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Introduction: The early detection of gastric neoplasms (GNs) leads to favorable treatment outcomes. The latest endoscopic system, EVIS X1, includes third-generation narrow-band imaging (3G-NBI), texture and color enhancement imaging (TXI), and high-definition white-light imaging (WLI). Therefore, this randomized phase II trial aimed to identify the most promising imaging modality for GN detection using 3G-NBI and TXI., Methods: Patients with scheduled surveillance endoscopy after a history of esophageal cancer or GN or preoperative endoscopy for known esophageal cancer or GN were randomly assigned to the 3G-NBI, TXI, or WLI groups. Endoscopic observations were performed to detect new GN lesions, and all suspected lesions were biopsied. The primary endpoint was the GN detection rate during primary observation. Secondary endpoints were the rate of missed GNs, early gastric cancer detection rate, and positive predictive value for a GN diagnosis. The decision rule had a higher GN detection rate between 3G-NBI and TXI, outperforming WLI by >1.0%., Results: Finally, 901 patients were enrolled and assigned to the 3G-NBI, TXI, and WLI groups (300, 300, and 301 patients, respectively). GN detection rates in the 3G-NBI, TXI, and WLI groups were 7.3, 5.0, and 5.6%, respectively. The rates of missed GNs were 1.0, 0.7, and 1.0%, the detection rates of early gastric cancer were 5.7, 4.0, and 5.6%, and the positive predictive values for the diagnosis of GN were 36.5, 21.3, and 36.8% in the 3G-NBI, TXI, and WLI groups, respectively., Discussion: Compared with TXI and WLI, 3G-NBI is a more promising modality for GN detection., (Copyright © 2024 by The American College of Gastroenterology.)

Background: This study aimed to evaluate the risk factors for developing metachronous primary Gastric Cancer (GC) after Endoscopic Resection (ER) for esophageal Squamous Cell Carcinoma (SCC)., Methods: We studied 283 patients with esophageal SCC who underwent ER. The study outcomes were as follows: (1) incidence of metachronous primary GC after ER; and (2) predictors for the development of metachronous primary GC after ER by the Cox proportional hazards model., Results: The median follow-up was 43.1 months (1.81-79.1), and the 3-year cumulative incidence of metachronous primary GC was 6.5% (95%CI: 4.1-10.4). The incidence of metachronous primary GC during the follow-up period was 2.31 per 100 person-years. The frequencies of severe gastric atrophy and macrocytosis at the timing of ER were significantly higher in patients with than without metachronous primary GC (91.7% vs. 73.2%, p = 0.0422, 20.8% vs. 5.2%, p = 0.0046, respectively). Severe gastric atrophy was associated with the development of metachronous primary GC (sex-and-age adjusted hazard ratio (HR) [95%CI] = 4.12 [0.95-27.78], p = 0.0093). Macrocytosis was associated with the development of metachronous primary GC (sex-and-age adjusted HR = 4.76 [1.75-13.0], p = 0.0012) and found to be an independent predictor for metachronous primary GC by multivariate Cox proportional hazards analysis (HR [95%CI] = 4.35 [1.60-11.84], p = 0.004)., Conclusions: Severe gastric atrophy and macrocytosis should be noted in the development of metachronous primary GC after ER for esophageal SCC. In particular, macrocytosis at the timing of ER was considered an important predictor., Clinical Trials Registry Number: UMIN000001676., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Purpose: Nivolumab is useful for the treatment of unresectable/recurrent gastric cancer as third-line or later chemotherapy. However, the factors that predict the efficacy of nivolumab monotherapy remain unclear., Methods: We retrospectively studied the predictive factors of response in 59 consecutive patients treated with nivolumab as third-line or later chemotherapy for unresectable/recurrent gastric cancer at our hospital from October 2017 to May 2020., Results: The median follow-up was 5.9 months. The study included 45 men and 14 women (median age: 71 years). We observed that 7 patients had an Eastern Cooperative Oncology Group performance status of 0 and 52 patients had a performance status of 1-2. Forty-three patients were treated with third-line therapy, seven with fourth-line therapy, and three with fifth-line therapy. The response rate to nivolumab was 6.7% and disease control rate was 35.5%. There were 19 (32.2%) immune-related adverse events for all grades and 9 (15.2%) for grades 3 and 4. Progression-free survival was 1.90 months, and overall survival was 6.30 months. Patients with immune-related adverse events had significantly longer overall survival than those without immune-related adverse events. Multivariate analysis showed that the occurrence of immune-related adverse events and a ratio for neutrophil-to-lymphocyte ratio after 8 weeks of nivolumab treatment to the baseline neutrophil-to-lymphocyte ratio before treatment of ≤ 1.5 were independent prognostic factors for overall survival., Conclusions: Occurrence of immune-related adverse events and changes in neutrophil-to-lymphocyte ratio during nivolumab treatment may help predict the therapeutic efficacy of nivolumab monotherapy for unresectable or recurrent gastric cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Single endoscopic examination often misses early gastric cancer (GC), even when both high-definition white light imaging and narrow-band imaging are used. It is unknown whether new GC can be detected approximately 1 year after intensive index endoscopic examination., Objective: To examine whether new GC can be detected approximately 1 year after intensive index endoscopic examination using both white light and narrow-band imaging., Design, Setting, and Participants: This case-control study was a preplanned secondary analysis of a randomized clinical trial involving 4523 patients with a high risk of GC who were enrolled between October 1, 2014, and September 22, 2017. Data were analyzed from December 26, 2019, to April 21, 2021. Participants in the clinical trial received index endoscopy to detect early GC via 2 examinations of the entire stomach using white light and narrow-band imaging. The duration of follow-up was 15 months. The secondary analysis included 107 patients with newly detected GC (case group) and 107 matched patients without newly detected GC (control group) within 15 months after index endoscopy., Interventions: Surveillance endoscopy was scheduled between 9 and 15 months after index endoscopy. If new lesions suspected of being early GC were detected during surveillance endoscopy, biopsies were obtained to confirm the presence of cancer., Main Outcomes and Measures: The primary end point was the rate of new GC detected within 15 months after index endoscopy. The main secondary end point was identification of risk factors associated with new GC detected within 15 months after index endoscopy., Results: Among 4523 patients (mean [SD] age, 70.6 [7.5] years; 3527 men [78.0%]; all of Japanese ethnicity) enrolled in the clinical trial, 4472 received index endoscopy; the rate of early GC detected on index endoscopy was 3.0% (133 patients). Surveillance endoscopy was performed in 4146 of 4472 patients (92.7%) who received an index endoscopy; the rate of new GC detected within 15 months after index endoscopy was 2.6% (107 patients). Among 133 patients for whom early GC was detected during index endoscopy, 110 patients (82.7%) received surveillance endoscopy within 15 months after index endoscopy; the rate of newly detected GC was 10.9% (12 patients). For the secondary analysis of risk factors associated with newly detected GC, characteristics were well balanced between the 107 patients included in the case group vs the 107 patients included in the matched control group (mean [SD] age, 71.7 [7.2] years vs 71.8 [7.0] years; 94 men [87.9%] in each group; 82 patients [76.6%] vs 87 patients [81.3%] with a history of gastric neoplasm). Multivariate analysis revealed that the presence of open-type atrophic gastritis (odds ratio, 6.00; 95% CI, 2.25-16.01; P < .001) and early GC detection by index endoscopy (odds ratio, 4.67; 95% CI, 1.08-20.21; P = .04) were independent risk factors associated with new GC detection., Conclusions and Relevance: In this study, the rate of new GC detected by surveillance endoscopy approximately 1 year after index endoscopy was similar to that of early GC detected by index endoscopy. These findings suggest that 1-year surveillance is warranted for patients at high risk of GC.

Purpose: Postoperative infectious complications have a negative impact on survival outcomes in patients with gastric cancer. It is recently reported that preoperative chemotherapy may eliminate this negative impact. This study aimed to confirm whether preoperative chemotherapy can eliminate the negative impact of postoperative infectious complications (IC) on survival outcomes and elucidate the association between postoperative infectious complications and recurrence patterns., Methods: We retrospectively reviewed data of 86 patients who received preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by R0 gastrectomy at the Kitasato University between 2006 and 2016. Patients who developed grade II or higher infectious complications during hospitalization were grouped into the IC group, while others were grouped into the non-IC (NIC) group. Survival outcomes and recurrence patterns were analyzed between the two groups., Results: Infectious complications with Clavien-Dindo classification of grade II or higher were found in 12 patients (14.0%, IC group). The median observational period was 61 months. Overall survival and progression-free survival were similar in the IC and NIC groups. Recurrence occurred in 39 patients. The proportions of peritoneal and lymph node recurrences were not significantly different between the two groups. However, the proportion of distant metastasis in the IC group was significantly higher than that in NIC group (3/4 [75%] vs. 9/35 [17%], p = 0.04)., Conclusions: Pathological stage after neoadjuvant therapy plays a stronger role in recurrence than postoperative complications. Lymph node and peritoneal metastasis may be suppressed by preoperative chemotherapy.

Objective: Early detection of gastric cancer has been the topic of major efforts in high prevalence areas. Whether advanced imaging methods, such as second-generation narrow band imaging (2G-NBI) can improve early detection, is unknown., Design: This open-label, randomised, controlled tandem trial was conducted in 13 hospitals. Patients at increased risk for gastric cancer were randomly assigned to primary white light imaging (WLI) followed by secondary 2G-NBI (WLI group: n=2258) and primary 2G-NBI followed by secondary WLI (2G-NBI group: n=2265) performed by the same examiner. Suspected early gastric cancer (EGC) lesions in both groups were biopsied. Primary endpoint was the rate of EGC patients in the primary examination. The main secondary endpoint was the positive predictive value (PPV) for EGC in suspicious lesions detected (primary examination)., Results: EGCs were found in 44 (1.9%) and 53 (2.3%; p=0.412) patients in the WLI and 2G-NBI groups, respectively, during primary EGD. In a post hoc analysis, the overall rate of lesions detected at the second examination was 25% (n=36/145), with no significant differences between groups. PPV for EGC in suspicious lesions was 13.5% and 20.9% in the WLI (50/371 target lesions) and 2G-NBI groups (59/282 target lesions), respectively (p=0.015)., Conclusion: The overall sensitivity of primary endoscopy for the detection of EGC in high-risk patients was only 75% and should be improved. 2G-NBI did not increase EGC detection rate over conventional WLI. The impact of a slightly better PPV of 2G-NBI has to be evaluated further., Trial Registration Number: UMIN000014503., Competing Interests: Competing interests: MM received grants from Olympus during the study period. TY received personal fees and non-financial support from Olympus, outside this study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 76-year-old man had a diagnosis of double primary cancers consisting of poorly differentiated esophageal squamous cell carcinoma (ESCC) invading the submucosa and poorly differentiated gastric adenocarcinoma (GAC) invading the submucosa. The clinical stage of both ESCC and GAC was T1N0M0 stage I. The tumor diameter of ESCC and GAC was 20 mm and 25 mm, respectively. We performed chemoradiotherapy for ESCC. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m 2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m 2 on days 1-5, repeated every 4 weeks for two cycles. Radiotherapy consisted of 50.4 Gy in 28 fractions for ESCC. GAC was down-staged after chemoradiotherapy for ESCC and was treated by endoscopic submucosal dissection (ESD). The tumor was histopathologically confirmed to be down-staged to intramucosal cancer with a diameter of 18 mm and no evidence of lymphovascular invasion and ulceration. Multiple metastasis occurred in the stomach, the small intestine and the colorectum after ESD. ESD is not a curative treatment even if chemotherapy is effective for poorly differentiated GAC invading the submucosa. Multiple gastrointestinal metastasis may be a unique recurrence pattern after ESD for such a lesion.

Purpose: The purpose of this study is to evaluate the long-term survival outcomes of KDOG1001 trial after a minimum follow-up of 3 years., Methods: Patients with bulky N2 lymph nodes, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m 2 , cisplatin at 60 mg/m 2 on day 1, and S-1 at 40 mg/m 2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy plus adjuvant S-1 therapy for 1 year. The final preplanned analysis of long-term outcomes including overall survival and relapse-free survival was conducted after minimum follow-up of 3 years. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN 000003642, and has been completed., Results: From May 2010 through January 2017, 40 patients were enrolled. All included patients underwent neoadjuvant chemotherapy with DCS followed by gastrectomy with D2 lymphadenectomy, and 32 (80%) completed adjuvant S-1 therapy for 1 year. After a median follow-up for surviving patients of 68 months at the last follow-up in January 2020, 3-year overall survival rate was 77.5% (95% confidence interval 62.1-87.9%), while 3-year relapse-free survival rate was 62.5% (95% confidence interval 46.8-76.0%)., Conclusion: Neoadjuvant chemotherapy with 4 cycles of DCS followed by D2 gastrectomy plus adjuvant S-1 was associated with relatively good long-term oncologic outcomes for patients with the high-risk gastric cancer.

Background: The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG)., Methods: Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m 2 , day 1), oxaliplatin (mg/m 2 , day 1), and S-1 (mg/day, days 1-14) were: 50/100/80-120 at level 1, and 60/100/80-120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210)., Results: We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen., Conclusion: Recommended doses of docetaxel (mg/m 2 ), oxaliplatin (mg/m 2 ), and S-1 (mg/day) were 60/100/80-120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.

Background: The prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis., Methods: Patients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m 2 , cisplatin at 60 mg/m 2 on day 1, and S-1 at 40 mg/m 2 twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%., Results: Between 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%., Conclusions: Neoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.

Background: Very few studies have evaluated the effectiveness of oral proton-pump inhibitors for the prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric tumors. The aim of our study was to establish the non-inferiority of lansoprazole orally disintegrating (OD) tablets to intravenous lansoprazole for the prevention of bleeding from artificial ulcers after ESD., Patients and Methods: Consecutive patients who underwent ESD for gastric tumors were randomly assigned to receive lansoprazole OD tablets (OD group) or intravenous lansoprazole (IV group). In the OD group, lansoprazole OD tablets (30 mg) were given orally once daily for 8 weeks (56 days), starting on the day before ESD. In the IV group, lansoprazole (30 mg) was given as a continuous intravenous infusion twice daily for 3 days, starting on the day before ESD, and lansoprazole OD tablets (30 mg) were given orally once daily on days 4-56. The primary endpoint was the incidence of bleeding events within 8 weeks after ESD., Results: Among 310 enrolled patients, 304 patients (152 in the OD group and 152 in the IV group) were included in the analysis. Endoscopic hemostasis was performed in 38 patients (19 in the OD group and 19 in the IV group). The incidence of bleeding events within 8 weeks after ESD did not differ significantly between the groups (p = 0.487). Endoscopic hemostasis was performed at second-look endoscopy in 17 patients (11.2%) in the OD group and 19 patients (12.5%) in the IV group (difference, 1.3 percentage points; 90% confidence interval, - 4.8-7.4%; non-inferiority, p < 0.001)., Conclusions: The effectiveness of lansoprazole OD tablets for the prevention of bleeding from artificial ulcers after ESD was similar to that of intravenous lansoprazole. Lansoprazole OD tablets are thus considered a treatment option in patients who undergo ESD.

Background: Gastric cancer treatment guidelines recommend additional surgery as the standard treatment for lesions for which endoscopic submucosal dissection (ESD) is not indicated. However, the incidence of lymph-node metastasis is low in most patients., Methods and Materials: The study comprised 231 patients (231 lesions) who underwent ESD for early gastric cancer (EGC) in our hospital from September 2002 through March 2015 and were found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD. The patients were divided into the additional operation group and the follow-up group, and long-term outcomes were studied retrospectively. Risk factors for metastasis and recurrence were also studied (capture rate, 98.7%)., Results: The median follow-up was 48 months. There were 174 men and 57 women with a median age of 72 years. The additional operation group comprised 118 patients, and the follow-up group comprised 113 patients. The rates of 5-year cause-specific survival and 5-year overall survival were significantly higher in the additional operation group (100 and 96.0%, respectively) than in the follow-up group (92.6 and 73.3%, respectively; p = 0.010, p < 0.001). In the follow-up group, 5 patients (4.4%) died of gastric cancer (p = 0.021). Among elderly patients 75 years or older, long-term outcomes did not differ significantly between the groups. Sixteen patients had metastasis or recurrence, and the presence of lymphatic involvement was an independent risk factor for metastasis, recurrence, or both (p = 0.003; odds ratio 10.594; 95% confidence interval 2.294-48.927)., Conclusions: In patients with EGC who are confirmed to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD, additional surgery should be aggressively performed if the patient can tolerate such treatment. In elderly patients aged 75 years or older and patients with serious underlying diseases, follow-up observation was suggested to be one option in patients who give informed consent after receiving an explanation of the risk of recurrence.

Background/aims: Few studies have classified risk factors according to the onset time of bleeding after endoscopic submucosal dissection (post-ESD bleeding)., Methods: We studied 1767 consecutive lesions in patients who underwent ESD for early gastric cancer from December 2006 through June 2016. Patients who had a remnant stomach or who had undergone reconstruction with a gastric tube were excluded. Post-ESD bleeding was classified into acute bleeding (0-5 days after ESD) and delayed bleeding (6 or more days after ESD), and the risk factors for each type of bleeding were compared., Results: Post-ESD bleeding occurred in 150 (8.5%) of 1767 lesions. Bleeding was acute in 129 lesions (7.3%) and delayed in 21 (1.2%). Acute post-ESD bleeding was frequently associated with lesions located in the distal stomach, expanded indications or non-indicated lesions, a specimen diameter of ≥40 mm, and antithrombotic therapy. Delayed post-ESD bleeding was often associated with lesions located in the proximal stomach, hemodialysis, and antithrombotic therapy. Among 334 lesions in patients who received antithrombotic therapy, post-ESD bleeding occurred in 47 lesions (14.1%). Independent risk factors for post-ESD bleeding were a specimen diameter of ≥40 mm and treatment with 2 or more antithrombotic agents., Conclusions: Acute post-ESD bleeding and delayed post-ESD bleeding were associated with different clinical characteristics. Antithrombotic therapy is a risk factor for post-ESD bleeding in both the acute and delayed phases.

We conducted a randomized trial to compare the safety and effectiveness of aprepitant, granisetron, and dexamethasone (AGD) with those of palonosetron and dexamethasone (PD) in patients who received highly emetogenic chemotherapy (HEC). Patients with esophageal or gastric cancer who were scheduled to receive HEC including at least 60 mg/m of cisplatin as the first-line treatment were randomly assigned to receive AGD (oral aprepitant 125 mg on day 1 and 80 mg on days 2-3; intravenous granisetron 3 mg on day 1; intravenous dexamethasone 6.6 mg on day 1 and oral dexamethasone 4 mg on days 2-3) or PD (intravenous palonosetron 0.75 mg on day 1; intravenous dexamethasone 13.2 mg on day 1 and oral dexamethasone 8 mg on days 2-3). The primary endpoint was a complete response during the overall study period (0-120 h after the start of chemotherapy) in the first cycle. Eighty-five patients were enrolled, and 84 were eligible. The complete response rate did not differ between the treatment groups, but the proportion of patients with no vomiting was significantly higher in the AGD group than in the PD group (81.4 vs. 58.5%; P=0.031). The results of a quality-of-life survey indicated that the proportion of patients with no or minimal impact on daily life in the vomiting domain was significantly higher in the AGD group (79.1 vs. 53.7%; P=0.020). The primary endpoint of complete response was not achieved, but AGD seems to be more effective than PD for the prevention of HEC-induced vomiting.

Objectives: Whether chemoradiotherapy (CRT) is clinically beneficial for the management of postoperative recurrence of advanced gastric cancer remains unclear. We retrospectively studied treatment outcomes in patients who had unresectable localized recurrence after surgery for advanced gastric cancer and evaluated the safety and efficacy of CRT., Methods: The study group comprised 21 patients who received concurrent CRT for unresectable localized recurrence after undergoing R0 resection for stage II/III advanced gastric cancer. Localized recurrence was defined as a few or limited recurrent lesions., Results: The recurrence pattern was anastomotic recurrence in 7 patients, abdominal lymph-node recurrence in 12, and anastomotic recurrence plus abdominal lymph-node recurrence in 2. The median total dose of radiotherapy was 48.6 Gy (range 39.6-56.0), and the CRT completion rate was 100 % (21 of 21 patients). CRT-related grade 3 or higher toxicity comprised neutropenia in 33.3 % of patients and anorexia in 9.5 %. The response rate was 61.9 % (complete response 38.1 %, partial response 23.8 %). The median overall survival was 35.0 months., Conclusions: We conclude that CRT may become one treatment strategy for the management of unresectable localized recurrence after curative resection of advanced gastric cancer.

Background: Many malignant tumors consist of heterogeneous subpopulations of cells. This heterogeneity is associated with genetic characteristics. However, it remains unclear whether gene expression levels differ among specific sites of tumors in gastric cancer., Methods: We studied differences in gene expression levels among specific sites of primary tumors and synchronous lymph node metastases, using formalin-fixed, paraffin-embedded specimens resected surgically from 48 patients with previously untreated advanced gastric cancer. Specimens were obtained by laser-captured microdissection from five regions: (1) nonneoplastic mucosa, (2) surface layer (mucosa) of the primary tumor (surface sections), (3) middle layer (submucosa) of the primary tumor (middle sections), (4) the deepest layer of the primary tumor (muscularis propria or deeper) at the site of deepest invasion (deep sections), and (5) level 1 synchronous lymph node metastasis (lymph node metastases). Expression levels of the following target genes were determined by quantitative real-time polymerase chain reaction: thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF1α)., Results: TP, DPD, EGFR, and HIF1α gene expression levels were significantly higher in deep sections than in surface sections. TP, EGFR, VEGF, and HIF1α gene expression levels were significantly higher in lymph node metastases than in surface sections. TP, DPD, EGFR, VEGF, and HIF1α gene expression levels were positively correlated with the specific samples harvested from the tumors., Conclusions: Our results show that the expression levels of some genes in tumor cells can change in specific sites of tumors and can become higher in association with tumor progression.

Background: Type IV macroscopic gastric cancer has the poorest prognosis of all gastric cancer types. Although progress of multidisciplinary treatments is outstanding, the current survival outcome of such therapies is obscure., Patients and Methods: Among 5,172 patients with gastric cancer between 1971 and 2013, 287 cases of type IV were identified (5%). We divided time period into early (1971-2004) and late periods (2005-2013), and compared their prognosis. Multivariate Cox proportional hazards model was applied to the univariate prognostic factors, and identified independent prognostic factors and long-term survivors., Results: Five-year overall survival (OS) was 13% and 31% in the early and late periods, respectively (p=0.0010). Univariate prognostic factors were age, pathological tumor depth of invasion (pT), pathological lymph node metastasis (pN), peritoneal dissemination (P), intra-peritoneal cytology test (CY), and margin status. Multivariate analysis determined independent prognostic factors to be treatment period (p=0.0001), pT (p=0.0024) and P (p=0.035). Survival outcomes were stratified by combination of pT and P in both periods, where OS was improved in the late period. Long-term survivors often underwent long-term postoperative chemotherapy with S-1., Conclusion: Long-term postoperative S-1 chemotherapy may improve survival outcome of patients with type IV gastric cancer, and their prognosis is predicted by pT and P status., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer., Methods: We studied 780 lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the extended National Cancer Center (NCC) criteria from April 1995 to December 2007. A total of 359 lesions were treated by endoscopic aspiration mucosectomy (EAM) between April 1995 and March 2003 (EAM group), and 421 lesions were treated by ESD between April 2003 and December 2007 (ESD group). Long-term outcomes (local recurrence rate, overall survival) were compared between the groups., Results: The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) (p < 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group (p < 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group (p < 0.05). There was no significant difference between the groups in overall survival., Conclusions: On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.

Approximately 80%-95% of gastrointestinal stromal tumors (GISTs) show positive staining for KIT, while the other 5%-20% show negative staining. If the tumor is negative for KIT, but is positive for CD34, a histological diagnosis is possible. However, if the tumor is negative for KIT, CD34, S-100, and SMA, a definitive diagnosis is often challenging. Recently, Discovered on GIST-1 (DOG1) has received considerable attention as a useful molecule for the diagnosis of GIST. DOG1, a membrane channel protein, is known to be overexpressed in GIST. Because the sensitivity and specificity of DOG1 are higher than those of KIT, positive staining for DOG1 has been reported, even in KIT-negative GISTs. KIT-negative GISTs most commonly arise in the stomach and are mainly characterized by epithelioid features histologically. We describe our experience with a rare case of a KIT-negative GIST of the stomach that was diagnosed by positive immunohistochemical staining for DOG1 in a patient who presented with severe anemia. Our findings suggest that immunohistochemical staining for DOG1, in addition to gene analysis, is useful for the diagnosis of KIT-negative tumors that are suspected to be GISTs.

Background: Endoscopic submucosal dissection (ESD) for early gastric cancer accompanied by an ulcer scar remains challenging. Several counter-traction techniques have been attempted to facilitate ESD, but a standard procedure remains to be established., Objective: To evaluate the efficacy and safety of double-endoscope ESD by using a single light source in patients with early gastric cancer accompanied by an ulcer scar., Design: Single center, retrospective study., Setting: Kitasato University East Hospital., Patients: A total of 30 early gastric cancers with ulcer scars were treated by double-endoscope ESD in 30 patients from October 2008 through May 2012., Intervention: Double-endoscope ESD., Main Outcome Measurements: En bloc resection rate, complete resection rate, treatment time, and adverse events., Results: The use of two endoscopes for ESD provided a good field of vision and allowed counter-traction to be applied to the lesion, clearly facilitating submucosal dissection. Because only a single light source was used, the working space of the endoscope room was not compromised. Moreover, it was unnecessary to prepare another light source or to coordinate image filing. The en bloc resection rate and complete resection rate were 100% and 90%, respectively, and the median treatment time was 80 minutes. As compared with historical control data obtained before the introduction of double-endoscope ESD, the rate of cutting into the specimen was significantly lower (7% vs 35%; P = .01). No serious adverse events occurred during the procedure. Postoperatively, however, 3 patients (10%) had delayed hemorrhage, and 1 (3.3%) had a delayed perforation., Limitations: Single-center, nonrandomized study., Conclusion: Our experience indicates that our procedure for double-endoscope ESD is useful and feasible in patients with early gastric cancer accompanied by an ulcer scar., (Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Endoscopic submucosal dissection is associated with a longer treatment time and a higher risk of patient discomfort than conventional procedures. Adequate, safe sedation is therefore essential. Sedation can cause adverse effects such as hypoxemia and hypotension, requiring continuous intraoperative and postoperative monitoring of blood pressure, use of the electrocardiogram, and arterial blood oxygen saturation by pulse oximetry. A physician and a nurse solely responsible for sedating and monitoring the patient should be present during treatment.A combination of benzodiazepines and analgesics are generally used for sedation, but new sedatives such as propofol and dexmedetomidine hydrochloride are expected to be useful agents. Endoscopists should become more familiar with sedatives, analgesics, and emergency procedures in the future., (© 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.)

Purpose: We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer., Methods: Docetaxel (40 mg/m(2)) and cisplatin (70 or 60 mg/m(2)) were given on day 1 of a 28-day cycle. S-1 (40 mg/m(2)) was given twice daily on days 1-14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1., Results: Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1-25). Because some patients had serious myelosuppression and renal dysfunction with 70 mg/m(2) of cisplatin, dose of cisplatin was reduced to 60 mg/m(2) after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71-91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6-21.5) and 8.7 (95% CI, 6.7-10.7) months, respectively., Conclusions: Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60 mg/m(2) of cisplatin is as effective as 70 mg/m(2) of cisplatin.

Background: In Western countries, the response of gastric cancer to chemotherapy is evaluated by assessing measurable metastatic lesions (MMLs) according to the response evaluation criteria in solid tumors (RECIST). In Japan, the response of primary lesions is assessed according to local Japanese criteria. We compared the response to chemotherapy as evaluated by these two sets of criteria., Methods: Patients with unresectable, advanced gastric cancer who had primary lesions and had received first-line chemotherapy were studied. Responses of MMLs were evaluated with RECIST. Responses of primary lesions were evaluated with the Japanese criteria. Median survival times (MSTs) were compared according to treatment response by each set of criteria., Results: Data from 341 patients were analyzed. Of the 242 patients with MMLs, 108 were MML responders and 134 were MML nonresponders. MST was significantly longer in MML responders (293 days; 95% confidence interval [CI], 244-342) than in MML nonresponders (159 days; 95% CI, 127-191; P < 0.0001). According to the Japanese criteria, there were 128 primary-lesion responders and 213 primary-lesion nonresponders. MST was significantly longer in responders (304 days; 95% CI, 266-342) than in nonresponders (168 days; 95% CI, 143-193, P < 0.0001). Of the 99 patients without MMLs, 26 were primary-lesion responders and 73, primary-lesion nonresponders; MST was significantly longer in the former (300 days; 95% CI, 266-334) than in the latter group (173 days; 95% CI, 111-235; P = 0.019)., Conclusion: The responses of primary lesions according to the Japanese criteria and the responses of MMLs according to the RECIST were both significantly related to the MST. Use of the RECIST alone might bias the evaluation of treatment response because response cannot be evaluated in patients without an MML.

A phase III trial of S-1 plus cisplatin (SP) versus S-1 alone, for first-line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S-1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S-1 alone than SP. We studied 120 patients who received S-1 alone or SP for first-line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor-A, and epidermal growth factor receptor in paraffin-embedded specimens of primary tumors. Multivariate survival analysis in patients who received S-1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n = 23) than their cutoff values, the S-1 alone group (n = 15) had longer overall survival than the SP group (n = 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S-1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S-1 alone will yield survival benefit.

An 81-year-old woman presented with dysphagia. Stage IV (cT3, cN3, cH0, cM1) type 4 advanced gastric cancer was diagnosed. The left adrenal gland and the paragastric, mediastinal, and abdominal para-aortic lymph nodes were enlarged. Ascites was present. The patient started to receive S-1 (100 mg/day), given orally for 4 weeks followed by 2 weeks of rest. During the first course of treatment, grade 2 anorexia, grade 2 vomiting, and grade 2 diarrhea developed. Treatment with S-1 was therefore discontinued on day 27. The tumor had shrunk and was severely deformed. There was marked narrowing of the pyloric antrum. Abdominal computed tomography revealed that ascites and enlargement of the left adrenal gland and paragastric lymph nodes had resolved. To ensure adequate oral intake and improve the patient's quality of life, a total gastrectomy with a limited (D1) lymph node dissection was performed. The primary gastric tumor, resected lymph nodes, and a peritoneal-lavage specimen were all negative for tumor. Histologically, the tumor had a complete pathological response to S-1. Two years after surgery, the patient is alive, with no evidence of metastasis or recurrence.

Objective: This dose-escalation study of a combination of docetaxel, cisplatin and S-1 investigated the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) and antitumor activity in advanced gastric cancer., Patients and Methods: Patients received docetaxel (40 mg/m(2)), cisplatin (DIV on day 1) and S-1 (40 mg/m(2) p.o., twice daily, on days 1-14 every 28 days). The starting dose of cisplatin was 60 mg/m(2) (level 1); the dose was escalated to 70 (level 2) and 80 mg/m(2) (level 3) in a stepwise fashion., Results: Fourteen patients were enrolled. The MTD of cisplatin was 80 mg/m(2) (level 3). DLT was grade 3 diarrhea, febrile neutropenia and delayed resumption of treatment. The RD of cisplatin was considered to be 70 mg/m(2) (level 2). DLT was liver dysfunction, occurring in only 1 patient at level 2. The response rate was 69.2% (9/13)., Conclusions: For combined treatment with docetaxel, cisplatin and S-1 in patients with advanced gastric cancer, RD were docetaxel 40 mg/m(2), cisplatin 70 mg/m(2) and S-1 80 mg/m(2)/day. This regimen yields a high rate of tumor response and can be administered safely. Phase II studies of this regimen are under way., (Copyright 2008 S. Karger AG, Basel.)

Type 4 gastric cancer has a poor prognosis compared with other types of advanced gastric cancer because of the high incidence of peritoneal metastasis which causes intestinal obstruction, hydronephrosis, or obstructive jaundice. Surgical treatment is often only palliative, and systematic chemotherapy is considered to be important for long survival. S-1 showed a higher response rate for undifferentiated-type adenocarcinoma, and S-1 alone or its combination regimens demonstrated greater anti-tumor effects and longer survival time for gastric linitis plastica compared with conventional 5-FU regimens in our historical control study (response rate: S-1/non S-1 57.9%/27.9%, p<0.01; MST: S-1/non S-1 402 days/213 days, p<0.01). S-1 regimens may also improve the survival in patients with type 4 gastric cancer in neoadjuvant or adjuvant settings, but further prospective studies are warranted to prove its significance. Paclitaxel also has a high response rate for undifferentiated-type adenocarcinoma, and can be expected to show high efficacy for peritoneal dissemination. Irinotecan should not be administered in case of intestinal obstruction because its toxicity may be increased. However,survival of patients with type 4 gastric cancer may improve with the availability of active agents like S-1, taxanes, irinotecan as reported in colorectal cancer. Therefore,irinotecan should be administered carefully before intestinal obstruction occurs.

A 78-year-old woman was admitted to our hospital because of tarry stools. A gastric stromal tumor with liver metastasis was diagnosed. Treatment with imatinib mesilate was begun in a dose of 400 mg daily. After 1 month, the primary tumor showed a partial response; the response of the liver metastasis was stable disease. However, grade 2 edema, leukocytopenia, and anemia developed, and the dose of imatinib mesilate was reduced to 200 mg daily. The adverse reactions resolved promptly, and a partial response of both the primary tumor and liver metastasis to imatinib mesilate has been maintained for 28 months. Strategies for lowering the dose of imatinib mesilate are reviewed.

The 5-FU plus cisplatin containing regimen like FP, ECF and DCF, is considered to be the most effective treatment for advanced gastric cancer in the United States, Europe, and Korea. In Japan, oral fluoropyrimidine S-1 (TS-1) is currently considered to be the first candidate as the standard drug for advanced gastric cancer. S-1 based combination therapies with other promising drugs like cisplatin, irinotecan and taxanes, are expected to yield good results. Above all, S-1+CDDP therapy showed a high efficacy and expected to be a standard therapy for advanced gastric cancer. Two large phase III studies, JCOG 9912 5-FU vs S-1 vs CPT-11 +CDDP and S-1 vs S-1+CDDP, are now on going to establish an acceptable frontline standard for patients with AGC. We therefore need to develop new agents and combination chemotherapy regimens to achieve a greater survival benefit in AGC.