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This study evaluated the safety, effectiveness, and feasibility of indocyanine green (ICG) tracing in guiding lymph-node (LN) dissection during laparoscopic D2 radical gastrectomy in patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC). We retrospectively analyzed data on 313 patients with clinical stage of cT1-4N0-3M0 who underwent laparoscopic radical gastrectomy after NAC between February 2010 and October 2020 from two hospitals in China. Grouped according to whether ICG was injected. For the ICG group (n = 102) and non-ICG group (n = 211), 1:1 propensity matching analysis was used. After matching, there was no significant difference in the general clinical pathological data between the two groups (ICG vs. non-ICG: 94 vs. 94). The average number of total LN dissections was significantly higher in the ICG group and lower LN non-compliance rate than in the non-ICG group. Subgroup analysis showed that among patients with LN and tumor did not shrink after NAC, the number of LN dissections was significantly more and LN non-compliance rate was lower in the ICG group than in the non-ICG group. Intraoperative blood loss was significantly lesser in the ICG group than in the non-ICG group, while the recovery and complications of the two groups were similar. For patients with poor NAC outcomes, ICG tracing can increase the number of LN dissections during laparoscopic radical gastrectomy, reduce the rate of LN non-compliance, and reduce intraoperative bleeding. Patients with AGC should routinely undergo ICG-guided laparoscopic radical gastrectomy.

Body composition profiles influence the prognosis of several types of cancer; however, the role of body composition in patients with locally advanced gastric cancer (LAGC) after neoadjuvant treatment (NT) has not been well characterized.A total of 213 patients with LAGC who underwent gastrectomy after NT at a high-volume institution from southern China were comprehensively evaluated for primary analysis. Additionally, 170 and 77 patients from Western China and Italy, respectively, were reviewed for external validation. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and the subcutaneous as well as the visceral adiposity index were assessed from clinically acquired CT scans at diagnosis and preoperatively.Overall, none of the body composition parameters significantly changed after NT. The pre-NT skeletal muscle radiodensity (SMD) and change in SMI (ΔSMI) were both significantly lower in the patients with poor response (tumor regression50%; mean SMD: 43.5 vs 46.5, P = 0.003; mean ΔSMI: -1.0 vs 2.2, P 0.001), and the cutoff values were calculated according to the Youden index as 43.7 and 1.2, respectively. Based on these 2 parameters, a novel model, the Skeletal Muscle Score (SMS), was proposed to predict the pathological response (AUC = 0.764 alone and = 0.822 in combination with the radiological response). Moreover, patients with an SMI loss1.2 had a significantly prolonged drainage tube removal time (mean: 10.0 vs 8.2, P = 0.003) and postoperative hospital stay (mean: 11.1 vs 9.8, P = 0.048), as well as a significantly higher rate of postoperative complications (30.9% vs 16.7%, P = 0.015). In the multivariate analysis, SMI loss1.2 independently predicted poor overall survival (HR: 1.677, 95% CI 1.040-2.704, P = 0.034) and recurrence-free survival (HR: 1.924, 95% CI 1.165-3.175, P = 0.011). ΔSMI was also significantly associated with pathological response, surgical outcomes, and survival in the 2 external cohorts (P all 0.05).For LAGC, the pre-NT SMD and ΔSMI could accurately predict the pathological response after NT. An SMI loss1.2 is closely associated with poorer outcomes and may indicate the need more supportive treatment.

The systemic inflammatory response caused by host-tumor interactions is currently recognized as a hallmark feature of cancer. No study has confirmed which systemic inflammatory factors can accurately predict the progression and long-term prognosis of gastric cancer (GC). Through the analysis of receiver operating characteristic curve (ROC), in the discovery cohort, a variety of indicators composed of usual inflammatory factors were compared. Fibrinogen-albumin ratio (FAR), which can accurately predict the long-term survival of GC patients was selected and was further verified in the test cohort and the external validation cohort. The ROC curve analysis showed that the area under curve (AUC) value of FAR on the overall survival (OS) of GC patients was higher than that of other combined markers (P < 0.01). Patients in the high FAR group showed more advanced pathological stages, larger tumor diameters, and more poorly differentiated pathological type than those in the low FAR group (P < 0.05). Logistic regression analysis elucidated that, FAR was an independent risk factor for LN metastasis and tumor invasion of GC. High FAR was an independent risk factor for poor prognosis of GC patients. The relationship between FAR and pathological stage of GC and long-term prognosis of patients was verified in the test cohort and the external validation cohort with the same FAR cutoff value. The results are consistent with those of the discovery cohort. As a new developed inflammation-related marker, FAR can independently and effectively predict the tumor burden and long-term prognosis of patients with advanced GC.

PURPOSE To investigate the effect of dynamic changes in systemic inflammatory markers (SIM) on long-term prognosis of patients with gastric cancer (GC). METHODS A retrospective analysis was performed on the data of 2180 patients with GC who underwent radical gastrectomy in the Fujian medical university Union Hospital from January 2009 to December 2014. Changes in SIM between preoperatively and 1-6 months and 12 months postoperatively were reported. RESULTS In multivariate analysis, higher preoperative systemic inflammation score (pre-SIS) was independent predictor of poor prognosis (p

The application of splenic hilar lymph node (no. 10 LN) dissection (no. 10 LND) for proximal gastric cancer (PGC) remains controversial. This study aimed to investigate the clinical relevance of no. 10 LND from the perspective of long-term survival. The main study population included 995 previously untreated patients who underwent laparoscopic radical total gastrectomy between January 2008 and December 2014. Of these 995 patients, 564 underwent no. 10 LND (no. 10D+ group) and the remaining 431 patients did not (no. 10D– group). Propensity score-matching was applied to reduce the effects of confounding factors. The study end points were overall survival (OS) and disease-free survival (DFS). Additionally, 39 patients who received neoadjuvant chemotherapy during the same period also were included as a separate population for analysis. The metastasis rate for no. 10 LN was 10.5 % (59/564). No significant differences were observed in intra- and postoperative complications nor in mortality between the no. 10D+ and no. 10D– groups (all P > 0.05). After 1:1 matching, the two groups were comparable in clinicopathologic characteristics. The no. 10D+ group had significantly better survival than the no. 10D– group (5-year OS: 63.3 % vs 52.2 %, P = 0.003; 5-year DFS: 60.4 % vs 48.1 %, P = 0.013). For the patients who received neoadjuvant chemotherapy, the 5-year OS rates in the no. 10D+ and no. 10D– groups were respectively 50.6 % and 31.3 % (P = 0.150) and the 5-year DFS rates were respectively 51.5 % and 31.3 % (P = 0.123). Patients with untreated PGC may achieve the benefit of long-term survival from no. 10 LND. For patients with PGC who undergo neoadjuvant chemotherapy, no. 10 LND may not bring survival benefits. However, further validation with a large-sample study is needed.

Background: Compared with other histologic types, signet ring cell gastric carcinoma (SRC) has unique oncological characteristics, and its implication on the prognosis of gastric cancer patients remains unclear. The purpose of this study was to evaluate the prognostic impact of body mass index (BMI) on SRC patients. Methods: A retrospective analysis was performed using the clinical records of 3342 patients with SRC or tubular adenocarcinoma who underwent radical gastrectomy between 2000 and 2014. Patients were divided into three groups according to histologic subtype: SRC, well-to-moderately differentiated adenocarcinoma (WMD), and poorly differentiated adenocarcinoma (PD). We compared the survival of SRC patients with that of tubular adenocarcinoma patients according to BMI. Results: The 5-year survival of SRC was significantly worse than that of WMD (P 0.05) and better than that of PD (P

Background: Carcinoembryonic antigen (CEA) is one of the important indexes for the diagnosis and prognosis of gastrointestinal cancer. Systemic inflammatory response (SIR) is closely related to the occurrence and development of gastrointestinal cancer. Methods: A total of 803 patients who underwent radical gastrectomy in Qinghai University Affiliated Hospital from January 2012 to December 2016 were included as training set. Multivariable Cox proportional hazard regression was used to identify associations with outcome of gastric cancer (GC). CNLR was established by combining CEA and the neutrophils to lymphocytes ratio (NLR, a typical parameter in SIR) to generate a novel prognostic score system and its prognostic value was externally validated. Results: Multivariate analysis showed that CEA and NLR were independent prognostic factors for GC patients (both p < 0.05). A higher CNLR was significantly associated with older age, male sex, larger tumor size, vascular invasion and advanced stages (all p < 0.05). Patients with higher CNLR had poor prognosis than those with lower CNLR (p < 0.05). Multivariate analysis showed that CNLR was an independent prognostic factor (p < 0.05). Incorporation of the CNLR into a prognostic model including age and TNM stage generated a nomogram, which predicted accurately 3- and 5-year survival for GC patients. And similar results were obtained in the external validation set. Conclusions: The CNLR prognostic scoring system established by combining CEA and NLR is an independent prognostic factor for GC, which can be incorporated into the traditional TNM staging to improve the prediction of long-term survival outcomes.

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

The effect of POC1 centriolar protein A (POC1A) on gastric cancer (GC) has not been clearly defined. In this study, POC1A expression and clinical information in patients with GC were analyzed. Multiple databases were used to investigate the genes that were co-expressed with POC1A and genes whose changes co-occurred with genetic alternations of POC1A. Moreover, the TISIDB and TIMER databases were used to analyze immune infiltration. The GSE54129 GC dataset and LASSO regression model (tumor vs. normal) were employed, and 6 significant differentially expressed genes (LAMP5, CEBPB, ARMC9, PAOX, VMP1, POC1A) were identified. POC1A was selected for its high expression in adjacent tissues, which was confirmed with IHC. High POC1A expression was related to better overall and recurrence-free survival. GO and KEGG analyses demonstrated that POC1A may regulate the cell cycle, DNA replication and cell growth. Furthermore, POC1A was found to be correlated with immune infiltration levels in GC according to the TISIDB and TIMER databases. These findings indicate that POC1A acts as a tumor suppressor in GC by regulating the cell cycle and cell growth. In addition, POC1A preferentially regulates the immune infiltration of GC via several immune genes. However, the specific mechanism requires further study.

Background The benefits of neoadjuvant therapy for patients with locally advanced gastric cancer (GC) are increasingly recognized. The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. This study aims to develop a modified ypTNM staging. Patients and Methods Clinicopathological data of 1,791 patients who underwent curative-intent gastrectomy after neoadjuvant therapy in the Surveillance, Epidemiology, and End Results database, as the development cohort, were retrospectively analyzed. Modified ypTNM staging was established based on overall survival (OS). We compared the prognostic performance of the AJCC 8th edition ypTNM staging and the modified staging for patients after neoadjuvant therapy. Results In the development cohort, the 5-year OS for AJCC stages I, II, and III was 58.8%, 39.1%, and 21.6%, respectively, compared with 69.9%, 54.4%, 34.4%, 24.1%, and 13.6% for modified ypTNM stages IA, IB, II, IIIA, and IIIB. The modified staging had better discriminatory ability (C-index: 0.620 vs. 0.589, p < .001), predictive homogeneity (likelihood ratio chi-square: 140.71 vs. 218.66, p < .001), predictive accuracy (mean difference in Bayesian information criterion: 64.94; net reclassification index: 35.54%; integrated discrimination improvement index: 0.032; all p < .001), and model stability (time-dependent receiver operating characteristics curves) over AJCC. Decision curve analysis showed that the modified staging achieved a better net benefit than AJCC. In external validation (n = 266), the modified ypTNM staging had superior prognostic predictive power (all p < .05). Conclusion We have developed and validated a modified ypTNM staging through multicenter data that is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with GC after neoadjuvant therapy. Implications for Practice The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. Based on multi-institutional data, this study developed a modified ypTNM staging, which is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with gastric cancer after neoadjuvant therapy.

Background Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance. Methods We examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft. Results We show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA. Conclusions Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.

Background BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Methods We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. Results BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. Conclusions Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p

Background In clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear. Methods Consecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan–Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated. Results A total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P P Conclusion Pre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

Background: There are controverted whether the long-term use of proton pump inhibitors (PPI) will increase the risk of gastric cancer. We performed a meta-analysis to assess the risk of gastric cancer in PPI users compared with non-PPI users. Methods: The main inclusion criteria were original studies reporting the incidence of gastric cancer in PPI users compared with non-PPI users. Key outcomes were the risk ratios (RR) for gastric cancer in association with PPI users or non-PPI users. Results: We analyzed data from 8 studies, comprising more than 927,684 patients. The risk of gastric cancer in PPI users was significantly higher than in non-PPI users [RR= 2.10, 95% CI (1.17-3.97)]. The risk of gastric cancer was similar between the 2 groups when the duration was ≤1 year [RR= 2.18, 95% CI (0.66-7.11)]. While the risk of gastric cancer for PPI users was higher than in non-PPI users when the duration was between 1-3 years, ≥1 year, ≥3 years and ≥5 years. The risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users [RR= 2.66, 95% CI (1.66 -4.27)], and the risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users when the duration ≥1 year [RR= 1.99, 95% CI (1.03-3.83)], but the risk for cardiac gastric cancer was similar between the 2 groups [RR= 1.86, 95% CI (0.71-4.89)]. Conclusions: We found the long-term use of PPI (duration ≥1 year) was significantly associated with a higher risk of non-cardiac gastric cancer.

Purpose: To evaluate whether the European Neuroendocrine Tumor Society (ENETS) system or the 8th American Joint Committee on Cancer (AJCC) staging manual are suitable for gastric neuroendocrine carcinomas and/or mixed adenoneuroendocrine carcinomas (G-NECs/MANECs). Methods: Patients in a multicentric series with G-NEC/MANEC who underwent curative-intent surgical resection for a primary tumor were included. An optimal staging system was proposed base on analysis of the T and N status and validated by the SEER database. Results: Compared with the ENETS system, the survival curves of the T category and N category in the 8th AJCC system were better separated and distributed in a more balanced way, but the survival curves of T2 vs. T3, N0 vs. N1, and N3a vs. N3b overlapped. For the T category, the 8th AJCC T category was modified by combining T2 and T3, which was consistent with the T category in the 6th AJCC manual for GC. For the N category, the optimal cut-off values of metastatic lymph nodes using X-tile were also similar to those of the N category in the 6th AJCC system. The Kaplan-Meier plots of the 6th AJCC system showed statistically significant differences between individual substages. Compared with the other 2 classifications, the 6th AJCC system also showed superior prognostic stratification. Similar results were obtained in both multicentric and SEER validation sets. Conclusions: Compared to the 8th AJCC and ENETS systems, the 6th AJCC staging system for GC is more suitable for G-NEC/MANEC and can be adopted in clinical practice.

Objective: To evaluate the prognostic significance of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging classification for gastric cancer. Methods: Prospective databases were reviewed to identify patients who underwent radical gastrectomy at two specialized eastern centers. The prognostic value of the eighth edition TNM classification was estimated and compared with that of the seventh edition. Additional external validation was performed using a dataset from a Western population. Results: Significant differences in 5-year overall survival (OS) rates were observed for each TNM stage when using the eighth edition system, and smaller Akaike information criteria (AIC) values and a higher c-statistic were observed relative to those of the seventh edition. However, the OS rates in each subgroup of stage III patients based on the eighth edition were significantly different. Patients with the same pN stage, namely, the pT4a and pT4b groups, showed similar 5-year OS (P>0.05). Based on the survival data, we propose a simplified staging system. In the improved TNM (iTNM) staging system, the subgroups of a given TNM stage do not show statistically significant differences in OS. The iTNM staging exhibits superior prognostic stratification, with lower AIC values and a higher c-statistic than the eighth edition TNM classification. Similar results were obtained with the external validation dataset from the IMIGASTRIC database. Conclusion: The prognostic prediction of the eighth edition of the AJCC TNM classification is superior to that of the seventh edition. However, it remains associated with some stage migration. The iTNM staging system permits simplification and slightly better prognostic prediction.

Background Application of indocyanine green (ICG) fluorescence imaging is effective in guiding laparoscopic radical lymphadenectomy for gastric cancer. However, the optimal approach for indocyanine green injection is controversial. Therefore, the objective of this study was aimed to compare the efficacy and ICG injection between the preoperative submucosal and intraoperative subserosal approaches for lymph node (LN) tracing during laparoscopic gastrectomy. Method This randomized controlled trial (ClinicalTrials.gov, NCT04219332) included 266 patients with potentially resectable gastric cancer (cT1–T4a, N0/+, M0) enrolled from a tertiary teaching center between December 2019 and October 2020. The primary endpoint was total number of retrieved LNs. Results In total, 259 patients (n = 130 and n = 129 in the submucosal and subserosal groups, respectively) were included in the per-protocol analysis. There are no significant differences in total number of retrieved LNs between the two groups (49.8 vs. 49.2, P = 0.713). The rate of LN noncompliance in the submucosal group was comparable to that in the subserosal group (32.3% vs. 33.3%, P = 0.860). No significant difference was found between the submucosal and subserosal groups in terms of the incidence (17.7% vs. 16.3%; P = 0.762) or severity of postoperative complications. The mean fluorescence cost in the submucosal group was higher than that in the subserosal group ($335.3 vs. $182.4; P < 0.001). The overall treatment satisfaction score was lower in the submucosal group than in the subserosal group (70.5 vs. 76.1%, P = 0.048). Conclusion ICG administered by subserosal injection was comparable to that administered by submucosal injection for lymph node tracing in gastric cancer. However, the former approach imposed a lower economic and mental burden on patients undergoing laparoscopic D2 lymphadenectomy. Trial registration ClinicalTrials.gov, NCT04219332.

This cross-sectional study examines the characteristics and presence of research waste, defined as unpublished data, inadequate reporting, or avoidable design limitations, among randomized clinical trials in gastric cancer., Key Points Question Is there research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) in randomized clinical trials (RCTs) of gastric cancer? Findings This cross-sectional study included 137 RCTs, of which 119 had 1 or more features of research waste. Additionally, 35 RCTs were referenced in guidelines, and 18 had their prospective data reused. Meaning This study found a research waste burden in gastric cancer RCTs during the past 20 years, which may provide evidence for the development of rational RCTs and reduction of waste in the future., Importance The results of numerous large randomized clinical trials (RCTs) have changed clinical practice in gastric cancer (GC). However, research waste (ie, unpublished data, inadequate reporting, or avoidable design limitations) is still a major challenge for evidence-based medicine. Objectives To determine the characteristics of GC RCTs in the past 20 years and the presence of research waste and to explore potential targets for improvement. Design, Setting, and Participants In this cross-sectional study of GC RCTs, ClinicalTrials.gov was searched for phase 3 or 4 RCTs registered from January 2000 to December 2019 using the keyword gastric cancer. Independent investigators undertook assessments and resolved discrepancies via consensus. Data were analyzed from August through December 2020. Main Outcomes and Measures The primary outcomes were descriptions of the characteristics of GC RCTs and the proportion of studies with signs of research waste. Research waste was defined as unpublished data, inadequate reporting, or avoidable design limitations. Publication status was determined by searching PubMed and Scopus databases. The adequacy of reporting was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline checklist. Avoidable design limitations were determined based on existing bias or lack of cited systematic literature reviews. In the analyses of research waste, 125 RCTs that ended after June 2016 without publication were excluded. Results A total of 262 GC RCTs were included. The number of RCTs increased from 25 trials in 2000 to 2004 to 97 trials in 2015 to 2019, with a greater increase among RCTs of targeted therapy or immunotherapy, which increased from 0 trials in 2000 to 2004 to 36 trials in 2015 to 2019. The proportion of RCTs that were multicenter was higher in non-Asian regions than in Asian regions (50 of 71 RCTs [70.4%] vs 96 of 191 RCTs [50.3%]; P = .004). The analysis of research waste included 137 RCTs, of which 81 (59.1%) were published. Among published RCTs, 65 (80.2%) were judged to be adequately reported and 63 (77.8%) had avoidable design defects. Additionally, 119 RCTs (86.9%) had 1 or more features of research waste. Study settings that included blinding (odds ratio [OR], 0.56; 95% CI, 0.33-0.93; P = .03), a greater number of participants (ie, ≥200 participants; OR, 0.07; 95% CI, 0.01-0.51; P = .01), and external funding support (OR, 0.22; 95% CI, 0.08-0.60; P = .004) were associated with lower odds of research waste. Additionally, 35 RCTs (49.3%) were referenced in guidelines, and 18 RCTs (22.2%) had their prospective data reused. Conclusions and Relevance To our knowledge, this study is the first to describe the characteristics of GC RCTs in the past 20 years, and it found a research waste burden, which may provide evidence for the development of rational RCTs and reduction of waste in the future.

Background: The laparoscopic approach in gastric cancer surgery is being increasingly adopted worldwide. However, studies focusing specifically on laparoscopic gastrectomy with D2 lymphadenectomy are still lacking in the literature. This retrospective study aimed to compare the short-term and long-term outcomes of laparoscopic versus open gastrectomy with D2 lymphadenectomy for gastric cancer. Methods: The protocol-based, international IMIGASTRIC (International study group on Minimally Invasive surgery for Gastric Cancer) registry was queried to retrieve data on patients undergoing laparoscopic or open gastrectomy with D2 lymphadenectomy for gastric cancer with curative intent from January 2000 to December 2014. Eleven predefined, demographical, clinical, and pathological variables were used to conduct a 1:1 propensity score matching (PSM) analysis to investigate intraoperative and recovery outcomes, complications, pathological findings, and survival data between the two groups. Predictive factors of long-term survival were also assessed. Results: A total of 3033 patients from 14 participating institutions were selected from the IMIGASTRIC database. After 1:1 PSM, a total of 1248 patients, 624 in the laparoscopic group and 624 in the open group, were matched and included in the final analysis. The total operative time (median 180 versus 240 min, p &lt, 0.0001) and the length of the postoperative hospital stay (median 10 versus 14.8 days, p &lt, 0.0001) were longer in the open group than in the laparoscopic group. The conversion to open rate was 1.9%. The proportion of patients with in-hospital complications was higher in the open group (21.3% versus 15.1%, p = 0.004). The median number of harvested lymph nodes was higher in the laparoscopic approach (median 32 versus 28, p &lt, 0.0001), and the proportion of positive resection margins was higher (p = 0.021) in the open group (5.9%) than in the laparoscopic group (3.2%). There was no significant difference between the groups in five-year overall survival rates (77.4% laparoscopic versus 75.2% open, p = 0.229). Conclusion: The adoption of the laparoscopic approach for gastric resection with D2 lymphadenectomy shortened the length of hospital stay and reduced postoperative complications with respect to the open approach. The five-year overall survival rate after laparoscopy was comparable to that for patients who underwent open D2 resection. The types of surgical approaches are not independent predictive factors for five-year overall survival.

The value of indocyanine green (ICG) fluorescence imaging in tracing metastatic lymph nodes (LNs) has rarely been reported. We aimed to evaluate the clinical implications of fluorescence imaging-guided lymphadenectomy and the sensitivity of fluorescent lymphography to detect metastatic LN stations in gastric cancer (GC).This analysis pooled data from two randomized controlled trials (FUGES-012 and FUGES-019 studies) on laparoscopic ICG tracer-guided lymphadenectomy for GC between November 2018 and October 2020. Patients who received ICG injection using either the intraoperative subserosal or preoperative submucosal approaches 1 day before surgery and underwent fluorescence imaging-guided lymphadenectomy were defined as the ICG group. Patients who underwent conventional lymphadenectomy without ICG injection and intraoperative imaging were defined as the non-ICG group.Among 514 enrolled patients, the ICG and non-ICG groups included 385 and 129, respectively. A significantly higher mean number of LNs was retrieved in the ICG group than in the non-ICG group (49.9 vs. 42.0, P 0.001). The ICG group showed a lower LN noncompliance rate than that in the non-ICG group (31.9% vs. 57.4%, P 0.001). The sensitivity of fluorescence imaging for detecting all metastatic LN stations was 86.8%. The negative predictive value was 92.2% for nonfluorescent stations. For detecting all metastatic stations, subgroup analysis revealed 97.7%, 91.7%, 86.2%, and 84.3% sensitivities for pT1, pT2, pT3, and pT4a tumors, respectively. Regardless of gastrectomy type, the diagnostic accuracy for detecting all metastatic stations in the D1+ and D2 stations for cT1-cT2 disease reached 100%.ICG fluorescence imaging, using either the subserosal or submucosal approaches, assisted in the thorough dissection of potentially metastatic LNs, as recommended for individualized laparoscopic lymphadenectomy for GC.

BackgroundLHPP, a histidine phosphatase, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. ResultsThe results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation, and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. ConclusionLHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

Key Points Question Are there any differences in prognoses or recurrence patterns associated with gastric neuroendocrine carcinoma, mixed adenoneuroendocrine carcinoma, or adenocarcinoma? Findings This cohort study included 3689 patients with resectable gastric adenocarcinoma, gastric neuroendocrine carcinoma, or gastric mixed adenoneuroendocrine carcinoma. Propensity score matching analysis found that, compared with gastric adenocarcinoma, gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma were independent risk factors associated with worse disease-free survival, postrecurrence survival, and distant recurrence outcomes. Meaning These findings suggest that different follow-up and treatment strategies should be developed to improve the long-term survival of patients with gastric neuroendocrine carcinoma or gastric mixed adenoneuroendocrine carcinoma, especially for patients with tumors penetrating into the subserosa or deeper layers and with lymph node metastasis., This cohort study examines differences in long-term survival and patterns of recurrence among patients with gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma., Importance Gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma are rare pathological types of gastric cancer, and there is a lack of multicenter studies comparing the prognosis and recurrence patterns of gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Objective To compare the differences in long-term survival and patterns of recurrence among gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Design, Setting, and Participants This cohort study included patients with resectable gastric neuroendocrine carcinoma and gastric mixed adenoneuroendocrine carcinoma at 23 hospitals in China from January 2006 to December 2016. In addition, patients with gastric adenocarcinoma were selected as controls. Propensity score–matched analysis was used to match pathological stage among the different pathological types, and disease-free survival (DFS), postrecurrence survival (PRS), and patterns of recurrence were examined. Data analysis was conducted from July 15, 2020, to October 21, 2020. Exposures Curative resection for gastric neuroendocrine carcinoma, gastric mixed adenoneuroendocrine carcinoma, and gastric adenocarcinoma. Main Outcomes and Measures The main outcomes were DFS and patterns of recurrence. Results A total of 3689 patients were analyzed (median [interquartile range] age, 62 [55-69] years; 2748 [74.5%] men), including 503 patients (13.6%) with gastric neuroendocrine carcinoma, 401 patients (10.9%) with gastric mixed adenoneuroendocrine carcinoma, and 2785 patients (75.5%) with gastric adenocarcinoma. After propensity score matching, 5-year DFS was 47.6% (95% CI, 42.7%-52.5%) for patients with gastric neuroendocrine carcinoma, compared with 57.6% (95% CI, 55.1%-60.1%) with gastric adenocarcinoma (P

ObjectiveTo validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery.MethodsTwo hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading.ResultsFor patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (pvs 19.5 months, respectively; p=0.01). Subgroup analyses by histological subtype indicated that the oxaliplatin-based regimen improved the OS in nonsignet ring cell carcinoma compared to the nonoxaliplatin-based regimen (53.7 months vs 19.5 months, respectively; p=0.011). However, similar findings were not observed in RFS.ConclusionTRG was an independent factor of AGC treated with neoadjuvant chemotherapy plus surgery. Oxaliplatin-based neoadjuvant chemotherapy regimens improve tumor response and may have an overall survival benefit for patients with nonsignet ring cell carcinoma.

Background: Several meta-analyses have tried to defi ne the role of minimally invasive approaches. However, further evidence to get a wider spread of these methods is necessary. Current studies describe minimally invasive surgery as a possible alternative to open surgery but deserving further clarifi cation. However, despite the increasing interest, the difficulty of planning prospective studies of adequate size accounts for the low level of evidence, which is mostly based on retrospective experiences. A multi-institutional prospective study allows the collection of an impressive amount of data to investigate various aspects of minimally invasive procedures with the opportunity of developing several subgroup analyses. A prospective data collection with high methodological quality on minimally invasive and open gastrectomies can clarify the role of diff erent procedures with the aim to develop specifi c guidelines. Methods and analysis: a multi-institutional prospective database will be established including information on surgical, clinical and oncological features of patients treated for gastric cancer with robotic, laparoscopic or open approaches and subsequent follow-up. The study has been shared by the members of the International study group on Minimally Invasive surgery for GASTRIc Cancer (IMIGASTRIC) The database is designed to be an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centers. Ethics: This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. Trial registration number: NCT02751086

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P, Patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages.

To examine the associations of the Age-Adjusted Charlson Comorbidity Index (ACCI) and preoperative systemic inflammation with survival in gastric cancer (GC) patients who underwent radical gastrectomy.Data from patients with GC who underwent radical gastrectomy between January 2009 and December 2014 in Fujian Medical University Union Hospital were retrospectively analyzed. Univariate and multivariate Cox regression analyses were performed to identify the prognostic factors. The relationship between the ACCI and systemic inflammation of the patients was explored, and the prognostic value of a new scoring system based on the ACCI and systemic inflammation (ANLR) was evaluated.A total of 2257 patients with GC were included. The ACCI and neutrophil to lymphocyte ratio (NLR) were independent prognostic factors for overall survival (both P 0.001) by multivariate analysis. A higher ACCI was an independent predictor of the increase in preoperative NLR (P 0.001). Based on the preoperative ACCI and NLR, we established a novel marker, ANLR. Multivariate analysis showed that the ANLR was a significant independent predictor of 5-year OS (P 0.001). The Harrell's C-statistics (C-index) of a model combining the ANLR and pTNM was 0.744 (95% CI: 0.728-0.760), which was significantly higher than the pTNM stage (0.717, 95% CI: 0.702-0.731; P 0.001).The ACCI of patients with gastric cancer was associated with preoperative systemic inflammation. The ACCI combined with the NLR, which are commonly collected biomarkers, could enhance prognostication for GC patients.

BACKGROUND The incidence of proximal gastric cancer (GC) is increasing, and methods for the prediction of the long-term survival of proximal GC patients have not been well established. AIM To develop nomograms for the prediction of long-term survival among proximal GC patients. METHODS Between January 2007 and June 2013, we prospectively collected and retrospectively analyzed the medical records of 746 patients with proximal GC, who were divided into a training set (n = 560, 75%) and a validation set (n = 186, 25%). A Cox regression analysis was used to identify the preoperative and postoperative risk factors for overall survival (OS). RESULTS Among the 746 patients examined, the 3- and 5-year OS rates were 66.1% and 58.4%, respectively. In the training set, preoperative T stage (cT), N stage (cN), CA19-9, tumor size, ASA core, and 3- to 6-mo weight loss were incorporated into the preoperative nomogram to predict the OS. In addition to these variables, lymphatic vascular infiltration (LVI), postoperative tumor size, T stage, N stage, blood transfusions, and complications were incorporated into the postoperative nomogram. All calibration curves used to determine the OS probability fit well. In the training set, the preoperative nomogram achieved a C-index of 0.751 [95% confidence interval (CI): 0.732-0.770] in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 86.8%, 73.0%, 43.72%, and 20.9%, P < 0.001). The postoperative nomogram had a C-index of 0.758 in predicting OS and accurately stratified the patients into four prognostic subgroups (5-year OS rates: 82.6%, 74.3%, 45.9%, and 18.9%, P < 0.001). CONCLUSION The nomograms accurately predicted the pre- and postoperative long-term survival of proximal GC patients.

BACKGROUND Because of the powerful abilities of self-learning and handling complex biological information, artificial neural network (ANN) models have been widely applied to disease diagnosis, imaging analysis, and prognosis prediction. However, there has been no trained preoperative ANN (preope-ANN) model to preoperatively predict the prognosis of patients with gastric cancer (GC). AIM To establish a neural network model that can predict long-term survival of GC patients before surgery to evaluate the tumor condition before the operation. METHODS The clinicopathological data of 1608 GC patients treated from January 2011 to April 2015 at the Department of Gastric Surgery, Fujian Medical University Union Hospital were analyzed retrospectively. The patients were randomly divided into a training set (70%) for establishing a preope-ANN model and a testing set (30%). The prognostic evaluation ability of the preope-ANN model was compared with that of the American Joint Commission on Cancer (8th edition) clinical TNM (cTNM) and pathological TNM (pTNM) staging through the receiver operating characteristic curve, Akaike information criterion index, Harrell's C index, and likelihood ratio chi-square. RESULTS We used the variables that were statistically significant factors for the 3-year overall survival as input-layer variables to develop a preope-ANN in the training set. The survival curves within each score of the preope-ANN had good discrimination (P < 0.05). Comparing the preope-ANN model, cTNM, and pTNM in both the training and testing sets, the preope-ANN model was superior to cTNM in predictive discrimination (C index), predictive homogeneity (likelihood ratio chi-square), and prediction accuracy (area under the curve). The prediction efficiency of the preope-ANN model is similar to that of pTNM. CONCLUSION The preope-ANN model can accurately predict the long-term survival of GC patients, and its predictive efficiency is not inferior to that of pTNM stage.

BACKGROUND Robotic surgery has been considered to be significantly better than laparoscopic surgery for complicated procedures. AIM To explore the short-term effect of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy (SPSHL) for advanced gastric cancer (GC) by Huang’s three-step maneuver. METHODS A total of 643 patients who underwent SPSHL were recruited from April 2012 to July 2017, including 35 patients who underwent robotic SPSHL (RSPSHL) and 608 who underwent laparoscopic SPSHL (LSPSHL). One-to-four propensity score matching was used to analyze the differences in clinical data between patients who underwent robotic SPSHL and those who underwent laparoscopic SPSHL. RESULTS In all, 175 patients were matched, including 35 patients who underwent RSPSHL and 140 who underwent LSPSHL. After matching, there were no significant differences detected in the baseline characteristics between the two groups. Significant differences in total operative time, estimated blood loss (EBL), splenic hilar blood loss (SHBL), splenic hilar dissection time (SHDT), and splenic trunk dissection time were evident between these groups (P < 0.05). Furthermore, no significant differences were observed between the two groups in the overall noncompliance rate of lymph node (LN) dissection (62.9% vs 60%, P = 0.757), number of retrieved No. 10 LNs (3.1 ± 1.4 vs 3.3 ± 2.5, P = 0.650), total number of examined LNs (37.8 ± 13.1 vs 40.6 ± 13.6, P = 0.274), and postoperative complications (14.3% vs 17.9%, P = 0.616). A stratified analysis that divided the patients receiving RSPSHL into an early group (EG) and a late group (LG) revealed that the LG experienced obvious improvements in SHDT and length of stay compared with the EG (P < 0.05). Logistic regression showed that robotic surgery was a significantly protective factor against both SHBL and SHDT (P < 0.05). CONCLUSION RSPSHL is safe and feasible, especially after overcoming the early learning curve, as this procedure results in a radical curative effect equivalent to that of LSPSHL.

Background Previous studies have elucidated that on average, long-term cancer survivors have better prognoses than newly diagnosed individuals. This study aimed to devise a nomogram to predict the conditional probability of cancer-specific survival (CPCS) in gastric cancer (GC) patients after D2 lymphadenectomy. Methods Clinicopathological data for 2,596 GC patients who underwent D2 lymphadenectomy in an Eastern institution (the training cohort) were retrospectively analysed. Cancer-specific survival (CSS) was predicted using Cox regression models. A nomogram was constructed to predict CPCS at 3 and 5 years post-gastrectomy. Two external validations were performed using a cohort of 2,198 Chinese patients and a cohort of 504 Italian patients. Results In the training cohort, the 5-year CPCS was 59.2% immediately post-gastrectomy and increased to 68.8%, 79.7%, and 88.8% at 1, 2, and 3 years post-gastrectomy, respectively. Multivariate Cox regression analyses showed that age; tumour site, size and invasion depth; numbers of examined and metastatic lymph nodes; and surgical margins were independent prognostic factors of CSS (all P Conclusions: we developed a robust nomogram to predict CPCS after D2 lymphadenectomy for GC based on survival duration.

Objective. Circular RNAs (circRNAs) have been reported to be widely involved in pathological processes of various cancers. However, little is known about their diagnostic values in early gastric cancer (EGC). This study is aimed at exploring whether circulating circRNAs in plasma could act as biomarkers for EGC diagnosis. Materials and Methods. Mass spectrometry (MS) was performed to identify the proteins that at significantly aberrantly levels in gastric cancer (GC) tissues. The target circRNA was identified by bioinformatics analysis. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic utility. Results. MS revealed that the ribosomal protein L6 (RPL6) expression was significantly downregulated only in EGC tissues vs. nontumorous tissues; this was validated by western blotting (n=30, p=0.0094). Bioinformatics analysis predicted that there is a hsa_circ_0006848/hsa_miR-329-5p/RPL6 axis in GC progression. The hsa_circ_0006848 expression was significantly downregulated in EGC tissues (vs. nontumorous tissues, n=30, p=0.0073) and plasma samples from EGC patients (vs. paired healthy volunteers, n=30, p=0.0089). In addition, the hsa_circ_0006848 plasma level in postoperative patients was significantly higher than that of preoperative patients (n=30, p=0.047). Furthermore, the decreased hsa_circ_0006848 expression in plasma was negatively correlated with poor differentiation (p=0.037) and tumor size (p=0.046). The area under the ROC curve (AUC) of hsa_circ_0006848 in plasma was 0.733, suggesting a good diagnostic value. The plasma hsa_circ_0006848 level combined with the carcinoembryonic antigen (CEA), carbohydrate-associated antigen 19-9 (CA19-9), and carbohydrate-associated antigen 72-4 (CA72-4) level increased the AUC to 0.825. Conclusion. Our results indicated that plasma hsa_circ_0006848 may be a novel noninvasive biomarker in EGC diagnosis.

Background UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. Methods Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. Results Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P P Conclusion UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

Background Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Methods Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. Results Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank ppn = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank pp Conclusions CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. Trial registration The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481) on December 30, 2014.

Background Examined lymph node counts of remnant gastric cancer patients are often insufficient, and the prognostic ability of tumor-node-metastasis staging is therefore limited. This study aimed to create a simple and universally applicable prediction model for RGC patients after completion of gastrectomy. Methods A 5-year overall survival prediction model for remnant gastric cancer patients was developed using a test dataset of 148 consecutive patients. Model coefficients were obtained based on the Cox analysis of clinicopathological factors. Prognostic performance was assessed with the concordance index (C-index) and decision curve analysis. For internal validation, the bootstrap method and calibration assessment were used. The model was validated using 2 external cohorts from China (First Affiliated Hospital of Fujian Medical University, n = 46) and the United States (Mayo Clinic, n = 20). Results Depth of tumor invasion, number of metastatic lymph nodes, distant metastasis, and operative time were independent prognostic factors. Our model’s C-index (0.761) showed better discriminatory power than that of the eighth tumor-node-metastasis staging system (0.714, P = .001). The model calibration was accurate at predicting 5-year survival. Decision curve analysis showed that the model had a greater benefit, and the results were also confirmed by bootstrap internal validation. In external validation, the C-index and decision curve analysis showed good prognostic performances in patient datasets from 2 participating institutions. Moreover, we verified the reliability of the model in an analysis of patients with different examined lymph node counts (>15 or ≤15). Conclusion Utilizing clinically practical information, we developed a universally applicable prediction model for accurately determining the 5-year overall survival of remnant gastric cancer patients after completion of gastrectomy. Our predictive model outperformed tumor-node-metastasis staging in diverse international datasets regardless of examined lymph node counts.

To evaluate the effects of three nutritional scoring systems: Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT), and Naples Prognostic Score (NPS) on the short- or long-term prognosis of gastric cancer (GC) patients who underwent radical gastrectomy. The clinicopathological data of 2182 patients who underwent radical gastrectomy at the Fujian Medical University Union Hospital (FMUUH) from 2009 to 2014 were retrospectively analyzed. The effects of the PNI, CONUT, and NPS on the short- or long-term prognosis of GC patients were analyzed. Overall, 359 (16.5%) patients had postoperative complications. There was no significant association between the PNI, CONUT, and NPS and postoperative complications (P > 0.05); however, high CONUT and NPS were significantly associated with severe postoperative complications (P

Background Neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy is commonly used for patients with locally advanced gastric adenocarcinoma. The eighth AJCC ypTNM staging system was validated based on patients undergoing more limited lymphadenectomy (less than D2). The aim of this study was to develop a system for accurate staging of patients with locally advanced gastric adenocarcinoma who receive neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy. Methods A modified system of ypTNM was developed, based on overall survival (OS) of patients receiving neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy at Memorial Sloan Kettering Cancer Center, and validated using data from an international cohort of patients who had similar treatment. Results Of 325 patients in the derivation cohort, 33 (10·2 per cent) had ypT0 N0/+ tumours, which are not classifiable under the AJCC system. The 5-year OS rate for modified ypTNM stages I, II, IIIA and IIIB was 89, 71, 42·3 and 10 per cent respectively, compared with 82, 65·2 and 24·1 for AJCC stages I, II and III respectively. The concordance index (0·730 versus 0·709), estimated area under the curve (0·765 versus 0·740) and time-dependent receiver operating characteristic (ROC) curve throughout the observation period were all superior for modified ypTNM staging. For the validation cohort of 186 patients, the modified system was again better at separating patients into prognostic groups for OS. Conclusion The modified ypTNM staging system improves the accuracy of OS prediction for patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy.

The aim of this study was to evaluate the prognostic value of the eighth AJCC TNM staging classification for patients with gastric cancer who had already survived for 5 years.Patients who underwent radical gastrectomy at a large eastern center were considered. The prognostic value of staging systems were assessed and compared. Additional external validation was performed using a dataset from the Surveillance, Epidemiology, and End Result (SEER) database.The 5-year overall survival (OS) rate for patients in the training set was 59.4%. With the prolongation of the survival time after surgery, the 5-year OS improved significantly (P 0.05). However, there were no significant differences in survival curves among patients who have survived 5 years after surgery. The AUC and χ2 of the eighth AJCC classification for predicting of 5-year OS decreased gradually after surgery and appeared stable after 5 years. For patients who survived 5 years after surgery, we constructed a new TNM staging system (nTNM) according to the survival curves of T stage and N stage. A 2-step multivariate analysis showed that nTNM, age and sex were independent prognostic factors. The nTNM demonstrated superior prognostic stratification, with higher c-statistic and likelihood ratio chi-square scores and lower AIC values than those of the AJCC classification. Similar results were observed in the external validation set.The nTNM predicted an additional survival more accurately than did the AJCC classification for patients who have survived 5 years after surgery; this may guide decisions regarding surveillance.

Background Whether the tumor‐node‐metastasis (TNM) staging system is appropriate for patients with node‐negative gastric cancer (GC) is still inconclusive. The modified staging system developed by recursive partitioning analysis (RPA) showed good prognostic performance in a variety of cancers. The application of RPA has not been reported in the prognostic prediction of GC. Methods Node‐negative GC patients who underwent radical resection at Fujian Medical University Union Hospital (n = 862) and Sun Yat‐sen University Cancer Center (n = 311) with at least 5 years of follow‐up were selected as the training set. RPA was used to develop a modified staging system. Patients from the Surveillance, Epidemiology, and End Results database (n = 1415) were selected as the validation set. Results The 5‐year overall survival (OS) rates of patients with 8th AJCC‐TNM stage IA‐IIIA in the training set were IA 95.2%, IB 87.1%, IIA 78.3%, IIB 75.8%, and IIIA 72.6%. Multivariate analysis (MVA) showed that larger tumor size, elder age, and deeper depth of invasion were independent predictors for OS in patients with node‐negative GC (all P

Objective The aim of this study was to investigate the prognostic value of preoperative sarcopenia and systemic inflammation for patients with resectable gastric cancer (GC) and develop a novel and powerful prognostic score based on these factors. Materials and Methods Patients with GC who underwent radical gastrectomy between December 2009 and December 2013 were included. A multivariate Cox regression analysis was performed to identify the prognostic factors. A novel prognostic score (SLMR) was developed based on preoperative sarcopenia and the lymphocyte-monocyte ratio (LMR), and its prognostic value was evaluated. Results In total, 1,167 patients with resectable GC were included in the study. On multivariate analysis, preoperative sarcopenia and the LMR were shown to be independent prognostic factors (both p < .001). A low LMR was an independent predictor from sarcopenia (p < .001). Based on preoperative sarcopenia and the LMR, we established the SLMR. An elevated SLMR was associated with older age, higher ASA scores, larger tumor size, advanced stages, and vascular invasion (all p < .05). Multivariate analysis revealed that the SLMR was a significant independent predictor (p < .001). We incorporated the SLMR into a prognostic model that included tumor size and TNM stage and generated a nomogram, which accurately predicted 3- and 5-year survival for GC patients. Conclusion Preoperative systemic inflammation is significantly associated with sarcopenia. The LMR combined with sarcopenia could enhance prognostication for patients with GC who underwent radical gastrectomy. Implications for Practice Increasing evidence shows that sarcopenia and systemic inflammation are closely associated with the prognosis of malignant tumors, and it is essential for clinicians to understand the relationship and combined prognostic effects of these factors for gastric cancer (GC). Based on a large data set, this study found that preoperative systemic inflammation was significantly associated with sarcopenia in GC, and combining these two predictors could effectively predict the prognosis and complement the prognostic value of the TNM staging system. These findings may lead to the development of new therapeutic avenues to improve cancer outcomes.

Background This study sought to explore whether lymphovascular invasion can affect the prognosis of patients with stage N0 gastric cancer and to evaluate the survival benefit of adjuvant chemotherapy for such patients. Method From January 2006 to December 2011, a total of 2102 gastric cancer patients undergoing radical gastric resection were enrolled in this study. Homogeneity, discriminatory ability, and monotonicity of gradients in the combination of lymphovascular invasion and the 8th edition of the AJCC staging system and the 8th edition of the AJCC staging system alone were compared using linear trend χ2, likelihood ratio χ2 statistics, and Akaike information criterion (AIC) calculations. The Kaplan-Meier method and the log-rank test were used to analyze between-group differences in survival rate. Result The median follow-up time of the whole group was 58 months, and the average age of the whole group was 63.9 years (range 21–89 years). The 3-year and 5-year overall survival rates in N0 patients with lymphovascular invasion were lower than those in N0 patients without lymphovascular invasion (3-year OS: 78.3% vs 92.5%, 5-year OS: 70.0% vs 88.3%, p

Few reports have examined the prognosis of or possible remedial treatments for patients with noncompliant D2 lymphadenectomy. We investigated the effect of noncompliance in lymph node (LN) dissection on long-term survival in gastric cancer (GC) patients after radical gastrectomy and explored intervention measures. Clinicopathological data were retrospectively analyzed in 2401 patients who underwent radical gastrectomy for GC. Noncompliance was defined as patients with more than one empty LN station, as described in the protocol of the Japanese GC Association. The overall noncompliance rate was 49.1%. The 3-year overall survival (OS) rate was significantly better in compliant than noncompliant patients (74.0% vs. 60.1%, P

The definition and predictors of early recurrence (ER) for gastric cancer (GC) patients after radical gastrectomy are unclear.A minimum-p value approach was used to evaluate the optimal cutoff value of recurrence-free survival to determine ER and late recurrence (LR). Receiver operating characteristic curves were generated for inflammatory indices. Potential risk factors for ER were assessed with a Cox regression model. A decision curve analysis was performed to evaluate the clinical utility.A total of 401 patients recruited in a clinical trial (NCT02327481) from January 2015 to April 2016 were included in this study. The optimal length of recurrence-free survival to distinguish between ER (n = 44) and LR (n = 52) was 12 months. Factors associated with ER included a preoperative C-reactive protein-albumin ratio (CAR) ≥ 0.131, stage III and postoperative adjuvant chemotherapy (PAC) 3 cycles. The risk model consisting of both the CAR and TNM stage had a higher predictive ability and better clinical utility than TNM stage alone. Further stratification analysis of the stage III patients found that for the patients with a CAR 0.131, both PAC with 1-3 cycles (p = 0.029) and 3 cycles (p 0.001) could reduce the risk of ER. However, for patients with a CAR ≥ 0.131, a benefit was observed only if they received PAC 3 cycles (54.2% vs 16.0%, p = 0.004), rather than 1-3 cycles (58.3% vs 54.2%, p = 0.824).A recurrence-free interval of 12 months was found to be the optimal threshold for differentiating between ER and LR. Preoperative CAR was a promising predictor of ER and PAC response. PAC with 1-3 cycles may not exert a protective effect against ER for stage III GC patients with CAR ≥ 0.131.

BACKGROUND Anastomotic leakage (AL) is a severe complication associated with high morbidity and mortality after radical gastrectomy (RG) for gastric cancer (GC). We hypothesized that a novel abdominal negative pressure lavage-drainage system (ANPLDS) can effectively reduce the failure-to-rescue (FTR) and the risk of reoperation, and it is a feasible management for AL. AIM To report our institution’s experience with a novel ANPLDS for AL after RG for GC. METHODS The study enrolled 4173 patients who underwent R0 resection for GC at our institution between June 2009 and December 2016. ANPLDS was routinely used for patients with AL after January 2014. Characterization of patients who underwent R0 resection was compared between different study periods. AL rates and postoperative outcome among patients with AL were compared before and after the ANPLDS therapy. We used multivariate analyses to evaluate clinicopathological and perioperative factors for associations with AL and FTR after AL. RESULTS AL occurred in 83 (83/4173, 2%) patients, leading to 7 deaths. The mean time of occurrence of AL was 5.6 days. The AL rate was similar before (2009-2013, period 1) and after (2014-2016, period 2) the implementation of the ANPLDS therapy (1.7% vs 2.3%, P = 0.121). Age and malnourishment were independently associated with AL. The FTR rate and abdominal bleeding rate after AL occurred were respectively 8.4% and 9.6% for the entire period; however, compared with period 1, this significantly decreased during period 2 (16.2% vs 2.2%, P = 0.041; 18.9% vs 2.2%, P = 0.020, respectively). Moreover, the reoperation rate was also reduced in period 2, although this result was not statistically significant (13.5% vs 2.2%, P = 0.084). Additionally, only ANPLDS therapy was an independent protective factor for FTR after AL (P = 0.04). CONCLUSION Our experience demonstrates that ANPLDS is a feasible management for AL after RG for GC.

The metro-ticket prognostic tool for hepatocellular carcinoma has been proven to predict outcome, but a similar concept has not been investigated for GC. The objective of the current study was to apply the principles of the metro-ticket paradigm to develop a novel TNM staging system (nTNM) for gastric cancer (GC). The nTNM considered the distance from the origin on a Cartesian plane incorporating the pN (x-axis) and pT (y-axis) stages. GC patients undergoing radical resection at Fujian Medical University Union Hospital (FMUUH) (n = 4267) were included. The nTNM was validated using 2 external cohorts from the Sun Yat-sen University Cancer Center (SYSUCC) (n = 1800) and Surveillance, Epidemiology, and End Results (SEER) (n = 3227) databases. nTNM classes with the same distance from the origin have same stage; the stage increases with this distance. Among all patients, 48.0% (n = 2049) were restaged in the nTNM compared with the 7th edition of the AJCC-TNM classification; 26.2% (n = 1116) were downstaged in the nTNM compared with the 8th edition. The nTNM provides significant survival differences between stages (all P

Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) was identified as a tumor suppressor in gastric cancer, while, minichromosome maintenance complex component 6 (MCM6), which is closely related to the initiation of DNA replication, was reported to be upregulated in multiple malignancies. However, the interaction between these two proteins has not been investigated in gastric cancer. Here, we evaluate the connection between CDK5RAP3 and MCM6 using mass spectrometry and immunoprecipitation. In cells, cell growth and invasiveness indicate that CDK5RAP3 acts as a tumor suppressor by preventing the effects of MCM6. The potential mechanism was revealed using immunofluorescence and nuclear protein extraction. In patients, immunohistochemistry and immunofluorescence show that the protein levels of CDK5RAP3 were markedly decreased in most gastric tumor tissues compared with adjacent nontumor tissues, and the expression levels of MCM6 in the nucleus showed the opposite trend. Prognostic analysis showed that the combined expression of CDK5RAP3 and MCM6 was an independent prognostic factor correlating with the overall survival of gastric cancer patients. Cox regression analysis indicated that the expression of CDK5RAP3 and MCM6 corresponded to T, N, and M stages. Our results demonstrate that CDK5RAP3 can interact with MCM6 and prevent MCM6 from translocating into the nucleus, which may be a potential mechanism through which CDK5RAP3 negatively regulates the proliferation of gastric cancer.

Background The eighth TNM classification for gastric cancer categorizes N3 as N3a and N3b in the final pathologic stage. The cutoff for N3a/N3b is defined as 15 metastatic lymph nodes, but the rationale for this cutoff remains unclear. This study aimed to determine the optimal N3a/N3b cutoff and evaluate its prognostic significance. Methods An international database was constructed by combining data from patients with N3 gastric cancer and complete five-year follow-up data from the Surveillance, Epidemiology, and End Results program database (n = 1833) and the Fujian Medical University Union Hospital database (n = 920) (total n = 2753). A log-rank test was performed to determine the optimal N3a/N3b cutoff, and its prognostic significance was confirmed in a two-step multivariate analysis and compared to that of the eighth TNM. Results A cut-point analysis performed at each metastatic lymph node number identified the greatest survival difference between N3a and N3b at 13 metastatic lymph nodes (χ2 = 157.671, P = 3.65 × 10− 36). In patients with 14–15 metastatic lymph nodes, prognoses were significantly worse than those in patients with 7–13 metastatic lymph nodes (P 15 metastatic lymph nodes (P = 0.078). Therefore, patients with 14–15 metastatic lymph nodes were incorporated into a modified N3b classification. In the two-step multivariate analysis, the eighth N3 classification fell out of the model, while the modified N3 classification remained intact (HR 1.51, P

BackgroundThe efficacy and benefits of adjuvant chemotherapy (AC) for patients with gastric cancer pT3N0M0 remain controversial.MethodsWe prospectively collected and retrospectively analyzed 235 patients with pT3N0M0 gastric cancer who underwent radical resection between February 2010 and January 2016. Patients were divided into two groups: the surgery-alone (SA) group (n = 82) and the AC group (n = 153). We analyzed the effects of AC on the overall survival (OS) and recurrence-free survival (RFS), and the relationship between the number of chemotherapy cycles (CC) and recurrence rate (RR).ResultsThe 5-year OS and RFS of the participants were 80.9% and 87.7%, respectively, and those in the AC group were significantly higher than those in the SA group (86.9% vs. 69.5%, p = 0.003). The RFS of the AC and SA groups were 88.9% and 85.4%, respectively; the difference was not statistically significant (p = 0.35). The independent risk factors affecting the OS were perineural invasion-positive (PNI+) (HR = 2.64, 95%CI: 1.45–4.82, p = 0.003) and age ≥ 65 years (HR = 2.58, 95%CI: 1.39–4.8, p = 0.003). The independent risk factor affecting the RFS was also PNI+ (HR3.11; 95%CI: 1.48–6.54, p = 0.003). Stratified analysis revealed that postoperative AC can significantly improve the OS of PNI+ patients (AC group versus SA group: 84.1% vs. 45.5%, p = 0.001) and RFS (86.4% vs. 63.6%, p = 0.017). However, perineural invasion negative (PNI-) patients did not show the same results (p = 0.13 and p = 0.48, respectively). According to the number of CC, divided into CC < 3 groups and CC ≥ 3 groups, the cumulative RR in the CC ≥ 3 group of patients with PNI+ was significantly lower than that of the CC < 3 group (7.4% vs. 28.2%, p = 0.037).ConclusionFor pT3N0M0 gastric cancer patients with PNI+, at least three cycles of postoperative AC can significantly reduce the overall RR. This finding should be verified by using large external sample data.

Background Artificial neural network models have a strong self-learning ability and can deal with complex biological information, but there is no artificial neural network model for predicting the benefits of adjuvant chemotherapy in patients with gastric cancer. Methods The clinicopathological data of patients who underwent radical resection of gastric cancer from January 2010 to September 2014 were analyzed retrospectively. Patients who underwent surgery combined with adjuvant chemotherapy were randomly divided into a training cohort (70%) and a validation cohort (30%). An artificial neural network model (potential-CT-benefit-ANN) was established, and its ability to predict the potential benefit of chemotherapy was evaluated by the C-index. The prognostic prediction and stratification ability of potential-CT-benefit-ANN and the eighth American Joint Committee on Cancer staging system were compared by receiver operating characteristic curves and Kaplan-Meier curves. Results In both the training and validation cohort, potential-CT-benefit-ANN shows good prediction accuracy for potential adjuvant chemotherapy benefit. The receiver operating characteristic curve showed that the prediction accuracy of potential-CT-benefit-ANN was better than that of the eighth American Joint Committee on Cancer staging system in all groups. The calibration plots showed that the predicted prognosis of potential-CT-benefit-ANN was highly consistent with the actual value. The survival curves showed that potential-CT-benefit-ANN could stratify prognosis well for all groups and performed significantly better than the eighth AJCC staging system. Conclusion The potential-CT-benefit-ANN model developed in this study can accurately predict the potential benefits of adjuvant chemotherapy in patients with stage II/III gastric cancer. The benefit score based on potential-CT-benefit-ANN can predict the long-term prognosis of patients with adjuvant chemotherapy and has good prognostic stratification ability.

OBJECTIVE To compare the short-term outcomes, surgery burden, and technical performance of robotic total gastrectomy (RTG) and laparoscopic total gastrectomy (LTG) for gastric cancer (GC). SUMMARY BACKGROUND DATA The impact of robotic systems on total gastrectomy remains obscure. METHODS This prospective study included 50 patients with advanced proximal GC underwent RTG combined with spleen-preserving splenic hilar lymphadenectomy between March 2018 and February 2020. Patients who underwent LTG in the FUGES-002, http://links.lww.com/SLA/C929 study were enrolled to compare the outcomes between RTG and LTG. RESULTS After propensity score matching, 48 patients in the RTG group and 96 patients in the LTG group were included in the analysis. The RTG group had a lower volume of intraoperative blood loss than the LTG group (38.7 vs. 66.4 mL, P = 0.042). Significantly more extraperigastric lymph nodes were retrieved in the RTG group than in the LTG group (20.2 vs. 17.5, P = 0.039). The average number of errors was lower in the RTG group than in the LTG group (43.2 vs. 53.8 times/case, P < 0.001). The RTG group had a higher technical skill score (30.2 vs. 28.4, P < 0.001) and a lower surgery task load index (33.2 vs. 39.8, P < 0.001) than the LTG group. No significant difference was found in terms of postoperative morbidity between the two groups (14.6% vs. 16.7%, P = 0.748). CONCLUSIONS In complex TG for GC, compared with traditional laparoscopic surgery, robotic surgery provides a technically superior operative environment and reduces surgeon workload at high-volume specialized institutions.