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Background: Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue., Methods: In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences., Results: Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.14-2.74). However, among the large type 3 tumors, a remarkable difference in prognosis was observed between the differentiated and undifferentiated histological types. A comparison was made between large type 3 with undifferentiated phenotype and type 4, each with 39 patients after propensity score matching. Outcomes in both groups were similar in terms of overall survival (HR 1.28; 95% CI 0.73-2.25) and relapse-free survival (HR 1.34; 95% CI 0.80-2.27). No statistically significant differences were observed in the incidence of peritoneal recurrence (35.9% vs. 46.1%, P = 0.36) and lymph node recurrence (25.6% vs. 12.8%, P = 0.15)., Conclusions: Large type 3 tumors with undifferentiated phenotype and type 4 tumors were oncologically similar. This subgroup could be considered as a new entity for future clinical trials., (© 2024. The Author(s).)

Purpose: Delay in initiating adjuvant chemotherapy (AC) after curative resection of colorectal cancer (CRC) has been reported to lead to poor prognosis, but few studies have looked at associated factors. This study aimed to identify risk factors for delay in initiating AC., Methods: Data from 200 consecutive patients who underwent curative resection and AC for stage III CRC between 2013 and 2018 were retrospectively collected and analyzed., Results: AC was initiated more than 8 weeks after surgery in 12.5% of patients (the delay group). Compared to those with no delay (the non-delay group), patients in the delay group had significantly higher rates of synchronous double cancers (2.3% vs. 16.0%, p = 0.001), preoperative bowel obstruction (10.3% vs. 32.0%, p = 0.003), laparotomy (56.0% vs. 80.0%, p = 0.02), concomitant resection (2.9% vs. 24.0%, p < 0.001), and postoperative complications (32.0% vs. 56.0%, p = 0.02), and a significantly longer length of hospital stay (median 12 vs. 30 days, p < 0.001). In multivariate analysis, synchronous double cancers (odds ratio 10.2, p = 0.008), preoperative bowel obstruction (odds ratio 4.6, p = 0.01), concomitant resection (odds ratio 5.2, p = 0.03), and postoperative complications of Clavien-Dindo grade ≥ IIIa (odds ratio 4.0, p = 0.03) were identified as independent risk factors for delay in initiating AC., Conclusion: Careful preoperative treatment planning for CRC patients with synchronous double cancers, preoperative bowel obstruction, and concomitant resection, and management for postoperative complication are necessary to avoid delay in initiating AC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis., Methods: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006., Results: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3-4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively., Conclusions: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: The number of patients who die from causes other than gastric cancer after R0 resection is increasing in Japan, due in part to the aging population. However, few studies have comprehensively investigated the clinicopathological risks associated with deaths from other causes after gastrectomy. This study aimed to build a risk score for predicting such deaths., Methods: We retrospectively reviewed clinical data for 3575 patients who underwent gastrectomy for gastric cancer at nine institutions in Japan between January 2010 and December 2014., Results: The final study population of 1758 patients were assigned to Group A (n = 187): patients who died from other causes within 5 years of surgery, and Group B (n = 1571): patients who survived ≥ 5 years after surgery. Multivariate analysis identified nine characteristics as risk factors for poor survival: age ≥ 75 years, male sex, body mass index < 22 kg/m 2 , Eastern Cooperative Oncology Group Performance Status (≥ 1), diabetes mellitus, cardiovascular/cerebrovascular disease, other malignant diseases, preoperative albumin level < 3.5 g/dL, and total gastrectomy. Patients with risk scores of 0-2, 3-4, or 5-9 (based on 1 point per characteristics) were classified into Low-risk, Intermediate-risk, and High-risk groups, respectively. The 5-year survival rates were 96.5%, 85.3%, and 56.5%, for the Low-, Intermediate-, and High-risk groups, respectively, and the hazard ratio (95% confidence intervals) was 16.33 (10.85-24.58, p < 0.001) for the High-risk group., Conclusions: The risk score defined here may be useful for predicting deaths from other causes after curative gastrectomy., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Nivolumab monotherapy has demonstrated superior efficacy in advanced unresectable gastric cancer (GC), but its impact on resectable GC remains unknown. This phase I study aimed to evaluate safety, feasibility, and potential biomarkers of neoadjuvant nivolumab monotherapy in resectable GC., Methods: Untreated, resectable, cT2 or more advanced gastric adenocarcinomas with clinical stage I, II, or III were treated with two doses of nivolumab before gastrectomy. Patients were excluded if their tumors may be applicable to neoadjuvant chemotherapy. The primary endpoint was the incidence of adverse event (AE) categories of special interest., Results: All of the 31 enrolled patients completed 2 doses of nivolumab monotherapy. While 30 (97%) patients underwent surgery with curative intent, 1 patient discontinued before the planned surgical intervention because of a newly emerging liver metastasis. Seven patients (23%) had nivolumab treatment-related AEs, and one patient had a treatment-related AE of grade 3-4. The incidences of treatment-related AE categories of special interest ranged from 0 to 6%. Notable surgical complications included two cases of grade 3 anastomotic leakage and two cases of pancreatic fistula. The major pathologic response (MPR) assessed by the independent pathology review committee was achieved in five (16%) patients, of which one patient had a pathologic complete response. The MPR was mostly observed in patients with positive PD-L1 expression, high microsatellite instability, and/or high tumor mutation burden., Conclusions: Neoadjuvant nivolumab monotherapy is feasible with an acceptable safety profile and induces a MPR in certain patients with resectable GC. (Registration: clinicaltrials.jp, JapicCTI-183895)., (© 2022. The Author(s).)

Background: Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer., Methods: Patients aged 20-75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS)., Results: Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% [95% confidence interval (CI)  54.1-69.6] in Arm A and 60.9% (95% CI  52.7-68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI  0.679-1.236)., Conclusions: For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment.

Background: Recent studies have found a negative impact of postoperative complications on long-term survival outcomes, but it has not been confirmed by data obtained from a prospective study with a large sample size. This study investigated the impact of postoperative complications on long-term survival outcomes, and considered the optimal definition of complication, using data from JCOG1001, which compared bursectomy and non-bursectomy for patients with cT3/4a locally advanced gastric cancer., Methods: This study included 1191 of 1204 patients enrolled in the JCOG1001 trial. Complications were graded by Clavien-Dindo (C-D) classification. Impact of the grade (≥ C-D grade II or ≥ grade III) or type (any or intra-abdominal infectious) of complication on survival outcome was evaluated by univariate and multivariable analyses using the Cox proportional hazard model., Results: The incidence of any ≥ C-D grade II and ≥ grade III complication was 23.0% and 9.7%, respectively, and that of ≥ grade II and ≥ grade III intra-abdominal infectious complication was 13.4% and 6.9%, respectively. Multivariable analysis showed all four definitions of complications were independent prognostic factors for overall survival. Conversely, only  any ≥ C-D grade III complication was found to be an independent prognostic factor for relapse-free survival (hazard ratio, 1.445; 95% confidence interval, 1.026-2.036; P = 0.035)., Conclusions: Postoperative complications adversely affect the long-term survival outcomes of patients with cT3/4a gastric cancer. Any ≥ C-D grade III complication seems to be the most suitable definition of complication for predicting negative long-term survival outcomes.

Background: Few well-controlled studies have compared postoperative complications between Billroth I (B-I) and Roux-en-Y (R-Y). The aim of the present study was to compare the incidence of overall and severe postoperative complications by reconstruction method after distal gastrectomy., Methods: We performed a multi-institutional dataset study of patients who underwent distal gastrectomy with B-I or R-Y reconstruction from 2010 to 2014. Using propensity scores to strictly balance the significant variables, we compared postoperative complications between the techniques., Results: After matching, we enrolled 1014 patients (n = 507 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (29% vs 17%, P < 0.0001). The incidence of intra-abdominal abscess (4.3% vs 1.8%, P = 0.0177), bowel obstruction (2.6% vs 0.6%, P = 0.0203), and delayed gastric emptying (5.3% vs 1.0%, P < 0.0001) in the R-Y group was significantly higher vs the B-I group, respectively; we saw no significant difference in leakage (3.4% vs 4.1%, P = 0.5084). The incidence of grade ≥ III severe postoperative complications in the R-Y group was significantly higher vs the B-I group (13% vs 7.1%, P = 0.0013). Multivariable analysis showed that R-Y reconstruction was a strong independent risk factor for overall postoperative complications (odds ratio 1.58, P = 0.0044) and grade ≥ III severe postoperative complications (odds ratio 1.75, P = 0.0127). A forest plot revealed that R-Y reconstruction was associated with a greater risk of both overall and grade ≥ III severe postoperative complications in any subgroups., Conclusions: R-Y reconstruction was associated with increasing overall postoperative complications, as well as severe postoperative complications.

Background: Preoperative chemotherapy with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis. In the JCOG1002, we added docetaxel to CS (DCS) to further improve long-term outcomes. However, the primary endpoint, clinical response rate (RR), did not reach the expected level (Ito et al. in Gastric Cancer 20:322-31, 2017). Herein, we report our long-term survival results., Methods: Patients with BN and/or PAN metastasis received 2 or 3 cycles of DCS therapy (docetaxel at 40 mg/m 2 and cisplatin at 60 mg/m 2 on day 1 and S-1 at 80 mg/m 2 per day for 2 weeks, followed by a 2-week rest) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year., Results: Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% had both PAN and BN metastasis, and the rest had either PAN (26.4%) or BN (56.6%) metastasis. Among all eligible patients, the 5-year overall survival was 54.9% (95% confidence interval 40.3-67.3%) at the last follow-up in May 2018. Among 44 eligible patients with R0 resection, the 5-year relapse-free survival was 47.7% (95% confidence interval 32.5-61.5%)., Conclusions: Adding docetaxel to CS in preoperative chemotherapy for extensive nodal metastasis improved neither short-term outcomes nor long-term survival. Preoperative chemotherapy with CS followed by D2 + PAN dissection and postoperative S-1 remains the standard of care for patients with extensive nodal metastasis.

Background: This study aimed to evaluate whether the timing of initiating postoperative chemotherapy with S-1 monotherapy affects gastric cancer patients' prognosis., Methods: A multi-institution dataset identified patients with pStage II or III gastric cancer who received S-1 monotherapy for over 6 months after curative resection between 2010 and 2014. Patients were divided into three groups based on the timing of S-1 monotherapy initiation. Prognostic factors for relapse-free survival (RFS) were investigated., Results: We classified 401 patients into groups as follows: S-1 administered within 6 weeks (n = 247), between 6 and 8 weeks (n = 95), and after 8 weeks (n = 59). The RFS times were not significantly different in the within 6 weeks group and the between 6 and 8 weeks group, but the after 8 weeks group had a shorter RFS time compared with the other two groups (within 6 weeks group vs. after 8 weeks group; P = 0.0044). By disease stage, this trend was the same. The multivariable analysis showed that a larger tumor size (≥ 50 mm), pStage III, and the after 8 weeks group were independent prognostic factors for RFS (after 8 weeks group: hazard ratio, 2.05; P = 0.0069). The prevalence of hematogenous metastasis as the initial recurrence site increased by delayed initiation of S-1. A forest plot revealed that delayed administration after 8 weeks was associated with a greater risk of recurrence in most subgroups., Conclusions: Postoperative chemotherapy with S-1 monotherapy for gastric cancer is recommended to begin within 8 weeks after surgery.

Background: The prognostic significance of the number of retrieved lymph nodes (RLNs) in gastric cancer remains controversial. Therefore, we designed a multicenter collaborative database to investigate the correlation between the number of RLNs and prognosis of patients with advanced gastric cancer after curative resection., Methods: We retrospectively analyzed 1103 patients who underwent gastrectomy for stage II/III gastric cancer between 2010 and 2014. Lymph nodes, which were retrieved by surgeons from surgically resected specimens, were validated by pathologists. A target population and the optimal cutoff were determined using receiver operating characteristic (ROC) curve analysis. After propensity score matching of eight variables, including splenectomy and adjuvant chemotherapy, the prognostic significance of RLNs was evaluated., Results: According to ROC curve analysis, the optimum cutoff score for predicting postoperative survival was 40. After matching, the backgrounds of patients in the RLN < 40 and RLN ≥ 40 groups (n = 87 each) became well-balanced. The RLN < 40 group experienced significantly shorter relapse-free and overall survival. The prevalence of peritoneal recurrence was significantly increased in the RLN < 40 group. RLN < 40 was an independent prognostic factor in multivariable analysis, although pathological N status was not. A forest plot revealed that the RLN < 40 group was at greater risk of recurrence in most subgroups., Conclusions: RLN < 40 was associated with an adverse prognosis of patients with stage III gastric cancer who underwent total gastrectomy.

Background: Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer., Methods: We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways., Results: ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04-6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (P interaction  = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed., Conclusion: The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.

Background: Neoadjuvant chemotherapy (NAC) followed by radical surgery is a promising strategy to improve survival of patients with stage III gastric cancer, but is associated with the risk of preoperative overdiagnosis by which patients with early disease may receive unnecessary intensive chemotherapy., Methods: We assessed the validity of a preoperative diagnostic criterion in a prospective multicenter study. Patients with gastric cancer with a clinical diagnosis of T2/T3/T4, M0, except for diffuse large tumors and extensive bulky nodal disease, were eligible. Prospectively recorded clinical diagnoses (cT category, cN category) were compared with postoperative pathological diagnoses (pT category, pN category, and pathological stage). The primary endpoint was the proportion of pathological stage I tumors among those diagnosed as cT3/T4, which we expected to be 5% or less., Results: Data from 1260 patients enrolled from 53 institutions were analyzed. The proportion of pathological stage I tumors in those with a diagnosis of cT3/T4 (primary endpoint) was 12.3%, which was much higher than the prespecified value. The positive predictive value and the sensitivity for pathological stage III tumors were 43.6% and 87.8% respectively. The sensitivity and specificity of contrast-enhanced CT for lymph node metastasis were 62.5% and 65.7% respectively. After exploring several diagnostic criteria, we propose, for future NAC trials in Japan, a diagnosis of "cT3/T4 with cN1/N2/N3," by which inclusion of pathological stage I tumors was reduced to 6.5%, although its sensitivity for pathological stage III tumors decreased to 64.5%., Conclusion: Clinical diagnosis of T3/T4 tumors was not an optimal criterion to select patients for intensive NAC trials because more than 10% of patients with pathological stage I disease were included. We propose the criterion "cT3/T4 and cN1/N2/N3" instead.

Background: Postoperative malnutrition after gastrectomy is deemed inevitable, which could have prejudicial influence on survival for gastric cancer patients. A prospective feasibility study was conducted to evaluate the efficacy of postoperative oral nutritional supplements., Methods: Stage I-III gastric cancer patients who underwent distal or total gastrectomy received oral administration of Racol ®  NF (Otsuka Pharmaceutical Factory, Japan), a liquid enteral nutritional formula, as a supplement to regular meals. Racol ®  NF administration at a recommended dosage of 400 kcal/400 ml per day was started within 7 days postoperatively and was continued for 3 months postoperatively. The primary end point was ratio of the weight loss at 3 months postoperatively to the preoperative body weight (body weight loss ratio). Secondary end points were the adherence to Racol ®  NF therapy and changes in body composition., Results: One hundred eighteen patients were registered before surgery, 82 of whom were eligible for efficacy analyses. The average rate of body weight loss after 3 months postoperatively was 8.3%. The mean daily intake of Racol ®  NF was 211 ml. There was a significant correlation between adherence to Racol ®  NF therapy and body weight loss ratio (P < 0.001). Adherence to Racol ®  NF therapy was the only factor that correlated with the body weight loss ratio among all clinical characteristics by the multiple linear regression analysis (P = 0.007)., Conclusions: Oral nutritional supplementation with Racol ®  NF led to a significant reduction in body weight loss for gastrectomized patients who tolerated more than 200 ml of the nutrient per day compared with those who could not tolerate this amount.

Background: Gastric cancer with extensive lymph node metastasis is commonly considered unresectable, with a poor prognosis. We previously reported the results of the use of cisplatin and S-1 as preoperative chemotherapy for gastric cancer with extensive lymph node metastasis; docetaxel, cisplatin, and S-1 (DCS) have now been investigated for the same purpose., Methods: Patients received two or three 28-day cycles of DCS therapy (docetaxel at 40 mg/m 2 and cisplatin at 60 mg/m 2 on day 1, S-1 at 40 mg/m 2 twice daily for 2 weeks) followed by gastrectomy with D2 plus para-aortic nodal dissection. After R0 resection, S-1 chemotherapy was given for 1 year. The primary end point was the response rate (RR) to preoperative chemotherapy determined by central peer review according to the Response Evaluation Criteria in Solid Tumors version 1.0. The planned sample size was 50, with one-sided alpha of 10 %, power of 80 %, expected RR of 80 %, and threshold of 65 %., Results: Between July 2011 and May 2013, 53 patients were enrolled, of whom 52 were eligible. The clinical RR was 57.7 % [30/52, 80 % confidence interval 47.9-67.1 %, p = 0.89], and R0 resection was achieved in 84.6 % of patients (44/52). Common grade 3 or grade 4 adverse events during DCS therapy were leukocytopenia (18.9 %), neutropenia (39.6 %), and hyponatremia (15.1 %). The common grade 3 or grade 4 surgical morbidity was abdominal infection (10.2 %). The pathological RR was 50.0 % (26/52)., Conclusions: Preoperative DCS therapy was feasible but did not show a sufficient RR. Preoperative cisplatin and S-1 therapy is still considered the tentative standard treatment for this population until survival results are known.

Background: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer., Methods: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m 2 twice daily on days 1-14, plus intravenous oxaliplatin 130 mg/m 2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate., Results: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9-72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4-78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77-91 %). No new safety signals were identified., Conclusions: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

Background: Gastric cancer (GC) is highly influenced by aberrant methylation, and accumulation of aberrant methylation in gastric mucosae produces an epigenetic field for cancerization. Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC., Methods: A transcription start site was determined by the 5' rapid amplification of complementary DNA ends method. DNA methylation was analyzed by bisulfite sequencing with use of a next-generation sequencer or quantitative methylation-specific PCR. Gene expression was analyzed by quantitative reverse transcription PCR., Results: A single transcription start site was identified for FAT4 in gastric epithelial cells, and a CpG island was located in the FAT4 promoter region. FAT4 was highly methylated in two of 13 GC cell lines and was not expressed in them. Removal of FAT4 methylation by a DNA demethylating agent (5-aza-2'-deoxycytidine) restored its expression in the two cell lines. In primary GC samples, FAT4 was methylated in 12 of 82 GCs (14.6 %). FAT4 methylation was associated with the presence of the CpG island methylator phenotype but not with prognosis, tumor invasion, lymph node metastasis, or histological types. In noncancerous gastric mucosae, high FAT4 methylation levels were associated with the presence of GC and Helicobacter pylori infection., Conclusions: FAT4 was methylation-silenced in GCs. Its methylation in gastric mucosae was associated with H. pylori infection and likely contributed to epigenetic field cancerization.

Background: The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated a survival benefit by adjuvant S-1 monotherapy in patients who had undergone curative resection of stage II/III gastric cancer, but there is still a need to improve the efficacy of treatment of stage III disease. We investigated the tolerability and safety of S-1 and oxaliplatin as adjuvant chemotherapy for stage III gastric cancer., Methods: Japanese patients with stage III gastric cancer who had undergone D2 or more extensive lymphadenectomy were enrolled. In the first cycle, S-1 (40-60 mg/m 2 twice daily) alone was given orally for 2 weeks of a 3-week cycle. From the second cycle, S-1 was administered as in the first cycle and oxaliplatin (100 mg/m 2 ) was infused intravenously on day 1. Treatment was continued for 8 cycles. The primary end point was the treatment completion rate for eight cycles., Results: Sixty-three patients were enrolled and 62 patients were included in analysis. The treatment completion rate was 74.2 %, which was higher than the expected completion rate of 72.0 %. The median relative dose intensities were 77.1 % for S-1 and 72.6 % for oxaliplatin, with 41.9 and 61.7 % patients requiring dose reduction of S-1 and oxaliplatin, respectively. Neutropenia was the only grade 3 or higher adverse event with an incidence 10 % or greater (32.3 %). There was no grade 3 or higher peripheral sensory neuropathy or treatment-related death., Conclusions: S-1 and oxaliplatin therapy is suggested to be manageable and safe with optimal dose reduction and delay in selected patients for stage III gastric cancer after D2 gastrectomy, and warrants further evaluation in larger studies.

Background: Total gastrectomy has detrimental effects on postoperative nutritional status and quality of life (QOL), but it is often unavoidable in the treatment of gastric cancer. Roux-en-Y (RY) is the most common reconstruction method following total gastrectomy. Trials to explore other means of reconstruction have been conducted but have failed to identify a method that is globally accepted., Methods: Aboral pouch reconstruction (AP), in which an anisoperistaltic jejunal pouch is created in the Y limb of the RY reconstruction, is considered effective and technically feasible. A prospective randomized trial was conducted to compare AP with RY. Gastric cancer patients requiring total gastrectomy for R0 resection were randomly assigned during surgery to receive either RY (n = 51) or AP (n = 49). Postoperative QOL as assessed by the EORTC QLQ-C30 and STO22, body composition, and morbidity were compared between the two reconstruction methods. The physical functioning score of the QLQ-C30 was selected as the primary endpoint., Results: The incidences of postoperative complications were similar between the two groups (29 % in the RY group and 27 % in the AP group). No significant difference was observed in the physical functioning score, and the superiority of AP was demonstrated only for the nausea and vomiting score at 12 months (p = 0.041) and the reflux score at 1 month (p = 0.036). No significant differences were observed in body composition or serum biochemistry., Conclusions: Although AP was safely implemented, no increased benefits in nutritional or QOL-related parameters were observed for this method over RY within 12 months postoperatively.

Background: The aim of this study was to explore whether a combination of S-1 and paclitaxel offers any benefit over paclitaxel alone to patients pretreated by S-1., Methods: Gastric cancer patients who developed progression during S-1-based first-line chemotherapy or had recurrence during postoperative adjuvant chemotherapy by S-1 were randomly assigned to receive second-line treatment either by weekly administration of paclitaxel at 80 mg/m(2) three times every 4 weeks or daily oral S-1 (80 mg/m(2)) for 2 weeks plus paclitaxel (50 mg/m(2)) given on days 1 and 8, every 3 weeks (S-1 plus paclitaxel). The primary endpoint was progression-free survival (PFS) at 4 months after the initiation of treatment., Results: A total of 78 patients were eligible for efficacy analyses-40 were assigned to the paclitaxel group and 38 to the S-1 plus paclitaxel group. PFS at 4 months was similar between the groups (50 % for paclitaxel vs 55 % for S-1 plus paclitaxel, P = 0.641). There were no differences between the groups either in progression-free survival (4.6 vs 4.6 months, respectively, P = 0.526), overall survival (10.0 vs 10.0 months, respectively, P = 0.464), or overall response rate (27 vs 22 %, respectively, P = 0.767). The incidences of grade 3 or 4 hematological and non-hematological toxicities were also equivalent between the two groups (25 vs 26 % and 24 vs 26 %, respectively)., Conclusions: No benefit of S-1 administration beyond progression was shown when paclitaxel was selected as the key drug for second-line chemotherapy.

Backgrounds: The aim of this study was to evaluate the theoretical therapeutic impact of dissecting each lymph node station for adenocarcinoma and squamous cell carcinoma of the esophagogastric junction., Methods: This multicenter study included 431 junctional cancer patients (381 adenocarcinomas and 50 squamous cell carcinomas) who fulfilled the following criteria: (1) the center of the tumor was located between 1 cm above and 2 cm below the esophagogastric junction, and (2) the tumor invaded the junction. The theoretical therapeutic impact of dissecting each lymph node station was evaluated based on the therapeutic value index calculated by multiplying the frequency of metastasis to each station and the 5-year survival rate of patients with metastasis to that station., Results: The 5-year overall survival rates (95% confidence interval) were 60.4% (55.1-65.7) in the adenocarcinoma cases and 52.3% (35.6-69.0) in the squamous cell carcinoma cases. The nodal stations showing the first to fifth highest index were the paracardial and lesser curvature nodes (nos. 1, 2 and 3), nodes at the root of the left gastric artery (no. 7) and lower mediastinal lymph nodes, regardless of the histology., Conclusions: Nodal dissection achieved by proximal gastrectomy and lower esophagectomy should be the minimal requirement for junctional cancer regardless of the histology, considering the therapeutic value indices for the relevant lymph node stations.

Background: Despite recent clinical trials, the sensitivity and resistance of metastatic gastric cancer to anti-HER2 and anti-EGFR therapy are still unclear., Materials and Methods: To clarify the HER2 and EGFR expression status in the metastatic sites, we immunohistochemically compared HER2 and EGFR expression between primary and metastatic tumors from 52 gastric cancer patients with liver metastases and 85 patients with peritoneal metastases., Results: The HER2 positivity rate of primary and metastatic tumors in patients with liver metastases, especially with intestinal-type histology (70.6 and 80.0 %, respectively), was significantly higher than in primary and metastatic tumors (22.4 and 16.4 %, respectively) in patients with peritoneal metastases. HER2 positivity of the primary tumor and liver metastases showed good concordance (87.5 %) in patients with liver metastases. In contrast, the EGFR positivity rate of metastatic tumors (70.1 %) in patients with peritoneal metastases was significantly higher than that of metastatic tumors (37.5 %) in patients with liver metastases. HER2 and EGFR expression tended to be mutually exclusive, and HER2/EGFR double-positive cases were rare in patients with liver or peritoneal metastases. In four such patients with HER2/EGFR double-positive primary tumors, the HER2- and EGFR-positive areas were separate, and corresponding liver metastasis was only positive for HER2 and peritoneal metastasis only positive for EGFR., Conclusion: These results indicate that HER2 and EGFR are preferentially expressed in the liver and peritoneal metastases, respectively, which would be potential targets for anti-HER2 and anti-EGFR molecular therapy in metastatic gastric cancer patients.

Background: The aim of this study was to compare the postoperative health-related quality of life (HRQOL) between open and laparoscopic distal gastrectomy., Methods: A multi-institutional nonrandomized study was conducted. Patients with clinical T1 gastric cancer were prospectively enrolled and underwent distal gastrectomy by either the open or laparoscopic approach. HRQOL was measured using the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 and the site-specific module for gastric cancer. Questionnaires were completed at baseline and at 1, 3, 6, and 12 months postoperatively. Clinicopathological characteristics and short-term outcome including postoperative morbidity and HRQOL were compared between the approaches., Results: A total of 145 patients (open, n = 72; laparoscopic, n = 73) were enrolled between September 2008 and January 2011 and analyzed. The laparoscopic approach was associated with longer operating time, less blood loss, and a similar incidence of postoperative complications. At each time point, the questionnaires were retrieved from more than 90 % of the patients. The worst scores for most of the scales were observed at 1 month postoperatively and improved thereafter. No statistically significant differences were observed regarding physical functioning, the primary endpoint. On the other hand, role, emotional, cognitive, and social functioning scores were superior in the laparoscopic group at 6 and 12 months postoperatively. Symptom scales including fatigue, pain, eating restriction, taste problems, and anxiety were better in the laparoscopic group before 6 months but not at 12 months., Conclusions: The study was considered to be negative because no benefit of the laparoscopic approach was observed in terms of physical functioning. However, more favorable scores for some of the symptom scales during the first 6 months and several functioning scales at 12 months after surgery suggest a potential benefit of the laparoscopic approach.

Background: The standard of care for stage II/III gastric cancer in Japan is D2 dissection followed by adjuvant S-1 monotherapy. Outcome of patients with stage III disease remains unsatisfactory, calling for a more intensive adjuvant chemotherapy regimen, for which evidence in advanced/metastatic cancer research suggests S-1/cisplatin (CDDP) as a candidate. Although S-1/CDDP was poorly tolerated postoperatively in the previous trial, compliance was dramatically improved by insertion of one cycle of S-1 monotherapy, which delayed administration of CDDP by 6 weeks., Methods: A feasibility study of post-gastrectomy S-1/CDDP was performed. Patients with stage III/IV gastric cancer were eligible. The first cycle of chemotherapy consisted of S-1 monotherapy, and intensive antiemetic drugs were prescribed when patients were administered CDDP. The primary endpoint was the completion rate of four cycles of S-1/CDDP. The secondary endpoints were the relative dose intensity, safety, progression-free survival time and overall survival time. Several criteria to skip, postpone or reduce the dose had been predetermined., Results: Between 2010 and 2011, 33 patients were enrolled. Four patients had stage IIIA disease, 7 patients had stage IIIB disease, 11 patients had stage IIIC disease, and 11 patients had stage IV disease. The completion rate of the protocol treatment was 60.6%. The relative dose intensity of S-1 was 77.3% and that of CDDP was 72.3%., Conclusions: The protocol-specified delay in the administration of CDDP dramatically improved the relative drug intensity in the postoperative adjuvant setting, although the completion rate did not reach the expected level.

Liver metastases from gastric cancer are rarely indicated for surgery because they are often diagnosed as multiple nodules occupying both lobes and coexist with extra hepatic disease. A literature search identified no clinical trials on hepatectomy for this disease; only retrospective studies of a relatively small number of cases collected over more than a decade, mostly from a single institution, were found. Five-year survival rates from these reports ranged from 0 % to 37 %, and long-term survivors were observed among carefully selected case series. The most commonly reported prognostic factor was the number of metastatic nodules, and patients with a solitary metastasis tended to have superior outcome. Patients diagnosed to have a small number of metastatic nodules by modern imaging tools could be indicated for surgery. Because both intrahepatic and extrahepatic recurrences are common,patients are likely to benefit from perioperative adjuvant chemotherapy, although it is not possible at this time to specify which regimen is the most appropriate

Background: We previously reported that S-1 plus cisplatin was feasible as adjuvant chemotherapy for stage III gastric cancer after D2 gastrectomy. Herein we evaluate the recurrence-free survival and overall survival rates as secondary endpoints based on updated follow-up data., Methods: Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Treatment consisted of 3 cycles of S-1 (40 mg/m(2) PO) twice daily on days 1-21 and cisplatin (60 mg/m(2) IV) on day 8, and S-1 was given on days 1-28 every 6 weeks until 1 year after surgery., Results: From August 2007 to September 2009, 63 patients were accrued. Overall, 34 and 25 patients had stage IIIA and IIIB disease, respectively. After a median follow-up of 3.9 years, 16 patients experienced recurrence and 11 patients died. The 3-year recurrence-free survival rate was 74.1 % (95 % CI: 60.8-83.5 %, IIIA 81.8 %, IIIB 64.0 %). The 3-year overall survival rate was 84.5 % (95 % CI: 72.3-91.6 %, IIIA 87.9 %, IIIB 80.0 %). Recurrence sites included the peritoneum (n = 8), hematogenous sites (n = 6), and lymph nodes (n = 4)., Conclusion: The present results indicate that adjuvant therapy with S-1 plus 3 cycles of cisplatin may provide a survival benefit to patients with stage III gastric cancer.

Background: The purpose of this study was to evaluate the impact of human epidermal growth factor receptor 2 (HER2) status and trastuzumab treatment on the prognosis of patients with advanced gastric cancer (AGC)., Methods: We retrospectively analyzed 364 AGC patients who received systemic chemotherapy. To evaluate the impact of trastuzumab exposure during any type of chemotherapy, our analysis used time-varying covariates to avoid a possible lead-time bias., Results: Among the 364 patients, 58 (15.9 %) were HER2-positive. The median overall survival of the HER2-positive patients treated with trastuzumab (n = 43) was significantly longer than that of the HER2-negative patients [n = 306; 24.7 vs. 13.9 months, with an adjusted hazard ratio (HR) of 0.58; 95 % confidence interval (CI), 0.36-0.95; P = 0.03]. Notably, 22 patients continued with trastuzumab beyond the date of progression. By contrast, the HER2-positive patients not treated with trastuzumab (n = 15) showed survival similar to that of the HER2-negative patients (13.5 vs. 13.9 months, with an adjusted HR of 1.04; 95 % CI, 0.52-2.11; P = 0.91). According to the multivariate analysis, exposure to trastuzumab was independently associated with a better prognosis (HR 0.56; 95 % CI; 0.33-0.93; P = 0.026)., Conclusions: Recent HER2-positive AGC patients have a better prognosis than HER2-negative patients, particularly when treated with trastuzumab.

Background: Poorly differentiated signet-ring cell carcinoma (SRCC) and non signet-ring cell carcinoma (NSRCC) are prevalent histological subtypes of gastric cancers with distinct morphological features. To date, however, the molecular basis of their growth, differentiation, and metastasis still remains unclear, because of the limitation of available cell lines., Methods: In the present study, we established novel SRCC and NSRCC cell lines (designated GPM-2 and GPM-1) derived from the ascites of two individual gastric cancer patients with peritoneal metastasis., Results: Immunohistochemical and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that GPM-2 cells showed both gastric and intestinal differentiation phenotypes (E-cadherin+/MUC5AC+/MUC6+/Villin+), and formed xenografted tumors with typical SRCC histology in nude mice. In contrast, GPM-1 cells only weakly expressed differentiation markers, showing a phenotype of E-cadherin(low)+/MUC2-/MUC5AC-/Villin(low)+. Characteristically, GPM-2 cells were found to highly express both membrane-bound mucin (MUC1/MUC4) and secreted mucin glycoproteins (MUC5AC/MUC6), whose expression is regulated by an epigenetic mechanism such as histone acetylation. GPM-2 cells also secreted a large amount of sTn antigen into the culture medium. These mucin profiles of GPM-2 cells are distinct from those of conventional SRCC cell lines (KATO III and HSC-39), which preferentially express intestinal MUC2/MUC4 as well as sLe(x) and sLe(A) antigens. In addition, GPM-2 cells showed a slow growth rate, and a lower metastatic potential than GPM-1 cells., Conclusions: These results indicate that the cells of the new SRCC line, GPM-2 cells, are more differentiated and less aggressive than NSRCC-type GPM-1 cells, and would thus offer an excellent model for understanding the molecular mechanism underlying the growth, differentiation, and mucin production of an SRCC gastric cancer cell line.

Background: In gastric cancer patients who have positive results for peritoneal lavage cytology the disease is defined as CY1, and classified as stage IV, and this population has generally suffered a dismal outcome. For this population, we had conducted a phase II trial, with the 2-year survival rate as the primary endpoint, to test the strategy of D2 dissection followed by chemotherapy with single-agent S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium). Forty-eight patients were enrolled, of whom 47 were found to have been eligible for analysis. The 2-year survival rate of 46 % exceeded our expectations., Methods: Further follow up was conducted to confirm whether radical surgery could be recommended for the CY1 population., Results: The 5-year overall and relapse-free survival rates were 26 and 21 %, respectively., Conclusions: Gastrectomy with curative intent could be considered for patients with CY1 disease provided they are scheduled to receive effective postoperative chemotherapy.

Background: Laparoscopy-assisted gastrectomy (LAG) is an advanced surgery that requires the mastery of complex surgical skills. We evaluate the feasibility of LAG with systemic lymph node dissection when participating surgeons have sufficient knowledge and experience to conduct open surgery for gastric cancer and basic laparoscopic skills., Methods: All operations were performed by two Japan Surgical Society board-certified attending surgeons who had performed over 50 conventional gastrectomies and 30 laparoscopic cholecystectomies. The surgeons went through an established program, including training at the wet and dry laboratories. In addition, surgeries for the first 10 cases were assisted by an expert surgeon with experience of >300 cases. To be eligible for the LAG procedure, patients had to have a preoperative diagnosis of T1, N0 and M0 gastric carcinoma. The morbidity rate was used as the study endpoint. Variables such as operating time, intraoperative blood loss and number of retrieved lymph nodes were evaluated as complementary surgical endpoints. These variables were compared between the first 25 cases and the latter 25 cases., Results: A total of 50 patients who were scheduled to undergo LAG were prospectively enrolled between 2005 and 2008. Morbidity rate was 4% (2/50), with one case due to intestinal injury and one case due to an intra-abdominal abscess. Complications related to laparoscopy were observed in 2% (1/50), with one case of mesenteric injury. The conversion rate to laparotomy was 6% (3/50). However, there were no serious consequences in converted cases. The operating time was 263.7 ± 45.0 min. The intraoperative blood loss was 94.5 ± 106.5 g. The total number of regional lymph nodes retrieved was 34.7 ± 12.2. A significant improvement in the blood loss was only noted after the first 25 procedures. All patients are alive and disease-free after a median follow-up of 38.8 months., Conclusion: An adequate training program, including site visits by expert surgeons, in conjunction with basic laparoscopy skills and solid backgrounds in open gastrectomy from the perspective of the trainees are currently key to the successful and safe implementation of LAG. Whether the procedure is oncologically feasible remains to be confirmed by long-term follow-up.

Background: Although fluoropyrimidines, platinum agents, taxanes, and irinotecan are used in the treatment of advanced gastric cancer (AGC), it remains unclear whether these agents in any line of chemotherapy are associated with overall survival (OS) in these patients., Methods: We retrospectively analyzed 704 patients with AGC. To avoid possible lead-time bias, we applied time-varying covariate analysis for chemotherapy with four agents in any line., Results: Median OS was 12.3 months. The frequency of exposure to each agent class during all lines of treatment was 92.6% for FU (5-fluorouracil or oral fluoropyrimidine), 48.2% for platinum agents, 65.1% for taxanes, and 39.1% for irinotecan. According to a multivariate Cox model with exposure to each agent class as a time-varying covariate, the hazard ratios (HRs) of death were 0.41 (95% confidence interval [CI], 0.27-0.57; p < 0.001) for FU, 0.71 (95% CI, 0.58-0.84; p < 0.001) for platinum agents, 0.51 (95% CI, 0.41-0.63; p < 0.001) for taxanes, and 0.53 (95% CI, 0.43-0.65; p < 0.001) for irinotecan. Although other agents were used in 18.6% of the patients, they did not affect survival., Conclusions: Each of the four agent classes (FU, platinum agents, taxanes, and irinotecan) appears to be independently associated with improved OS in patients with AGC regardless of timing. This result suggests the importance of developing strategies which make these active agents available to all patients with AGC to prolong OS.

Background: The clinical significance of isolated tumor cells (ITC) detected immunohistochemically in the lymph nodes of gastric cancer patients is controversial. The aim of this study was to examine the prognostic impact of ITC in patients with gastric cancer., Methods: The data of a total of 402 patients with pathological T2N0 and T2N1 gastric cancer who underwent gastrectomy with D2 lymph node dissection between 1984 and 1990 at four participant hospitals were analyzed. All resected lymph nodes were reexamined by serial sectioning with hematoxylin & eosin (H&E) staining, and evaluated by immunohistochemistry using antibody against cytokeratin (AE1/3). The prevalence and prognostic significance of ITC were investigated., Results: ITC were detected in 187 of the 402 (47%) patients. A multivariate analysis identified the nodal status, histological type, and tumor size as significant factors predictive of the presence/absence of ITC. The 5-year and 10-year overall survival rates of patients with vs those without ITC were 84.4% (95% confidence interval [CI], 79.1-89.0) and 70.4% (95% CI, 64.1-76.7) vs 83.9% (95% CI, 78.6-89.2) and 72.0% (95% CI, 65.4-78.5), respectively. The hazard ratio for death in patients with ITC as compared with those without ITC was 0.90 (95% CI, 0.64-1.26; P = 0.53)., Conclusions: The presence of ITC in the lymph nodes does not affect the prognosis of patients with gastric cancer who have undergone gastrectomy with D2 lymph node dissection.

Background: The outcome of stage III gastric cancer patients treated by D2 dissection followed by adjuvant chemotherapy with S-1 remains unsatisfactory. Moreover, some patients with a preoperative diagnosis of stage II/III turn out to be stage IV after surgical exploration, and a standard postoperative treatment for this population has not been established., Methods: A feasibility study of postoperative S-1/cisplatin (CDDP) was performed with patients who underwent gastrectomy for what turned out to be a stage IV gastric cancer. The primary endpoint of the trial was the relative dose intensity during five courses of S-1/CDDP. Several criteria to skip, postpone, or reduce the dose had been predetermined., Results: Between 2007 and 2009, 31 patients were accrued, including 19 patients who were positive for peritoneal washing cytology, 6 with peritoneal seeding, 5 with metastasis to the paraaortic nodes, and 4 with other distant metastases. Only 7 patients completed five cycles as planned (median, two cycles). The median relative dose intensities of S-1 and CDDP were 37% and 40%, respectively. Causes of treatment failure were failure to fulfill criteria for starting a new course within 5 weeks of the last administration of S-1 in 7, patient refusal in 6, disease recurrence/progression in 4, need to reduce dose by two levels in 4, and two successive skips of CDDP in 3 patients. The median progression-free survival time of all patients was 363 days., Conclusions: Although promising in the neoadjuvant and advanced/metastatic setting, S-1/CDDP is too toxic as a postgastrectomy treatment for Japanese patients.

Background: Bursectomy, which has been performed so as to resect peritoneal deposits disseminated within the omental bursa, is considered as an essential component of radical surgery for gastric carcinoma in Japan. Bursectomy has also been described in the Japanese Treatment Guidelines for Gastric Carcinoma as a mandatory procedure for the treatment of serosa-positive cancer. However, no evidence to support the prognostic significance of this procedure has been reported to date., Methods: Cytologic examination and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the peritoneal washes obtained from the Douglas pouch, left subphrenic cavity, and inside the omental bursa were performed for 136 patients who underwent potentially curative surgery for gastric carcinoma., Results: Carcinoembryonic antigen (CEA) or cytokeratin (CK) 20 mRNA was detected in one or more samples from the three different sites of peritoneal washes in 43 of the 136 patients. In 14 patients, the mRNAs were detected in samples obtained from the bursa omentalis (10.3% of all patients and 32.6% of patients with positive RT-PCR results). In 12 of these 14 patients, the mRNAs were also detected in samples taken from either or both of the remaining two sites. Only in the 2 other patients was the sample only from inside the omental bursa positive for CEA., Conclusion: It is unlikely that viable cancer cells disseminated into the bursa remain restricted to this cavity without migrating into the free abdominal cavity. Routine bursectomy may not be an essential procedure for resecting gastric cancer, from the viewpoint of eliminating microscopic peritoneal deposits within the omental bursa.

Background: Therapy guided by chemotherapy sensitivity and resistance assays may lead to rational treatment decisions. Paclitaxel, one of several new drugs for gastric carcinoma, has not been extensively evaluated by in vitro chemosensitivity tests., Methods: Chemosensitivity testing by histoculture drug response assay (HDRA) was performed with fresh specimens of primary tumor from 113 patients with gastric carcinoma. The test was performed in medium containing paclitaxel at three different concentrations for the initial 45 samples. Correlations between the results of chemosensitivity testing, determined at the optimal concentration, and the patients' clinicopathologic factors and outcome were then assessed for all patients., Results: By analyzing the initial 45 samples, 10 microg/ml was considered the optimal concentration of paclitaxel for this test. HDRA was successfully performed for 100 of 113 samples and chemosensitivity, calculated as the percentage of optical density of a tumor treated with anticancer drugs in relation to the optical density of the tumor cultured in the medium only, was distributed widely at this concentration. No significant correlation was observed between chemosensitivity and age, sex, clinical stage, histopathologic type, and outcome of patients with gastric carcinoma., Conclusion: A histoculture drug response assay can now be performed to predict the chemosensitivity of paclitaxel at the concentration found in the current study. The accuracy of the assay to actually predict survival needs to be validated by a prospective clinical trial involving patients who have received paclitaxel in the postoperative adjuvant setting.

Background: In patients with gastric cancer, the presence of gastric cancer cells in the peritoneal cavity detected by cytologic examination, is a significant prognostic factor. A more sensitive, reverse transcriptase-polymerase chain reaction (RT-PCR) technique, amplifying carcinoembryonic antigen (CEA), was introduced as a new detection system, but produced some false-positive results. A search for other molecular markers is ongoing., Methods: Peritoneal washes were obtained from 195 patients with gastric carcinoma during surgery. Cytokeratin 20 (CK20) mRNA levels were quantified, in addition to those of CEA, using the LightCycler, and the feasibility of CK20 as a target was evaluated., Results: CK20 was limited, in terms of sensitivity, for detecting disseminated cancer cells (sensitivity, 63%; specificity, 91%; positive predictive value, 70%; and negative predictive value, 88%). Multimarker analysis was performed, in which samples positive for either CK20 or CEA mRNA were considered to be positive for cancer cells. Multivariate analysis identified the multimarker analysis as a significant independent prognostic determinant., Conclusion: CK20 RT-PCR produced information that could add a significant impact to the knowledge obtained by CEA RT-PCR, although detection by CK20 alone was not sufficiently sensitive to replace CEA in the detection system.

Background: It has been suggested that the prevalence of microsatellite instability (MSI) is high in intramucosal differentiated gastric cancers with gastric foveolar phenotypic expression, and that these tumors are prone to lose their glandular structures and progress to undifferentiated-type lesions. To test this hypothesis, we examined the relationships among human MutL homologue 1 (hMLH1) expression (which is linked to MSI), the phenotype, and the histological type in patients with advanced and intramucosal gastric cancer., Methods: We analyzed hMLH1 expression by immunohistochemistry in 70 advanced and 30 intramucosal gastric cancers with histological evaluation and assessment of the phenotype, and Cdx2 expression determined by immunohistochemistry. The MSI status was also examined in 20 cases., Results: Thirteen (18.6%) advanced and 5 (16.7%) intramucosal gastric cancers were judged to be hMLH1-negative. In the advanced cases, no association was observed between the histological type and the phenotype and loss of hMLH1. In the intramucosal cases, MUC5AC expression was observed in all 5 hMLH1-negative differentiated-type cancers. However, no hMLH1-negative lesions were detected in the intramucosal undifferentiated cancers (0/14; P < 0.05 vs differentiated types). In the advanced cases, MSI-positivity (MSI +) and loss of hMLH1 expression did correlate (P < 0.0001), while no association was observed between MSI +, histological type, and phenotype., Conclusion: Our data support the hypothesis that, phenotypically, some MSI-positive differentiated gastric cancers of gastric foveolar phenotypic expression may easily change, from gastric to intestinal phenotypic expression, also changing, histologically, from differentiated to undifferentiated type with progression.

Background: Peritoneal lavage cytology is an excellent prognostic determinant but lacks sensitivity. Quantification of carcinoembryonic antigen (CEA) mRNA in peritoneal washes by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was found to be a more sensitive method to detect free cancer cells. It may be beneficial to explore, by the same method, a sample of the omentum, which is known to harbor cancer cells before the establishment of gross peritoneal metastasis., Methods: Greater omentum and peritoneal washes were obtained from 90 gastric carcinoma patients during laparotomy. The CEA mRNA levels in these materials were quantified using a real-time RT-PCR system with hybridization probes. The significance of CEA mRNA levels in both materials, as a predictive factor of peritoneal metastasis, was explored by univariate and multivariate analyses., Results: After a median follow-up of 718 days, 13 patients had clinical evidence of peritoneal metastasis. Under the assumption that these patients had free cancer cells in the peritoneal cavity, the sensitivity and specificity of conventional cytology for the detection of these cells were 31% and 100%, respectively. The sensitivity and specificity of the CEA mRNA levels extracted from the peritoneal washing samples were 77% and 94%, while those of the omentum were 46% and 90%. Multivariate analysis, with the diagnosis of peritoneal metastasis as an endpoint, revealed that CEA mRNA level in the peritoneal washes was the only significant risk factor., Conclusion: Quantitative RT-PCR of peritoneal washes remains the first choice as a tool to sensitively predict intraperitoneal recurrence in gastric carcinoma patients.