island methylation and has shown to be a marker of poor prognosis and increased sensitivity to treatment with taxanes. We hypothesized that the mathylation status in CHFR could be correlated with clinicopathological factors and prognosis in RGC. We retrospectively investigated the methylation status in RGC and the correlation between the methylation status, clinicopathological factors and prognosis. Methods : Sixty nine PGC patients and 22 RGC patients who underwent curative surgery were enrolled in the present study. We investigated the mathylation status of CHFR using quantitative methylation specific PCR. Using ROC curve, we defined a methylation rate of ≥ 5.5% as high group. Results : There was no significant difference in CHFR methylation rate between PGC and RGC lesions (P = 0.72). There were 17 PGC patients (24.6%) and 5 RGC patients (22.7%) with the CHFR methylation high group (P = 1.00). There was a trend towards a higher proportion of undifferentiated histology and higher clinical stage in the CHFR methylation high group, compared with the low group. On multivariate analyses, the CHFR methylation high group was found to be a significant independent prognostic factor (Hazard ratio = 3.39, 95% CI 1.14-10.11, P = 0.03). Conclusion : CHFR methylation rate was not significantly different between primary and remnant gastric cancers. But, CHFR methylation rate may be a significant independent prognostic factor in patients with gastric cancer. Univariate and multivariate analyses according to the clinicopathological factorsClinicopathological factorsVariablesUnivariate analysisMaltivariate analysisP-valueHazard ratio95%CIP-valueAge≥ 700.63GenderMale0.30TypeRemnant0.85DifferentiationUndifferentiated0.38Invasion depthT40.0042.350.66 - 9.420.19LN metastasisN(+)0.0083.460.76 - 19.290.10StageIII0.0020.920.18 - 4.620.92CHFR methylation rateHigh group0.0083.391.14 - 10.110.03 Citation Format: Kiichi Sugimoto, Alicia Hulbert, Zhihao Lu, Chen Chen, Tomoaki Ito, Hiromitsu Komiyama, Yutaka Kojima, Michitoshi Goto, Yuichi Tomiki, Hajime Orita, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock. CHFR methylation is an independent prognostic marker of poor prognosis in gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4769. doi:10.1158/1538-7445.AM2015-4769

Risk factors for survival in primary gastric cancer patients without lymph node metastasis

Risk factors for survival in primary gastric cancer patients without lymph node metastasis

Targeting mast cells in gastric cancer with special reference to bone metastases.

Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases.

Odd-skipped related 1 is a novel tumour suppressor gene and a potential prognostic biomarker in gastric cancer.

We report that the odd-skipped related 1 (OSR1) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or down-regulated in gastric cancer cell lines. OSR1 expression was also significantly down-regulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or down-regulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested the cell cycle, and induced apoptosis in the gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1-short hairpin RNA significantly enhanced cell growth, promoted the cell cycle, and inhibited apoptosis in the normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5, and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in the p53 signalling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in the Wnt/β-catenin signalling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulphite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan–Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stage I–III patients. In conclusion, OSR1 acts as a functional tumour suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of the early stage of gastric cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

D-Dimer: Not Just an Indicator of Venous Thrombosis but a Predictor of Asymptomatic Hematogenous Metastasis in Gastric Cancer Patients

BackgroundPlasma D-dimer levels have been shown to be high in advanced tumor stage patients and can be used to predict clinical outcome in cancer patients. As most advanced tumor stage patients exhibit asymptomatic metastasis, which contributes to early tumor recurrence after surgery, we hypothesized that plasma D-dimer levels can be used to predict patients with potential metastasis.MethodsWe enrolled 1042 primary gastric cancer patients in three multiple cancer centers in Northwest China and examined plasma D-dimer levels using the latex-enhanced immunoturbidimetric assay (LEIA) method. Plasma D-dimer levels were compared with the clinicopathological characteristics in this large-scale case-control study with follow up. We also performed regular follow-up studies for 395 patients to analyze the 2-year survival rate and early tumor recurrence.ResultsIn this large-scale clinical study, we found that plasma D-dimer levels were increased in patients with distant metastasis and especially hematogenous metastasis patients. The cut-off value of the D-dimer levels was determined to be 1.5 mg/ml based on the ROC curve, and the sensitivity and specificity for metastasis prediction were 61.9% and 86.6%, respectively. Additionally, patients with high D-dimer levels displayed early tumor recurrence and poor outcome during the follow-up study.ConclusionPlasma D-dimer may represent an easy to measure and lower cost marker for the testing of gastric cancer patients to predict asymptomatic hematogenous metastasis.

Impact of preoperative sarcopenia on morbidity in gastric cancer surgery.

40 Background: Skeletal muscle depletion, known as sarcopenia, is characterized by decrease in muscle mass and function. Recent reports demonstrated that sarcopenia was a significant risk factor for complications in colorectal cancer surgery. This study aimed to evaluate impact of preoperative sarcopenia on morbidity in gastric cancer surgery. Methods: Between May 2011 and June 2013, 293 consecutive primary gastric cancer patients who underwent curative surgery were retrospectively examined. All patients received the same perioperative care of enhanced recovery after surgery program. Preoperative skeletal muscle mass was evaluated by bioelectrical impedance analysis and was expressed as skeletal muscle index or SMI (muscle mass/height2) by adjusting absolute muscle mass with height. Preoperative muscle function was measured by hand grip strength (HGS). Each cutoff value was determined as the gender-specific lowest 20% of the distribution of each measurement. Grade 2 or higher morbidity, evaluated by Clavien-Dindo classification, was picked-up from the patient record. Risk factor for morbidity was examined by uni- and multi-variate analyses. Results: Median age (range) was 68 years (37-85 years). Male to female ratio was 192:101. Operative procedure was 122 total, 169 distal, and 2 proximal gastrectomy. Lymphadenectomy was 162 D1+ and 131 D2 including 53 splenectomy. Pathological stage was I in 149, II in 39, III in 91, and IV in 14 patients. Morbidity included 7 pancreatic leakage, 12 anastomotic leakage, 4 intra-abdominal abscess, and others. In total, morbidity was observed in 39 patients (13.3%); 21 in grade 2, 16 in grade 3a, 1 in grade 3b, and 1 in grade 4. No mortality was observed. Univariate analysis showed that male, total gastrectomy, splenectomy, and low HGS were significant risk factor for morbidity. Low SMI was not a risk factor. By multi-variate analysis, low HGS(HR 2.457, p=0.029), male(HR 2.610, p=0.038)and total gastrectomy(HR 2.747, p=0.027)remained significant. Conclusions: Low hand grip strength was one of significant risk factor for morbidity in gastric cancer surgery. Hand grip strength as a surgical risk has a value to be examined in the future prospective studies.

Outcomes of minimally invasive surgery for early gastric cancer are comparable with those for open surgery: analysis of 1,013 minimally invasive surgeries at a single institution

This study aimed to compare the short- and long-term results of minimally invasive surgery (MIS) and open surgery for primary early gastric cancer (EGC) at a single high-volume institution. The clinicopathologic and survival data of primary gastric cancer patients who underwent a minimally invasive radical gastrectomy at Seoul National University Hospital from December 2003 to January 2012 were retrospectively analyzed. For comparison of short-term outcomes, the data for 1,112 patients who underwent a radical open gastrectomy from 2007 to 2011 were collected. For long-term outcome analysis, the data for 962 patients who underwent a radical open gastrectomy from 2004 to 2006 were collected. Because the application of MIS was limited to suspected EGC, the control groups were similarly limited to patients deemed to have EGC as shown by preoperative endoscopy, endoscopic ultrasound, or both. The review of our database identified 1,013 patients who had undergone MIS for gastric cancer. In the short-term outcome analysis, the MIS group showed statistically better results than the open surgery group in terms of postoperative hospital stay (8.7 vs. 11.3 days; p < 0.001), estimated blood loss (75.4 vs. 142.3 ml; p < 0.001), and overall complication rate (17.5 vs. 24.4 %; p < 0.001). In the subset analysis of total gastrectomy, the local complication rate was much higher in the MIS group than in the open surgery group. Both uni- and multivariate analyses showed that not only the surgical approach but also age, chronic liver disease, chronic renal disease, and additional organ resection had significant effects on complications. In the long-term outcome analysis, the two groups showed comparable disease-free survival rates. The use of MIS for EGC showed a shorter operation time, a shorter postoperative hospital stay, and a lower overall complication rate than open surgery but a comparable disease-free survival rate. Total gastrectomy in the MIS group was associated with a higher complication rate than in the open group. Therefore, a new stable surgical technique needs to be established.

Overexpression of stathmin 1 is associated with poor prognosis of patients with gastric cancer

Recently, stathmin 1 has been proposed to function as an oncogene based on some relevant studies in multiple types of human cancers. However, the role of stathmin 1 in gastric cancer carcinogenesis has not been elucidated yet. The aim of this study was to investigate the expression of stathmin 1 as well as its association with overall survival of gastric cancer patients. The expression of stathmin 1 was detected by real-time quantitative reverse transcription polymerase chain reaction and Western blotting in gastric cancer and adjacent nontumor tissues. In addition, stathmin 1 expression was analyzed by immunohistochemistry in paraffin samples from 210 primary gastric cancer patients. The expression levels of stathmin 1 mRNA and protein in gastric cancer tissues were both significantly higher than those in adjacent nontumor tissues. In addition, the expression of stathmin 1 is correlated with Lauren's classification, depth of invasion, lymph node metastases, and tumor node metastasis (TNM) stage (all P < 0.05). Univariate analysis showed that high stathmin 1 expression was associated with poor prognosis in gastric cancer patients (P = 0.040). Multivariate analysis demonstrated that only lymph node metastasis and TNM stage were the independent prognostic indicators for gastric cancer. Stathmin 1 expression status is not an independent prognostic factor for patients with gastric cancer. Further subgroup analysis revealed that stathmin 1 expression was significantly correlated with prognosis in diffuse type gastric cancer. This research showed that the stathmin 1 overexpression might play an important role in the pathogenesis and subsequent progression of gastric cancer. Stathmin 1 could also be a potential therapeutic target in gastric cancer, especially for diffuse type gastric cancer.

Comparison of lymph node staging system in gastric cancer using time-dependent ROC analysis with Harrell’s concordance index.

12 Background: The aim this study was to clarify what the most informative pathologic lymph node staging system in gastric cancer is, by using time-dependent receiver operating characteristic (ROC) analysis with Harrell’s concordance (c) index. Methods: This study enrolled 2747 primary gastric cancer patients, without prior chemotherapy, who underwent R0 or R1 macroscopically curative resection. We calculated concordance indices of different 3 nodal staging systems (anatomical level based on JPN 13th edition vs. numbers of metastatic nodes based upon TNM 7th edition vs. ratio of metastatic nodes; derived from Yu’s definition {Yu et al. Br J Surg;1997,N0:0, N1;0-0.1, N2;0.1-0.25, N3;0.25-}) for survival. Results: (Anatomical level) Harrell’s c-index was 0.754 with 5-year survival rate of N0; 93%, N1; 73%, N2; 51%, N3; 19%. C-index without node-negative patients was 0.628. (Numbers of positive nodes) C-index was 0.767 with 5-year survival rate of N0; 93%, N1; 81%, N2; 68%, N3; 37%. C-index without node-negative patients was 0.669. (Ratio of nodal involvement) C-index was 0.770 with 5-year survival rate of N0; 93%, N1; 80%, N2; 63%, N3; 29%. C-index without node-negative patients was 0.691, which is significantly larger than those in anatomical level or numbers of positive nodes (p&lt;0.001, p=0.014, respectively). (Comparison of Staging System) If combined pT category with ratio grading system without pStage IA, new staging system is the significantly most informative (c-index; 0.760) than JPN 13th (c-index; 0.735) or TNM 7th (c-index; 0.742) (p=0.009, p=0.023, respectively). Conclusions: Lymph node staging system based on the conception of ratio of metastatic nodes is the most informative staging system than those with anatomical location or numbers of metastatic nodes. These results suggested that in gastric cancer pathologic staging system in next TNM classification should include the ratio of metastatic nodes.

Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer

Recent studies have suggested that dysregulation of autophagy plays a pivotal role in tumorigenesis. Here, we determined the prognostic value of autophagy-related protein Beclin 1 in gastric cancer. A total of 153 primary gastric cancer patients were subjected to analysis of Beclin 1 expression and survival prognosis. Among them, 68 patients were assigned randomly and used as a training set to generate a cutoff score for Beclin 1 expression by receive operating characteristic (ROC) curve analysis. The ROC-generated cutoff score was subjected to analyze the association of Beclin 1 with clinical characteristics and patient outcome. In a testing set (n = 85) and overall patients (n = 153), both univariate and multivariate analysis found that low expression of Beclin 1 predicted adverse overall survival and progression-free survival for gastric cancer patients. Furthermore, in each stage of gastric cancer patients, Beclin 1 expression was a prognostic indicator in patients with stage II, III and IV. Importantly, a reverse relationship between Beclin 1 and Bcl-xL expression was demonstrated. In patients of elevated Bcl-xL expression, a subset with lower Beclin 1 expression displayed an inferior overall survival and progression-free survival than those with higher Beclin 1 expression. Thus, our data demonstrated that low expression of Beclin 1, associated with high Bcl-xL, played as an independent biomarker, contributing to a more aggressive cancer cell phenotype and poor prognosis for gastric tumor.

Stage Migration Effect on Survival in Gastric Cancer Surgery With Extended Lymphadenectomy

The purpose of this study is to analyze the relationship between the number of examined lymph nodes (NexLN) and survival in gastric cancer and to determine whether the metastatic/examined lymph node ratio (LN ratio) system can compensate for the shortcomings of the UICC/AJCC staging. Prospective data of 8949 primary T1-T4a gastric cancer patients who underwent curative surgery were reviewed. The patients were stratified by T-stage and grouped according to NexLN; 1 to 14 exLN denoted the first group and every subsequent 10 LNs thereafter. Numbers of LN and 5-year survival rates were analyzed according to NexLN. "The NR-staging system" was generated using 0.2 and 0.5 as the cut-off values of LN ratio and then compared with UICC/AJCC stages. The proportion of advanced N-stage increased with NexLN. Survival and the LN ratio were constant regardless of NexLN when combining all N0-N3b patients, however, T2/3 and T4a patients showed an increasing tendency toward survival in N1/2 and N3a as NexLN increased, mainly due to a stage migration effect. The LN ratio system showed better patterns of distribution of the LN stage and survival graph. The power of the differential staging of the LN ratio system was fortified with higher NexLN. The relationship between NexLN and survival is probably affected by stage migration in a high-volume gastric cancer center. The LN ratio system could be a better option to compensate for this effect, and the value of the prognosis prediction in this system increases with a higher NexLN.

Sa1587 Is the Prevalence of Colorectal Adenoma Higher in Patients With Gastric Neoplasm?

Colorectal cancer is more frequently detected among primary gastric cancer patients. We aimed to compare the prevalence of colorectal adenomas between patients with gastric neoplasm and healthy controls. This study was retrospectively performed in Chung-Ang University Hospital from January 2005 through June 2010. A total of 172 patients with gastric neoplasm who underwent colonoscopy were enrolled. Age and sex matched 860 subjects without gastric neoplasm who underwent colonoscopy in health promotion center were enrolled as the controls. Various factors were evaluated such as gender, age, body mass index (BMI), abdominal circumference, and the frequency of multiple (≥2 sites), large (≥1cm) and proximal (cecum to splenic flexure) colorectal adenomas. Advanced colorectal adenoma was defined by any of the followings; (1) polyp size at least 1.0 cm, (2) containing ≥25% villous features, or high-grade dysplasia, or adenocarcinoma by histologic examination. The sex ratio was 132:40 (male: female) in the gastric neoplasm group and 662:198 in the controls. The mean age was 59.6±9.9 in the gastric neoplasm group and 57.9±10.0 in the controls. BMI and abdominal circumference were greater in the controls than in the gastric neoplasm group (23.1±2.9 vs. 24.2±2.8 and 79.7±2.9 vs. 83.7±2.8, respectively). Among 172 patients with gastric neoplasm, low grade dysplasia, high grade dysplasia, and adenomcarinoma were 54, 5, and 113 patients, respectively. The prevalence of colorectal adenoma and multiple adenomas were tended to be higher in the gastric neoplasm group than in the controls (36.9% vs. 29.9%, and 17.7% vs.12.2%, respectively, p>0.05). The prevalence of advanced, large, and proximal colon adenoma were significantly higher in the gastric neoplasm group than in the controls (11.5% vs. 3.0%, 10.8% vs. 4.5%, and 26.2% vs. 16.7%, respectively, p<0.05). These results were similar with those in the subgroup analyses among subjects without general and abdominal obesity. In the regression analyses, the odds ratios of advanced, large and proximal colon adenomas were 4.5 (95% CI 2.5-8.2), 2.3 (95% CI 1.3-3.9), and 1.6 (95% CI 1.1-2.3), respectively, in the patients with gastric neoplasm compared to the controls. The prevalence of advanced colorectal adenoma and proximal colon adenoma were significantly higher in patients with gastric neoplasm than in healthy subjects. The patients with gastric adenoma or adenocarcinoma might need more vigorous screening for colorectal adenoma.

Comparison of Two Diverse Populations, British Columbia, Canada, and Ardabil, Iran, Indicates Several Variables Associated with Gastric and Esophageal Cancer Survival

BackgroundGeographic variation and temporal trends in the epidemiology of esophageal and gastric cancers vary according to both tumor morphology and organ subsite. This study compares 1-year survival of gastric and esophageal cancers between two distinct populations: British Columbia (BC), Canada, and Ardabil, Iran.MethodsData for invasive primary esophageal and gastric cancer patients were obtained from the population-based cancer registries for BC and Ardabil. The relative survival rate was calculated using WHO Statistical Information System (WHOSIS) life-tables for each country. Chi-square and Fisher’s exact tests were used to compare survival differences between BC and Ardabil. T-tests, chi-square tests, and Fisher’s exact test were used to compare patient characteristics and tumor factors between the populations.ResultsThe overall 1-year age-standardized relative survivals for gastric cancer were 48% and 21% in BC and Ardabil, respectively (p < 0.01). The overall 1-year age-standardized relative survival for esophageal cancer was 33% and 17% in BC and Ardabil, respectively (p < 0.05). Overall and separately for each gender, age group, tumor location, and histology, there was greater 1-year survival of the gastric cancer patients in BC compared to Ardabil. For esophageal cancer; patients under age 65, patients with tumors in the middle or upper third of esophagus, and patients with squamous cell carcinoma had significantly better survival in BC than in Ardabil.ConclusionFindings of this study point to differences in disease characteristics and patient factors, not solely differences in healthcare systems, as being responsible for the survival difference in these populations.

Gastric Cardia Carcinoma is Associated with the Promoter -77T>C Gene Polymorphism of X-Ray Cross-Complementing Group 1 (XRCC1)

PurposeX-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the bas-excision repair pathway. Several single-nucleotide polymorphisms in the XRCC1 gene are identified and related with increased cancer risk development. In particular, the -77T>C polymorphism located on the promoter region relates with lung cancer risk development. The aim of this study is to analyze the -77T>C allelic frequencies in a population composed of 456 primary gastric cancer patients (GC) and 507 blood donor controls. MethodsGC patients were observed at the University of Siena, Italy; clinicopathological data and family history were available for the cancer group. The control group is composed of blood donors. Constitutional genomic DNA was PCR amplified, and XRCC1 -77T>C was detected using restriction enzyme BsrB I and analyzed in a 3% agarose gel. ResultsThe -77C>C homozygous genotype was significantly associated with increased risk of gastric cardia carcinoma (p = 0.023) with an odds ratio of 1.65 (95% confidence interval 1.14 to 2.4). In the family history stratification, we report a significant association (p = 0.043) between the -77T>C polymorphism and GC cases with familial lung cancer aggregation. ConclusionsOur results suggest that the XRCC1 -77T>C polymorphism is a relevant host susceptibility factor for gastric cardia cancer development and specific subsets of familial clustering of GC.

Characteristics of Epstein-Barr virus-associated gastric cancer: A study of 235 cases at a comprehensive cancer center in U.S.A

BackgroundEpstein-Barr virus (EBV) has been shown to be associated with gastric cancer. However, inconsistent findings have been reported regarding the distribution of EBV infected cells (in normal gastric epithelium vs. intestinal metaplastic cells vs. in neoplastic cells) and the characteristics of EBV-associated gastric cancer. Lymph node positive EBV-associated gastric cancer has not been systematically studied. The aims of this study were to evaluate EBV-associated gastric cancer, to assess the distribution of EBV infected cells including all positive lymph nodes, and to define the characteristics of EBV-associated gastric cancer.DesignThe study included primary gastric cancer patients who underwent surgical resection with no preoperative treatment at M.D. Anderson Cancer Center between 1987 and 2006. Formalin-fixed paraffin-embedded tissue from these resection specimens were assessed for EBV by in situ hybridization, the gold standard for EBV detection in tissue. EBV status was analyzed along with clinicopathologic parameters including age, gender, tumor type, lymph node status, and pathologic stage of the tumor.ResultsAmong 235 patients, 12 had intranuclear expression of EBV. EBV staining was seen only in tumor cells and no detectable EBV was observed in normal gastric mucosa, intestinal metaplasia or stromal cells. Eight of 12 patients with EBV-associated gastric cancer had regional lymph node metastasis. Of note, metastatic tumor cells in all of the involved lymph nodes of these 8 cases contained EBV. The epidemiologic data showed 11 of the 12 patients with EBV-associated gastric cancer were men, ranging in age from 54 to 78 years (mean age, 60 years; median age, 62.1 years). The age distribution for non-EBV associated gastric cancer patients ranged from 21 to 93 years (mean age, 67 years; median age, 66.4 years).ConclusionOur study demonstrated that EBV is present exclusively in gastric cancer cells. The detection of EBV in tumor cells in all of the lymph nodes involved with metastatic gastric carcinoma suggests simultaneous replication of EBV and tumor cells. The predominantly male gender and relatively younger age observed for the EBV-infected gastric cancer cases suggest an association between this disease and other factors, such as life style.