Identification of maximal tumor size associated with negligible lymph node metastasis for endoscopic submucosal dissection of undifferentiated-type early gastric cancer.

BACKGROUND AND AIMS: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC. METHODS: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%. RESULTS: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91-2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0-0.53%), PCC (95% CI 0-0.59%), or PD (95% CI 0-0.86%) histologic type. CONCLUSION: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type.

Associations of patient-generated subjective global assessment (PG-SGA) and NUTRISCORE with survival in gastric cancer patients: timing matters, a retrospective cohort study.

BACKGROUND: The timing of nutritional assessment may be important to treat cancer patients and predict their prognosis. This study examined whether Patient-Generated Subjective Global Assessment (PG-SGA) and NUTRISCORE scores were associated with survival among gastric cancer patients who underwent surgery and chemotherapy and whether the timing of the assessment after surgery mattered. METHODS: A total of 952 gastric cancer patients (622 men and 330 women) were included in this retrospective cohort study. The PG-SGA and NUTRISCORE scores were calculated at 1 month (n = 952), 2 months (n = 657), and 3 months (n = 294) after surgery. Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The PG-SGA scores assessed at 1 month after gastrectomy were not associated with survival. However, high PG-SGA scores at 2 months after gastrectomy (median = 65 days) were associated with an increased risk of mortality; the HR (95% CI) was 2.26 (1.22-4.21) for 9-11 vs. ≤ 5 of PG-SGA scores. When we included patients who received all three consecutive consultations, HR (95% CI) was 2.56 (1.02-6.42) for ≥ 9 (malnutrition) vs. ≤ 8 of PG-SGA scores assessed at 3 months after surgery (median days = 98 days). Likewise, high NUTRISCORE scores assessed at the 3-month follow-up were associated with higher mortality; the HR (95% CI) was 3.84 (1.18-12.55) for ≥ 7 vs. ≤ 4 of NUTRISCORE scores. CONCLUSION: Malnutrition assessed with the PG-SGA and NUTRISCORE at 2 to 3 months after gastrectomy was associated with poor survival among gastric cancer patients. Our findings suggest that the timing of the nutritional evaluation may be important in identifying and treating malnutrition related to gastric cancer prognosis.

A preoperative risk prediction model for high malignancy potential gastrointestinal stromal tumors of the stomach.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) exhibit various degrees of aggression and malignant potential. However, no systematic preoperative evaluation strategy to predict the malignancy potential of gastric GISTs has yet been developed. This study aimed to develop a reliable and easy-to-use preoperative risk-scoring model for predicting high malignancy potential (HMP) gastric GISTs. METHODS: The data of 542 patients with pathologically confirmed gastric GISTs who underwent resection were reviewed. Multivariate logistic regression analysis was used to identify significant predictors of HMP. The risk-scoring system (RSS) was based on the predictive factors for HMP, and its performance was validated using a split-sample approach. RESULTS: A total of 239 of 542 (44.1%) surgically resected gastric GISTs had HMP. Multivariate analysis demonstrated that tumor size, location, and surface changes were independent risk factors for HMP. Based on the accordant regression coefficients, the presence of surface ulceration was assigned 1 point. Tumor sizes of 4-6 cm and > 6 cm were assigned 2 and 5 points, respectively. Two points were assigned to cardia or fundus locations. A score of 3 points was the optimal cut-off value for HMP prediction. HMP were found in 19.8% and 82.7% of the low and high-risk groups of the RSS, respectively. The area under the receiver-operating characteristic curve for predicting HMP was 0.81 (95% confidence interval (CI) 0.75-0.86). Discrimination was good after validation (0.75, 95% CI 0.69-0.81). CONCLUSION: This simple RSS could be useful for predicting the malignancy potential of gastric GISTs and may aid preoperative clinical decision making to ensure optimal treatment.

Adjuvant Chemotherapy vs. Surgery Alone for pT3N0M0 Gastric Cancer.

BACKGROUND: As both the role and clinical application of adjuvant chemotherapy (CTx) for pT3N0M0 gastric cancer after curative gastrectomy have fluctuated chronologically, the oncological benefit of adjuvant CTx in patients should be elucidated. METHODS: Between 2000 and 2018, 1083 patients underwent radical gastrectomy for pT3N0M0 gastric cancer and were subsequently divided into two groups: the surgery-alone group (n = 471) and the adjuvant CTx group (n = 612). Chronological changes in adjuvant CTx and various chemotherapeutic regimens were evaluated and disease-free survival was compared between the two groups. Risk factors for tumor recurrence were also analyzed. RESULTS: The proportion of patients in the surgery-alone group was more than 60% until 2001, whereas in the CTx group this increased to over 80%, especially after publication of the American Joint Committee on Cancer (AJCC) 7th edition staging manual. The main chemotherapeutic agents were tegafur-uracil (UFT) and 5-fluorouracil with leucovorin until 2008, whereas tegafur/gimeracil/oteracil (TS-1) has been the main agent since 2009. The 5-year disease-free survival was 89.2% in the surgery-alone group and 89.9% in the CTx group, which was not significantly different (p = 0.694). In multivariate analysis, larger tumor size (≥ 4.5 cm) and venous invasion were significant risk factors for tumor recurrence. In addition, adjuvant CTx did not improve the oncological outcome, even in the large tumor size group (p = 0.760) and the venous invasion group (p = 0.753). CONCLUSIONS: As adjuvant CTx did not show any oncological benefit in pT3N0M0 gastric cancer in this large-scale study, it might be unnecessary for these patients after curative gastrectomy.

Nomogram to predict lymph node metastasis in patients with early gastric cancer: a useful clinical tool to reduce gastrectomy after endoscopic resection.

BACKGROUND: The indications for endoscopic dissection have been expanded to improve the quality of life of patients with early gastric cancer (EGC). This study aimed to develop a nomogram to predict the status of lymph node metastasis with the aim of avoiding unnecessary gastrectomies. METHODS: We reviewed the clinicopathological data of 10 579 patients who underwent curative resection for EGC. The nomogram was developed by multivariate analysis and was evaluated by external validation. Overall, disease-free and recurrence-free survival were compared between the gastrectomy group of 6641 patients and the endoscopic dissection group of 999 patients to show the efficacy of the nomogram. RESULTS: Multivariate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion, and histologic differentiation were all significant prognostic factors for lymph node metastasis. The nomogram had good discriminatory performance, with a concordance index of 0.846. This was supported by the external validation point of 0.813. For patients with low risk of lymph node metastasis on the nomogram (≤ 3 % of the provisional value in this study), the endoscopic dissection and gastrectomy groups had comparable rates of overall (P = 0.32), disease-free (P = 0.47), and recurrence-free (P = 0.09) survival. CONCLUSIONS: We developed and validated a nomogram that predicts the risk of lymph node metastasis in EGC based on a large database. This precision nomogram is useful to avoid unnecessary gastrectomy after endoscopic dissection, which may ultimately improve the quality of life of patients with EGC.

Bridging genomics and phenomics of gastric carcinoma.

Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter-relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer-related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n = 37) and all 19 MSI-H GCs were high TMB. High TMB was significantly more frequent in intestinal-type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%) and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c-MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1-mutant GC subgroup showed the worst survival (p < 0.001). PD-L1 expression was significantly associated with MSI-H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.

Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial.

BACKGROUND: Caucasian patients with microsatellite instability (MSI)-high gastric cancer (GC) may have better prognosis but worse outcomes. OBJECTIVE: Here we explored the prognostic role of MSI in Asian patients. METHODS: This post hoc analysis comprehended radically resected GC patients randomized to XP (capecitabine/cisplatin) or XPRT. MSI status was assessed by combining immunohistochemistry with multiplex polymerase chain reaction. The MSI prognostic effect on disease-free survival (DFS) and overall survival (OS) was evaluated. RESULTS: 393 tissue samples were analyzed and 35 (9%) were MSI-high. This subgroup was characterized by: older age, Borrmann classification 1-2, antral localization, T3-4 stage, and intestinal type. At univariable analysis, the microsatellite-stable subgroup showed a trend toward a worse prognosis as compared to the MSI-high group: 3-year DFS was 76.3 versus 85.4% (p = 0.122); 3-year OS was 81.7 versus 91.4% (p = 0.046). Multivariable analyses confirmed it in both DFS (hazard ratio, HR = 2.32 [95% CI 0.91, 5.88]; p = 0.077) and OS (HR = 3.17 [95% CI 0.97, 10.43]; p = 0.057). CONCLUSIONS: MSI-high status was associated with specific clinical-pathological features and a trend toward better outcomes of Asian GC patients.

Prognostic Impact of Increased Perioperative Platelet Count in Gastric Cancer Patients.

BACKGROUND: Solid tumors are a common cause of secondary (reactive) thrombocytosis, a paraneoplastic syndrome that is also a prognostic factor for various cancers. However, cutoff values for platelet count specific to gastric cancer and their prognostic roles are unknown. METHODS: We retrospectively analyzed records of 4643 patients with gastric cancer who underwent radical surgery from 2007 to 2010. The minimum P-value approach was used with the log-rank test to determine the optimal prognosis predicting threshold for preoperative platelet count. Change in perioperative platelet count over time was evaluated with a generalized estimating equation. Clinicopathologic features and prognostic significance were analyzed according to platelet count. RESULTS: Thrombocytosis prevalence (platelet count ≥40 × 104/µL) was 1.6% (75 of 4643 patients). The platelet count cutoff value with the lowest P-value was ≥25.5 × 104/µL, and patients with higher platelet count had more advanced disease. Multivariate analysis showed that cutoff value was an independent prognostic factor of overall survival (hazard ratio 1.19, 95% confidence interval 1.03-1.37, P = 0.017). Patients who underwent adjuvant chemotherapy (n = 1300) and had a greater than 10% increase in platelet count at postoperative 1 y compared to before surgery had significantly poorer overall survival (hazard ratio 1.65, 95% confidence interval 1.11-2.45, P = 0.013). CONCLUSIONS: Elevated preoperative platelet count (≥25.5 × 104/µL) and increased platelet count (≥10%) at postoperative 1 y in an adjuvant chemotherapy group were unfavorable prognostic factors. Platelet count could be a cost-effective biomarker for screening and monitoring patients with unfavorable survival outcomes.

A prediction model for lymph node metastasis in early-stage gastric cancer: Toward tailored lymphadenectomy.

BACKGROUND: The aim of this study was to develop a prediction model for the presence and location of lymph node metastasis (LNM) in early gastric cancer. METHOD: We reviewed medical records of 4 929 patients who underwent radical gastrectomy for early gastric cancer. Variables of age, sex, lymphatic invasion, depth of invasion, location, gross type, differentiation, and tumor size were analyzed. Logistic regression analysis was used to determine independent predictors of LNM at each LN station. RESULT: Overall incidence of LNM was 9.1% (448/4 929 patients). For the presence of LNM, risk factors of age, sex, lymphatic invasion, depth of invasion, anatomical part, gross ulceration, size, and tumor differentiation were significantly associated with LNM. The area under the curve (AUC) for predicting LNM after validation was 0.834 for the test set. For the location of LNM, age, sex, lymphatic invasion, depth of invasion, anatomical part, circumferential portion, gross type, differentiation, and tumor size were significantly associated with LNM. The AUC of each LN station was favorable with the test set. CONCLUSION: Predicting the location of metastatic LNs appeared to be possible in patients with early gastric cancer.

A comparison of short-term postoperative outcomes including nutritional status between gastrectomy with simultaneous cholecystectomy and gastrectomy only in patients with gastric cancer.

OBJECTIVE: We aimed to evaluate the effect of simultaneous cholecystectomy on the short-term postoperative outcomes and nutritional status in patients with gastric cancer. METHODS: We retrospectively reviewed data from 4,820 patients with gastric cancer who underwent gastrectomy from January 2011 to December 2016. Patients who underwent only gastrectomy (N=4,578) were matched to those who underwent simultaneous cholecystectomy during gastrectomy (N=242) at a 1:1 ratio using propensity score matching analysis. The nutritional status and inflammatory responses preoperatively and postoperatively and postoperative outcomes were compared between the groups. RESULTS: The simultaneous cholecystectomy group showed more intraoperative blood loss and a longer operative time than the gastrectomy only group [150.0 (100.0, 200.0) mL vs. 100.0 (100.0, 200.0) mL, P=0.006; 176.0 (150.0, 210.0) min vs. 155.0 (128.0, 188.0) min, P<0.001, respectively]. Intraoperative event rate, postoperative complication rate, and postoperative recovery did not differ between the groups. All parameters including body weight, the hemoglobin level, absolute lymphocyte count, total protein level, albumin level, fasting glucose level, and prognostic nutritional index excluding the cholesterol level were not significantly different between the groups, and their changing patterns were similar. Although the cholesterol level was significantly lower in the simultaneous cholecystectomy group than in the gastrectomy only group at all follow-up points, the mean value of the decreased cholesterol level was within normal range. CONCLUSIONS: In gastric cancer patients with gallbladder disease, simultaneous cholecystectomy is safe and not associated with additional nutritional loss.

Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer.

BACKGROUND: Biomarkers are needed for noninvasive early detection of gastric cancer (GC). We investigated salivary extracellular RNA (exRNA) biomarkers as potential clinical evaluation tools for GC. METHODS: Unstimulated whole saliva samples were prospectively collected from 294 individuals (163 GC and 131 non-GC patients) who underwent endoscopic evaluation at the Samsung Medical Center in Korea. Salivary transcriptomes of 63 GC and 31 non-GC patients were profiled, and mRNA biomarker candidates were verified with reverse transcription quantitative real-time PCR (RT-qPCR). In parallel, microRNA (miRNA) biomarkers were profiled and verified with saliva samples from 10 GC and 10 non-GC patients. Candidate biomarkers were validated with RT-qPCR in an independent cohort of 100/100 saliva samples from GC and non-GC patients. Validated individual markers were configured into a best performance panel. RESULTS: We identified 30 mRNA and 15 miRNA candidates whose expression pattern associated with the presence of GC. Among them, 12 mRNA and 6 miRNA candidates were verified with the discovery cohort by RT-qPCR and further validated with the independent cohort (n = 200). The configured biomarker panel consisted of 3 mRNAs (SPINK7, PPL, and SEMA4B) and 2 miRNAs (MIR140-5p and MIR301a), which were all significantly down-regulated in the GC group, and yielded an area under the ROC curve (AUC) of 0.81 (95% CI, 0.72-0.89). When combined with demographic factors, the AUC of the biomarker panel reached 0.87 (95% CI, 0.80-0.93). CONCLUSIONS: We have discovered and validated a panel of salivary exRNA biomarkers with credible clinical performance for the detection of GC. Our study demonstrates the potential utility of salivary exRNA biomarkers in screening and risk assessment for GC.

Prediction of Overall Survival and Novel Classification of Patients with Gastric Cancer Using the Survival Recurrent Network.

BACKGROUND: Artificial neural networks (ANNs) have been applied to many prediction and classification problems, and could also be used to develop a prediction model of survival outcomes for cancer patients. OBJECTIVE: The aim of this study is to develop a prediction model of survival outcomes for patients with gastric cancer using an ANN. METHODS: This study enrolled 1243 patients with stage IIA-IV gastric cancer who underwent D2 gastrectomy from January 2007 to June 2010. We used a recurrent neural network (RNN) to make the survival recurrent network (SRN), and patients were randomly sorted into a training set (80%) and a test set (20%). Fivefold cross-validation was performed with the training set, and the optimized model was evaluated with the test set. Receiver operating characteristic (ROC) curves and area under the curves (AUCs) were evaluated, and we compared the survival curves of the American Joint Committee on Cancer (AJCC) 8th stage groups with those of the groups classified by the SRN-predicted survival probability. RESULTS: The test data showed that the ROC AUC of the SRN was 0.81 at the fifth year. The SRN-predicted survival corresponded closely with the actual survival in the calibration curve, and the survival outcome could be more discriminately classified by using the SRN than by using the AJCC staging system. CONCLUSION: SRN was a more powerful tool for predicting the survival rates of gastric cancer patients than conventional TNM staging, and may also provide a more flexible and expandable method when compared with fixed prediction models such as nomograms.

Factors Associated With Host Immune Response and Number of Lymph Nodes: A Large Retrospective Cohort Study.

BACKGROUND: The host immune response (HIR) against tumor cells is one of the key players in antitumor activities. However, the relationship between HIR and regional lymph nodes (LN) and their impacts on prognosis have not been studied. METHODS: This study analyzed HIR and clinicopathologic factors for 8819 consecutive gastric cancer patients who underwent gastrectomy and D2 LN dissection. The findings confirmed Epstein-Barr virus (EBV) with Epstein-Barr encoding region in situ hybridization, HIR grading (G1, G2, and G3), LN numbers classified into seven groups, and performed ordinal regression analysis. RESULTS: The mean number of LNs was 41. A higher degree of HIR was significantly associated with male sex, EBV+, non-intestinal histology by Lauren classification, earlier American Joint Committee on Cancer (AJCC) stage, and greater number of LNs (P < 0.001). Female gender, younger age (< 60 years), EBV+, non-intestinal histology, higher HIR grade (G2 and G3), larger tumor size, and deeper invasion depth were significantly related to a higher number of LNs, with an odds ratio greater than 1. In cancer-specific survival analyses, EBV+, younger age, higher HIR grade (G3), and increased number of LNs were independent prognostic factors in addition to AJCC stage. CONCLUSIONS: The HIR was associated with increased number of LNs was a significant favorable prognosticator.

Lymphovascular invasion and lymph node metastasis rates in papillary adenocarcinoma of the stomach: implications for endoscopic resection.

BACKGROUND: Current Japanese gastric cancer treatment guidelines recommend the same endoscopic resection criteria for papillary early gastric cancer (EGC) and well-differentiated (WD) or moderately differentiated (MD) EGC. To evaluate the appropriateness of this recommendation, we compared the clinicopathological characteristics of papillary EGC with those of WD, MD, poorly differentiated (PD), and signet ring cell (SRC) EGC. METHODS: A total of 6710 patients who underwent radical gastrectomy for EGC were included. Clinicopathological characteristics of papillary EGC were retrospectively reviewed and compared with those in other EGC subtypes. RESULTS: Papillary EGC accounted for 1.9% (130/6710) of total cases. Patients with papillary EGC were older and showed a male predominance compared to patients with PD or SRC EGC. Papillary EGCs showed significantly higher submucosal and lymphovascular invasion rates than WD or MD EGC or PD or SRC EGC. However, the LN metastasis rate of papillary EGC was comparable to or lower than that in other EGC subtypes. LN metastasis rates in mucosal cancers were 1.5%, 1.1%, and 4.0%, and those in submucosal cancers were 9.4%, 11.9%, and 17.6% for papillary EGC, WD or MD EGC, and PD or SRC EGC, respectively. In multivariate analysis, lymphatic invasion and PD or SRC histology were the strongest risk factors for LN metastasis. Among 63 papillary EGC that met the curative endoscopic resection criteria, no case showed LN metastasis. CONCLUSIONS: Endoscopic resection can be indicated for papillary EGC according to current guidelines. Given a considerable lymphovascular invasion rate, careful histological evaluation is required after endoscopic resection for papillary EGC.

Oncological safety of use of ultrasonic activated shears in gastric cancer surgery: Long-term results of randomized controlled trial.

OBJECTIVE: Ultrasonically activated shears (UAS) have been applied in open gastric surgeries with no or little evidence. It was previously reported about the surgical outcome and effectiveness of UAS based on a randomized controlled trial of 256 patients with gastric cancer. We aimed to clarify the long-term oncological safety of the use of UAS in the aspect of overall survival and recurrence. METHODS: Gastric cancer patients who underwent gastrectomy with D2 lymph node dissection were enrolled and randomly assigned to either the conventional surgery group (n=125) or the UAS group (n=128). Survival, recurrence and long-term postoperative complications were compared between the two groups. The median follow-up period was 56 months. RESULTS: Gastric cancer-related death was higher in patients of the UAS group compared with the conventional group (P=0.019). Overall survival rates stratified by stage were not significantly different between the two groups (P=0.170). Disease-free survival rates stratified by stage and recurrence-free survival rates of gastric cancer were similar between the conventional group and the UAS group (P=0.313 and 0.199, respectively). The postoperative complication rate was not significantly different between the groups (P=1.000). CONCLUSIONS: It is suggested that the use of UAS in gastrectomy for gastric cancer showed oncologically acceptable safety compared with conventional electric instruments even in long-term period.

Comparison of Long-Term Outcomes After Non-curative Endoscopic Resection in Older Patients with Early Gastric Cancer.

BACKGROUND: Limited data exist that describe the long-term outcomes from additional surgery following non-curative endoscopic resection (ER) of early gastric cancer (EGC) in older people. This study aimed to determine the appropriate treatment strategy for these patients. METHODS: We analyzed data from 2895 patients who underwent ER for EGC, of whom 451 (15.6%) had non-curative resections followed by curative surgery or surveillance only. Of these patients, 138 were older (aged ≥70 years). We compared the long-term outcomes of the different treatment strategies in the older patients with non-curative resections for EGC, and the outcomes of each treatment strategy, with those in younger patients. RESULTS: The older patients underwent curative resections, non-curative resections with surgery, or non-curative resections with surveillance, and the 5-year disease-specific survival (DSS) rates were 100, 100, and 73%, respectively. There was a trend toward significance for DSS in favor of the non-curative resections with surgery group compared with the non-curative resections with surveillance-only group (p = 0.069). Among those who did not undergo additional surgery, the older patients had worse DSS than the younger patients, and patients who underwent additional surgery had better DSS, irrespective of their ages. Multivariable analysis adjusted for other-cause mortality generated similar results. Overall survival and recurrence-free survival did not differ according to treatment strategy, and perioperative morbidity and mortality did not differ significantly according to age. CONCLUSIONS: In older patients with non-curatively resected EGC, additional surgery demonstrated a trend toward better DSS, and perioperative complications did not increase significantly.

Effect of Intravenous Ferric Carboxymaltose on Hemoglobin Response Among Patients With Acute Isovolemic Anemia Following Gastrectomy: The FAIRY Randomized Clinical Trial.

IMPORTANCE: Acute isovolemic anemia occurs when blood loss is replaced with fluid. It is often observed after surgery and negatively influences short-term and long-term outcomes. OBJECTIVE: To evaluate the efficacy and safety of ferric carboxymaltose to treat acute isovolemic anemia following gastrectomy. DESIGN, SETTING, AND PARTICIPANTS: The FAIRY trial was a patient-blinded, randomized, phase 3, placebo-controlled, 12-week study conducted between February 4, 2013, and December 15, 2015, in 7 centers across the Republic of Korea. Patients with a serum hemoglobin level of 7 g/dL to less than 10 g/dL at 5 to 7 days following radical gastrectomy were included. INTERVENTIONS: Patients were randomized to receive a 1-time or 2-time injection of 500 mg or 1000 mg of ferric carboxymaltose according to body weight (ferric carboxymaltose group, 228 patients) or normal saline (placebo group, 226 patients). MAIN OUTCOMES AND MEASURES: The primary end point was the number of hemoglobin responders, defined as a hemoglobin increase of 2 g/dL or more from baseline, a hemoglobin level of 11 g/dL or more, or both at week 12. Secondary end points included changes in hemoglobin, ferritin, and transferrin saturation levels over time, percentage of patients requiring alternative anemia management (oral iron, transfusion, or both), and quality of life at weeks 3 and 12. RESULTS: Among 454 patients who were randomized (mean age, 61.1 years; women, 54.8%; mean baseline hemoglobin level, 9.1 g/dL), 96.3% completed the trial. At week 12, the number of hemoglobin responders was significantly greater for ferric carboxymaltose vs placebo (92.2% [200 patients] for the ferric carboxymaltose group vs 54.0% [115 patients] for the placebo group; absolute difference, 38.2% [95% CI, 33.6%-42.8%]; P = .001). Compared with the placebo group, patients in the ferric carboxymaltose group experienced significantly greater improvements in serum ferritin level (week 12: 233.3 ng/mL for the ferric carboxymaltose group vs 53.4 ng/mL for the placebo group; absolute difference, 179.9 ng/mL [95% CI, 150.2-209.5]; P = .001) and transferrin saturation level (week 12: 35.0% for the ferric carboxymaltose group vs 19.3% for the placebo group; absolute difference, 15.7% [95% CI, 13.1%-18.3%]; P = .001); but there were no significant differences in quality of life. Patients in the ferric carboxymaltose group required less alternative anemia management than patients in the placebo group (1.4% for the ferric carboxymaltose group vs 6.9% for the placebo group; absolute difference, 5.5% [95% CI, 3.3%-7.6%]; P = .006). The total rate of adverse events was higher in the ferric carboxymaltose group (15 patients [6.8%], including injection site reactions [5 patients] and urticaria [5 patients]) than the placebo group (1 patient [0.4%]), but no severe adverse events were reported in either group. CONCLUSION AND RELEVANCE: Among adults with isovolemic anemia following radical gastrectomy, the use of ferric carboxymaltose compared with placebo was more likely to result in improved hemoglobin response at 12 weeks. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01725789.

A Risk-prediction Model Based on Lymph-node Metastasis for Incorporation Into a Treatment Algorithm for Signet Ring Cell-type Intramucosal Gastric Cancer.

OBJECTIVE: The aim of the study was to develop a reliable and easy-to-use risk-scoring system (RSS) to predict lymph-node metastasis (LNM) and determine the feasibility of endoscopic submucosal dissection for mucosa-confined signet ring cell carcinomas (SRCs). BACKGROUND: Fewer LNM and better survival rates have been reported for early gastric SRCs compared with other undifferentiated early gastric cancers (EGCs). METHODS: Data from 1544 patients with mucosa-confined SRCs were reviewed. Stepwise logistic regression analysis determined the independent predictors of LNM. Risk scores were based on the final predictive factors for LNM, and performance was internally validated using a split-sample approach. External validation was also performed in an independent dataset (n = 208) to assess the discriminatory power of the RSS. RESULTS: The overall LNM incidence was 3.8% (57/1544). Three risk factors (tumor size ≥1.7 cm, tumors of elevated type, and lymphatic-vascular involvement) were significantly associated with LNM. These factors were incorporated into the RSS, and were assigned scores ranging from 0 to 4. The area under the receiver-operating characteristic curve for predicting LNM after internal and external validation was 0.68 (95% confidence interval, 0.0793-0.2865) and 0.686 (95% confidence interval, 0.618-0.748), respectively. A score of 2 points was the optimal cut-off value for LNM prediction, and the overall diagnostic accuracy was 96%. LNM were found in 2.9% and 23.8% of the low and high-risk groups of the RSS, respectively. CONCLUSIONS: A RSS may help to predict LNM and evaluate endoscopic submucosal dissection feasibility in patients with intramucosal SRC.

Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes.

BACKGROUND & AIMS: Patients with Epstein-Barr virus-associated gastric carcinoma (EBVaGC) have a better prognosis than those with gastric cancer not associated with EBV infection (EBVnGC). This is partly because EBV infection recruits lymphocytes, which infiltrate the tumor. A high degree of tumor heterogeneity is likely to be associated with poor response. We investigated differences in gene expression patterns between EBVaGC and EBVnGC. METHODS: We used gene expression profile analysis to compare tumor and nontumor gastric tissues from 12 patients with EBVaGC and 14 patients with EBVnGC. Findings were validated by whole transcriptome RNAseq and real-time quantitative polymerase chain reaction analyses. CD3(+) primary T cells were isolated from human blood samples; migration of these cells and of Jurkat cells were measured in culture with EBV-infected and uninfected gastric cancer cells. RESULTS: Based on Pearson correlation matrix analysis, EBVaGCs had a higher degree of homogeneity than EBVnGCs. Although 4550 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVnGC, only 186 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVaGC (P < .001). This finding supports the concept that EBVaGCs have fewer genetic and epigenetic alterations than EBVnGCs. Expression of major histocompatibility complex class II genes and genes that regulate chemokine activity were more often deregulated in EBVaGCs compared with nontumor tissues. In culture, more T cells migrated to EBV-infected gastric cancer cells than to uninfected cells; migration was blocked with a neutralizing antibody against CXCR3 (a receptor for many chemokines). CONCLUSIONS: Fewer genes are deregulated in EBVaGC than in EBVnGC. Most changes in EBVaGCs occur in immune response genes. These changes might allow EBVaGC to recruit reactive immune cells; this might contribute to the better outcomes of these patients compared with those with EBVnGC.

Long-Term Outcome of Endoscopic Resection vs. Surgery for Early Gastric Cancer: A Non-inferiority-Matched Cohort Study.

OBJECTIVES: Few studies have compared the long-term outcomes of endoscopic resection and surgery. The aim of this study was to compare the long-term outcomes of endoscopic resection with those of surgery for early gastric cancer (EGC). METHODS: We reviewed prospectively collected data of patients who had undergone endoscopic resection (1,290 patients) or surgery (1,273 patients) for EGC. To reduce the effect of selection bias, we performed a propensity score-matching analysis between the two groups. The primary outcome was overall survival (OS). The secondary outcomes were disease-specific survival, disease-free survival (DFS), recurrence-free survival (RFS), occurrence of metachronous gastric cancer, treatment-related complications, length of hospital stay, and 30-day outcomes. The study was designed as a non-inferiority study and tested in an intention-to-treat analysis. RESULTS: In a propensity-matched analysis of 611 pairs, the 10-year OS proportion was 96.7% in the endoscopic resection group and 94.9% in the surgery group (P=0.120) (risk difference -1.8%, 95% confidence interval (CI) -4.04-0.44, Pnon-inferiority=0.014), which met the non-inferiority criterion. In contrast, the 10-year RFS proportion was 93.5% in the endoscopic resection group and 98.2% in the surgery group (P<0.001) (risk difference 4.7%, 95% CI 2.50-6.97, Pnon-inferiority=0.820), which did not meet the non-inferiority criterion, mainly because of metachronous recurrence in the endoscopic resection group. The rate of early complications was higher in the endoscopic resection group than in the surgery group (9.0 vs. 6.6%, P=0.024), whereas the rate of late complications was higher in the surgery group than in the endoscopic resection group (0.5 vs. 2.9%, P<0.001). In the multiple Cox regression analysis, patient's age, the comorbidity index, the performance index, sex, tumor morphology, and depth of invasion were predictors of OS in patients with EGC. CONCLUSIONS: Endoscopic resection might not be inferior to surgery with respect to OS in patients with EGC lesions that meet the absolute or expanded criteria. However, DFS, RFS, and metachronous RFS might be lower after endoscopic resection than after surgery.