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Objective: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood., Design: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21 -floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms., Results: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1 + cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy., Conclusions: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Textbook outcome (TO) is widely recognized as a comprehensive prognostic indication for patients with gastric cancer (GC). This study aims to develop a modified TO (mTO) for elderly patients with GC., Methods: Data from the elderly patients (aged ≥ 65 years) in two Chinese tertiary referral hospitals were analyzed. 1389 patients from Fujian Medical University Union Hospital were assigned as the training cohort and 185 patients from Affiliated Hospital of Putian University as the validation cohort. Nomogram was developed by the independent prognostic factors of Overall Survival (OS) based on Cox regression., Results: In the training cohort, laparoscopic surgery was significantly correlated with higher TO rate (P < 0.05). Cox regression analysis revealed that surgical approach was also an independent factor of OS (P < 0.001), distinct from the traditional TO. In light of these findings, TO parameters were enhanced by the inclusion of surgical approach, rendering a modified TO (mTO). Further analysis showed that mTO, tumor size, pTNM staging, and adjuvant chemotherapy were independent prognostic factors associated with OS (all P < 0.05). Additionally, the nomogram incorporating these four indicators accurately predicted 1-, 3-, and 5-year OS in the training cohort, with AUC values of 0.793, 0.814, and 0.807, respectively, and exhibited outstanding predictive performance within the validation cohort., Conclusion: mTO holds a robust association with the prognosis of elderly patients with GC, meriting intensified attention in efforts aimed at enhancing surgical quality. Furthermore, the predictive model incorporating mTO demonstrates excellent predictive performance for elderly patients with GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Learning curves have been used in the field of robotic gastrectomy (RG). However, it should be noted that the previous study did not comprehensively investigate all changes related to the learning curve. This study aims to establish a learning curve for radical RG and evaluate its effect on the short-term outcomes of patients with gastric cancer., Methods: The clinicopathological data of 527 patients who underwent RG between August 2016 and June 2021 were retrospectively analyzed. Learning curves related to the operation time and postoperative hospital stay were determined separately using cumulative sum (CUSUM) analysis. Then, the impact of the learning curve on surgical efficacy was analyzed., Results: Combining the CUSUM curve break points and technical optimization time points, the entire cohort was divided into three phases (patients 1-100, 101-250, and 251-527). The postoperative complication rate and postoperative recovery time tended to decrease significantly with phase advancement ( P <0.05). More extraperigastric examined lymph nodes (LN) were retrieved in phase III than in phase I (I vs. III, 15.12±6.90 vs. 17.40±7.05, P =0.005). The rate of LN noncompliance decreased with phase advancement. Textbook outcome (TO) analysis showed that the learning phase was an independent factor in TO attainment ( P <0.05)., Conclusion: With learning phase advancement, the short-term outcomes were significantly improved. It is possible that our optimization of surgical procedures could have contributed to this improvement. The findings of this study facilitate the safe dissemination of RG in the minimally invasive era., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment., (© 2024. The Author(s).)

Objective: To study the historical global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035., Methods: Incidence data were retrieved from the Cancer Incidence in Five Continents (CI5) volumes I-XI, and mortality data were obtained from the latest update of the World Health Organization (WHO) mortality database. We used join-point regression analysis to examine historical incidence and mortality trends and used the package NORDPRED in R to predict the number of deaths and mortality rates by 2035 by country and sex., Results: More than 1,089,000 new cases of gastric cancer and 769,000 related deaths were reported in 2020. The average annual percent change (AAPC) in the incidence of gastric cancer from 2003 to 2012 among the male population, South Korea, Japan, Malta, Canada, Cyprus, and Switzerland showed an increasing trend (P > 0.05); among the female population, Canada [AAPC, 1.2; (95%Cl, 0.5-2), P < 0.05] showed an increasing trend; and South Korea, Ecuador, Thailand, and Cyprus showed an increasing trend (P > 0.05). AAPC in the mortality of gastric cancer from 2006 to 2015 among the male population, Thailand [3.5 (95%cl, 1.6-5.4), P < 0.05] showed an increasing trend; Malta Island, New Zealand, Turkey, Switzerland, and Cyprus had an increasing trend (P > 0.05); among the male population aged 20-44, Thailand [AAPC, 3.4; (95%cl, 1.3-5.4), P < 0.05] showed an increasing trend; Norway, New Zealand, The Netherlands, Slovakia, France, Colombia, Lithuania, and the USA showed an increasing trend (P > 0.05). It is predicted that the mortality rate in Slovenia and France's female population will show an increasing trend by 2035. It is predicted that the absolute number of deaths in the Israeli male population and in Chile, France, and Canada female population will increase by 2035., Conclusion: In the past decade, the incidence and mortality of gastric cancer have shown a decreasing trend; however, there are still some countries showing an increasing trend, especially among populations younger than 45 years. Although mortality in most countries is predicted to decline by 2035, the absolute number of deaths due to gastric cancer may further increase due to population growth., (© 2024. The Author(s).)

Background: Robotic gastrectomy is a safe and feasible approach for gastric cancer (GC); however, its long-term oncological efficacy remains unclear. The authors evaluated the long-term survival outcomes and recurrence patterns of patients with locally advanced proximal GC who underwent robotic total gastrectomy (RTG)., Methods: This prospective study (FUGES-014 study) enrolled 48 patients with locally advanced proximal GC who underwent RTG between March 2018 and February 2020 at a tertiary referral teaching hospital. Patients who underwent laparoscopic total gastrectomy (LTG) in the FUGES-002 study were enrolled in a 2:1 ratio to compare the survival outcomes between RTG and LTG. The primary endpoint of the FUGES-014 study was postoperative 30-day morbidity and has been previously reported. Here, the authors reported the results of 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence patterns., Results: After propensity score matching, 48 patients in the RTG and 96 patients in the LTG groups were included. The 3-year DFS rates were 77.1% (95% CI: 66.1-89.9%) for the RTG and 68.8% (95% CI: 60.1-78.7%) for the LTG groups ( P =0.261). The 3-year OS rates were not significantly different between the groups (85.4 vs. 74.0%, P =0.122). Recurrence occurred in nine patients (18.8%) in the RTG and 27 (28.1%) patients in the LTG groups ( P =0.234). Recurrence patterns and causes of death were similar between the groups ( P >0.05)., Conclusions: The oncological outcome of RTG was noninferior to that of LTG. Thus, RTG might be an alternative surgical treatment for locally advanced proximal GC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Splenic hilar lymphadenectomy has been recommended for locally advanced proximal gastric cancer (APGC) involving the greater curvature. However, it is unclear whether laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) is associated with a long-term survival benefit for APGC without greater curvature invasion., Objective: To present the 5-year follow-up data from a randomized clinical trial that compared laparoscopic total gastrectomy (D2 group) with D2 plus LSPSHL (D2 + No. 10 group) among patients with resectable APGC., Design, Setting, and Participants: This is a post hoc secondary analysis of a randomized clinical trial that enrolled 536 patients with potentially resectable APGC (cT2-4a, N0 or N+, and M0) without greater curvature invasion from January 5, 2015, to October 10, 2018. All patients were tracked for at least 5 years. The final follow-up was on October 30, 2023., Interventions: Patients were randomly assigned in a 1:1 ratio to the D2 + No. 10 or D2 groups., Main Outcomes and Measures: The 5-year disease-free survival (DFS) and overall survival (OS) rates were measured. Recurrence patterns and causes of death were compared., Results: A total of 526 patients (392 men [74.5%]; mean [SD] age, 60.6 [9.6] years) were included in the modified intent-to-treat analysis, with 263 patients in each group. The 5-year DFS rate was 63.9% (95% CI, 58.1%-69.7%) for the D2 + No. 10 group and 55.1% (95% CI, 49.1%-61.1%) for the D2 group (log-rank P = .04). A statistically significant difference was observed in the 5-year OS between the D2 + No. 10 group and the D2 group (66.2% [95% CI, 60.4%-71.9%] vs 57.4% [95% CI, 51.4%-63.4%]; log-rank P = .03). The No. 10 lymph node exhibited a therapeutic value index (TVI) of 6.5, surpassing that of Nos. 8a (TVI, 3.0), 11 (TVI, 5.8), and 12a (TVI, 0.8). A total of 86 patients in the D2 + No. 10 group (cumulative incidence, 32.7%) and 111 patients in the D2 group (cumulative incidence, 42.2%) experienced recurrence (hazard ratio, 0.72; 95% CI, 0.54-0.95; P = .02). The multivariable competing risk regression model demonstrated that D2 + No. 10 remained an independent protective factor for a lower 5-year cumulative recurrence rate after surgery (hazard ratio, 0.75; 95% CI, 0.56-1.00; P = .05). There was a significant difference in the 5-year cumulative recurrence rate at the No. 10 lymph node area between the 2 groups (D2 + No. 10 group vs D2 group: 0% vs 2.3% [n = 6]; P = .01)., Conclusions: This post hoc secondary analysis of a randomized clinical trial found that laparoscopic total gastrectomy with LSPSHL can improve the prognosis and reduce recurrence for APGC without greater curvature invasion. Future multicenter studies are warranted to validate these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT02333721.

Background: The impact of achieving textbook oncological outcome (TOO) as a multimodal therapy quality indicator on the prognosis of advanced gastric cancer (AGC) remains inadequately assessed., Methods: Patients with AGC who underwent curative gastrectomy between January 2010 and December 2017 at two East Asian medical centers were included. TOO was defined as achieving the textbook outcome (TO) and receiving neoadjuvant and/or adjuvant chemotherapy (NCT or ACT). Cox and logistic regression models were used to identify prognostic and non-TOO-associated risk factors., Results: Among 3626 patients, 57.6% achieved TOO (TOO group), exhibiting significantly better 5-year overall survival (OS) and disease-free survival (DFS) than the non-TOO group (both p < 0.05). Multivariate Cox regression identified TOO as an independent prognostic factor for 5-year OS (HR, 0.67; 95% CI, 0.61-0.74; p < 0.001) and DFS (HR, 0.73; 95% CI, 0.66-0.81; p < 0.001). Multivariate logistic regression showed that open gastrectomy, lack of health insurance, age ≥65 years, ASA score ≥ Ⅲ, and tumor size ≥50 mm are independent risk factors for non-achievement of TOO (all p < 0.05). On a sensitivity analysis of TOO's prognostic value using varying definitions of chemotherapy parameters, a stricter definition of chemotherapy resulted in a decrease in the TOO achievement rate from 57.6 to 22.3%. However, the associated reductions in the risk of death and recurrence fluctuated within the ranges of 33-39% and 28-37%, respectively., Conclusions: TOO is a reliable and stable metric for favorable prognosis in AGC. Optimizing the surgical approach and improving health insurance status may enhance TOO achievement., Competing Interests: Declaration of competing interest None reported., (© 2024 Published by Elsevier Ltd.)

Objective: To assess the effectiveness of indocyanine green (ICG)-guided lymph node (LN) dissection during laparoscopic radical gastrectomy after neoadjuvant chemotherapy (NAC) in patients with locally advanced gastric cancer (LAGC)., Background: Studies on ICG imaging use in patients with LAGC on NAC are rare., Methods: Patients with gastric adenocarcinoma (clinical T2-4NanyM0) who received NAC were randomly assigned to receive ICG-guided laparoscopic radical gastrectomy or laparoscopic radical gastrectomy alone. Here, we reported the secondary endpoints including the quality of lymphadenectomy (total retrieved LNs and LN noncompliance) and surgical outcomes., Results: Overall, 240 patients were randomized. Of whom, 236 patients were included in the primary analysis (118 in the ICG group and 118 in the non-ICG group). In the ICG group, the mean number of LNs retrieved was significantly higher than in the non-ICG group within the D2 dissection (48.2 vs 38.3, P < 0.001). The ICG fluorescence guidance significantly decreased the LN noncompliance rates (33.9% vs 55.1%, P = 0.001). In 165 patients without baseline measurable LNs, ICG significantly increased the number of retrieved LNs and decreased the LN noncompliance rate ( P < 0.05). For 71 patients with baseline measurable LNs, the quality of lymphadenectomy significantly improved in those who had a complete response ( P < 0.05) but not in those who did not ( P > 0.05). Surgical outcomes were comparable between the groups ( P > 0.05)., Conclusions: ICG can effectively improve the quality of lymphadenectomy in patients with LAGC who underwent laparoscopic radical gastrectomy after NAC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Robotic surgery may be an alternative to laparoscopic surgery for gastric cancer (GC). However, randomized controlled trials (RCTs) reporting the differences in survival between these two approaches are currently lacking. From September 2017 to January 2020, 300 patients with cT1-4a and N0/+ were enrolled and randomized to either the robotic (RDG) or laparoscopic distal gastrectomy (LDG) group (NCT03313700). The primary endpoint was 3-year disease-free survival (DFS); secondary endpoints reported here are the 3-year overall survival (OS) and recurrence patterns. The remaining secondary outcomes include intraoperative outcomes, postoperative recovery, quality of lymphadenectomy, and cost differences, which have previously been reported. There were 283 patients in the modified intention-to-treat analysis (RDG group: n = 141; LDG group: n = 142). The trial has met pre-specified endpoints. The 3-year DFS rates were 85.8% and 73.2% in the RDG and LDG groups, respectively (p = 0.011). Multivariable Cox regression model including age, tumor size, sex, ECOG PS, lymphovascular invasion, histology, pT stage, and pN stage showed that RDG was associated with better 3-year DFS (HR: 0.541; 95% CI: 0.314-0.932). The RDG also improved the 3-year cumulative recurrence rate (RDG vs. LDG: 12.1% vs. 21.1%; HR: 0.546, 95% CI: 0.302-0.990). Compared to LDG, RDG demonstrated non-inferiority in 3-year DFS rate., (© 2024. The Author(s).)

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes ( BATF2 , PTPRJ , RGS1 , and VCAN ), is a reliable and independent biomarker for GC. PRS low is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRS low marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Textbook outcome (TO) has been widely employed as a comprehensive indicator to assess the short-term prognosis of patients with cancer. Preoperative malnutrition is a potential risk factor for adverse surgical outcomes in patients with gastric cancer (GC). This study aimed to compare the TO between robotic-assisted gastrectomy (RAG) and laparoscopic-assisted gastrectomy (LAG) in malnourished patients with GC., Methods: According to the diagnostic consensus of malnutrition proposed by Global Leadership Initiative on Malnutrition (GLIM) and Nutrition Risk Index (NRI), 895 malnourished patients with GC who underwent RAG (n = 115) or LAG (n = 780) at a tertiary referral hospital between January 2016 and May 2021 were included in the propensity score matching (PSM, 1:2) analysis., Results: After PSM, no significant differences in clinicopathological characteristics were observed between the RAG (n = 97) and LAG (n = 194) groups. The RAG group had significantly higher operative time and lymph nodes harvested, as well as significantly lower blood loss and hospital stay time compared to the LAG group. More patients in the RAG achieved TO. Logistic regression analysis revealed that RAG was an independent protective factor for achieving TO. There were more adjuvant chemotherapy (AC) cycles in the RAG group than in the LAG group. After one year of surgery, a higher percentage of patients (36.7% vs. 22.8%; P < 0.05) in the RAG group recovered from malnutrition compared to the LAG group., Conclusions: For malnourished patients with GC, RAG performed by experienced surgeons can achieved a higher rate of TO than those of LAG, which directly contributed to better AC compliance and a faster restoration of nutritional status., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Laparoscopy-assisted gastrectomy (LG) is rapidly gaining popularity owing to its minimal invasiveness. Previous studies have found that compared with two-dimensional (2D)-LG, three-dimensional (3D)-LG showed better short-term outcomes. However, the long-term oncological outcomes in patients with locally resectable gastric cancer (GC) remain controversial., Methods: In this noninferiority, open-label, randomized clinical trial, a total of 438 eligible GC participants were randomly assigned in a 1:1 ratio to either 3D-LG or 2D-LG from January 2015 to April 2016. The primary endpoint was operating time, while the secondary endpoints included 5-year overall survival (OS), disease-free survival (DFS), and recurrence pattern., Results: Data from 401 participants were included in the per-protocol analysis, with 204 patients in the 3D group and 197 patients in the 2D group. The 5-year OS and DFS rates were comparable between the 3D and 2D groups (5-year OS: 70.6% vs. 71.1%, Log-rank P = 0.743; 5-year DFS: 68.1% vs. 69.0%, log-rank P = 0.712). No significant differences were observed between the 3D and 2D groups in the 5-year recurrence rate (28.9% vs. 28.9%, P = 0.958) or recurrence time (mean time, 22.6 vs. 20.5 months, P = 0.412). Further stratified analysis based on the type of gastrectomy, postoperative pathological staging, and preoperative BMI showed that the 5-year OS, DFS, and recurrence rates of the 3D group in each subgroup were similar to those of the 2D group (all P > 0.05)., Conclusions: For patients with locally resectable GC, 3D-LG performed by experienced surgeons in high-volume professional institutions can achieve long-term oncological outcomes comparable to those of 2D-LG., Registration Number: NCT02327481 ( http://clinicaltrials.gov )., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Objective: To assess the effect of preoperative sarcopenia on the short-term and long-term outcomes in older patients with locally advanced gastric cancer (LAGC)., Methods: Clinicopathological data of older patients with LAGC who underwent radical surgery were retrospectively analyzed. Sarcopenia was defined as a skeletal muscle index of less than 36.4 cm 2 /m 2 for men and less than 28.4 cm 2 /m 2 for women. Comparing the postoperative complications and survival between sarcopenia and non-sarcopenia groups using multicenter data., Results: A total of 406 older patients with LAGC were included in the analysis, including 145 (35.7%) with sarcopenia and 261 (64.3%) with non-sarcopenia. Multivariate logistic regression analysis showed that sarcopenia was an independent risk factor for postoperative complications with CD grade ≥ II (OR 1.616; P < 0.05). Kaplan-Meier survival curve analysis showed that the 5-year overall survival (OS) and 5-year recurrence-free survival (RFS) in the sarcopenia group were lower than those in the non-sarcopenia group (P both < 0.05). Multivariate Cox regression analyses showed that sarcopenia was an independent prognostic factor for 5-year OS and RFS (P both < 0.05). The 5-year recurrence rate in the sarcopenia group was 57.2%, which was significantly higher than that in the non-sarcopenia group (46.4%; P = 0.036). Recurrence pattern analysis showed that the incidence of distant metastases in patients with sarcopenia (42.8%) was significantly higher than non-sarcopenia (31.4%; P = 0.022)., Conclusion: Sarcopenia serves as a valuable predictor of both short-term and long-term outcomes in older patients with LAGC. Therefore, the significance of assessing preoperative nutritional status and implementing thorough postoperative follow-up for older LAGC patients with sarcopenia should be emphasized., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To explore the oncological outcomes of sequential laparoscopic gastrectomy after treatment with camrelizumab in combination with nab-paclitaxel plus S-1 for the treatment of gastric cancer with serosal invasion., Methods: This study is a retrospective cohort study and retrospectively analyzed the clinicopathological data of 128 patients with serosal invasion gastric cancer (cT4NxM0) who received nab-paclitaxel + S-1(SAP) or camrelizumab + nab-paclitaxel + S-1 (C-SAP) regimen and underwent laparoscopy assisted gastrectomy in Fujian Union Hospital from March 2019 to December 2020. The patients were divided into SAP group and C-SAP group. The 2-years overall survival rate, 2-year recurrence free survival rate recurrence rate and initial recurrence time were compared between the two groups., Results: A total of 128 patients were included, including 90 cases in SAP group and 38 cases in C-SAP group. There were no significant differences in age, gender, gastrectomy method, surgical approach, R0 resection, nerve invasion, vascular invasion, total number of harvested lymph nodes, number of positive lymph nodes and major pathologic response (MPR) rate between the two groups (P>0.05). However, the proportion of ypT0, ypN0 and pCR rate in C-SAP group were significantly higher than those in SAP group (P<0.05). The 2-year OS of C-SAP group (80.7%) was higher than that of SAP group (67.8%), and the difference was not statistically significant (P = 0.112); At 2 years after operation, the recurrence rate of C-SAP group (44.3%) was lower than that of SAP group (55.8%) (P = 0.097); Further analysis showed that the average time to recurrence in the C-SAP group was 18.9 months, which was longer than that in SAP group 13.1 months (P = 0.004); The 2-year recurrence free survival rate in C-SAP group was higher than that in SAP group (P=0.076); There was no significant difference in the overall survival time after recurrence between the two groups (P= 0.097)., Conclusion: Camrelizumab combined with neoadjuvant chemotherapy can improve the proportion of ypT0, ypN0 and pCR in patients, while prolonging the initial recurrence time of patients in the C-SAP group, but did not increase the immunotherapy/chemotherapy related side effects and postoperative complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Lin, Lin, Zhong, Lu, Zheng, Xie, Wang, Huang and Li.)

Prospective evidence regarding the combination of programmed cell death (PD)-1 and angiogenesis inhibitors in treating locally advanced gastric cancer (LAGC) is limited. In this multicenter, randomized, phase 2 trial (NCT04195828), patients with gastric adenocarcinoma (clinical T2-4N + M0) were randomly assigned (1:1) to receive neoadjuvant camrelizumab and apatinib combined with nab-paclitaxel plus S-1 (CA-SAP) or chemotherapy SAP alone (SAP) for 3 cycles. The primary endpoint was the major pathological response (MPR), defined as <10% residual tumor cells in resection specimens. Secondary endpoints included R0 resection rate, radiologic response, safety, overall survival, and progression-free survival. The modified intention-to-treat population was analyzed (CA-SAP [n = 51] versus SAP [n = 53]). The trial has met pre-specified endpoints. CA-SAP was associated with a significantly higher MPR rate (33.3%) than SAP (17.0%, P = 0.044). The CA-SAP group had a significantly higher objective response rate (66.0% versus 43.4%, P = 0.017) and R0 resection rate (94.1% versus 81.1%, P = 0.042) than the SAP group. Nonsurgical grade 3-4 adverse events were observed in 17 patients (33.3%) in the CA-SAP group and 14 (26.4%) in the SAP group. Survival results were not reported due to immature data. Camrelizumab and apatinib combined with chemotherapy as a neoadjuvant regimen was tolerable and associated with favorable responses for LAGC., (© 2024. The Author(s).)

Background: Indocyanine green (ICG) fluorescence imaging is effective in increasing the number of lymph node dissections during laparoscopic radical gastrectomy; however, no studies have attempted to explain this phenomenon., Methods: This study utilized the data from a previous randomized controlled trial (FUGES-012 study) investigating ICG-guided laparoscopic radical gastrectomy performed between November 2018 and July 2019. The Objective Structured Assessments of Technical Skills (OSATS) scoring system was used to grade videos from the ICG and non-ICG groups. Patients with an OSATS score greater than 29 were classified as the high-OSATS population, while those with an OSATS score less than or equal to 29 were classified as the low-OSATS population., Results: A total of 258 patients were included in the modified intention-to-treat analysis: 129 in the ICG group and 129 in the non-ICG group. The OSATS score of the ICG group was higher than that of the non-ICG group (29.6±2.6 vs. 26.6±3.6; P <0.001). The ICG group underwent a significantly higher mean total number of lymph node dissections than the non-ICG group (50.5±15.9 vs. 42.0±10.3; adjusted P <0.001). The group assigned to ICG use, better OSATS (high-OSATS) scores were observed, which correlated with greater D2 lymph node retrieval (54.1±15.0 vs. 47.2±8.7; adjusted P =0.039). Finally, the ICG group had a lower rate of lymph node noncompliance than that of the non-ICG group (31.8 vs. 57.4%; P <0.001)., Conclusions: By applying the ICG fluorescence navigation technique, better OSATS scores were observed, which correlated with greater lymph node retrieval and a lower lymph node noncompliance rate, as recommended for individualized laparoscopic radical gastrectomy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Laparoscopic gastrectomy for gastric cancer (GC) are increasing, yet the evidence of the relationship between the learning curve and long-term outcomes is limited., Aims: To analyze the relationship between the learning curve and survival in GC patients over a 10-year period., Methods: This retrospective cohort study studied 3674 patients who underwent laparoscopic radical gastrectomy for gastric cancer. Cusum and Cox regression analysis were used to assess the association between the surgeon's experience and the 3 years overall survival (OS)., Results: The 3-year OS of all patients was 71.8 %. This increase of 3-year OS was associated with laparoscopic cases (r = 0.638, p = 0.047). Analysis of the CUSUM curve showed a significant change in the 3-year OS of 1400 cases. Further propensity score matching (PSM) of patients during and after the learning curve (<1400 and ≥ 1400 cases) showed a significant difference in the 3-year OS between the two groups (68.5 % vs. 72.3 %, p = 0.045). Cox regression analysis verified that in ≥1400 cases, prior laparoscopic surgery (p = 0.045), textbook outcome (TO) and the number of retrieved lymph nodes (LNs) were independent protective factors. The LN non-compliance rate was an independent risk factor. In contrast, the rate of TO and the median number of retrieved LNs were significantly higher after the learning curve (≥1400 cases). Furthermore, the rates of LN non-compliance were significantly lower (p < 0.05)., Conclusions: Increasing laparoscopic surgical experience is associated with surgical quality and prognostic improvement in patients with gastric cancer. But improvements in outcomes accrued slowly over a long period., Competing Interests: Declaration of competing interest I confirm that none of the authors have any competing interests in the manuscript., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Nerves can support tumor development by secreting neurotransmitters that promote cancer cell proliferation and invasion. 5-Hydroxytryptamine (5-HT) is a critical neurotransmitter in the gastrointestinal nervous system, and 5-HT signaling has been shown to play a role in tumorigenesis. Here, we found that expression of the 5-HT receptor HTR2B was significantly elevated in human gastric adenocarcinoma tissues compared with nontumor tissues, and high HTR2B expression corresponded to shorter patient survival. Both 5-HT and a specific HTR2B agonist enhanced gastric adenocarcinoma cell viability under metabolic stress, reduced cellular and lipid reactive oxygen species, and suppressed ferroptosis; conversely, HTR2B loss or inhibition with a selective HTR2B antagonist yielded the inverse tumor suppressive effects. In a patient-derived xenograft tumor model, HTR2B-positive tumors displayed accelerated growth, which was inhibited by HTR2B antagonists. Single-cell analysis of human gastric adenocarcinoma tissues revealed enrichment of PI3K/Akt/mTOR and fatty acid metabolism-related gene clusters in cells expressing HTR2B compared with HTR2B-negative cells. Mechanistically, HTR2B cooperated with Fyn to directly regulate p85 activity and trigger the PI3K/Akt/mTOR signaling pathway, which led to increased expression of HIF1α and ABCD1 along with decreased levels of lipid peroxidation and ferroptosis. Together, these findings demonstrate that HTR2B activity modulates PI3K/Akt/mTOR signaling to stimulate gastric cancer cell survival and indicate that HTR2B expression could be a potential prognostic biomarker in patients with gastric cancer., Significance: Nerve cancer cross-talk mediated by HTR2B inhibits lipid peroxidation and ferroptosis in gastric cancer cells and promotes viability under metabolic stress, resulting in increased tumor growth and decreased patient survival., (©2023 American Association for Cancer Research.)

Background: Due to lacking evidence on surveillance for gastric cancer (GC), this study aimed to determine the optimal postsurgical surveillance strategy for pathological stage (pStage) II/III GC patients and compare its cost-effectiveness with traditional surveillance strategies., Methods: Prospectively collected data from stage II/III GC patients ( n =1661) who underwent upfront surgery at a large-volume tertiary cancer center in China (FJMUUH cohort) between January 2010 and October 2015. For external validation, two independent cohorts were included, which were composed of 380 stage II/III GC patients at an tertiary cancer center in U.S.A (Mayo cohort) between July 1991 and July 2012 and 270 stage II/III GC patients at another tertiary cancer center in China (QUAH cohort) between May 2010 and October 2014. Random forest models were used to predict dynamic recurrence hazards and to construct individual surveillance strategies for stage II/III GC. Cost-effectiveness was assessed by the Markov model., Results: The median follow-up period of the FJMUUH, the Mayo, and QUAH cohorts were 55, 158, and 70 months, respectively. In the FJMUUH cohort, the 5-year recurrence risk was higher in pStage III compared with pStage II GC patients ( P <0.001). Our novel individual surveillance strategy achieved optimal cost-effectiveness for pStage II GC patients (ICER =$490/QALY). The most intensive NCCN surveillance guideline was more cost-effective (ICER =$983/QALY) for pStage III GC patients. The external validations confirmed our results., Conclusion: For patients with pStage II GC, individualized risk-based surveillance outperformed the JGCTG and NCCN surveillance guidelines. However, the NCCN surveillance guideline may be more suitable for patients with pStage III GC. Even though our results are limited by the retrospective study design, the authors believe that our findings should be considered when recommending postoperative surveillance for stage II/III GC with upfront surgery in the absence of a randomized clinical trial., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P = 0.015; log-rank P = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC., (© 2023. The Author(s).)

Introduction: Prognostic factors for postoperative early recurrence (ER) of gastric cancer (GC) in patients with normal or abnormal preoperative tumor markers (pre-TMs) remain unclear., Materials and Methods: 2875 consecutive patients with GC who underwent radical gastrectomy (RG) between January 2010 and December 2016 were enrolled and randomly divided into training and internal validation groups. ER was defined as recurrence within two years of gastrectomy. Normal pre-TMs were defined as CEA≤5 ng/mL and CA199 ≤ 37 U/mL. Least absolute shrinkage selection operator (LASSO) Cox regression analysis was used to screen ER predictors. The scoring model was validated using 546 patients from another hospital., Results: A total of 3421 patients were included. Multivariate Cox analysis showed that pre-TMs was an independent prognostic factor for ER. Survival after ER was equally poor in the normal and abnormal pre-TMs groups (P = 0.160). Based on LASSO Cox regression, the ER of patients with abnormal pre-TMs was only associated with the pT and pN stages; however, in patients with normal pre-TMs, it was also associated with tumor size, perineural invasion, and prognostic nutritional index. Scoring model constructed for patients with normal pre-TMs had better predictive performance than TNM staging (concordance-index:0.826 vs. 0.807, P < 0.001) and good reproducibility in both validation sets. Moreover, through risk stratification, the scoring model could not only identify the risk of ER but also distinguish ER patterns and adjuvant chemotherapy benefit subgroups., Conclusion: pre-TMs is an independent prognostic factor for ER in GC after RG. The established scoring model demonstrates excellent predictive performance and clinical utility., Competing Interests: Declaration of competing interest None reported., (© 2023 Published by Elsevier Ltd.)

Background: The long-term dynamic recurrence hazard of locally advanced gastric cancer (LAGC) in the clinical setting of adjuvant chemotherapy (ACT) remains unclear., Purpose: This study aimed to investigate the dynamic recurrence risk of LAGC in patients who received ACT or not., Methods: The study assessed data from patients with LAGC who underwent radical gastrectomy between January, 2010 and October, 2015. Inverse probability of treatment weighting (IPTW) was performed to reduce selection bias between the ACT and observational (OBS) groups. Conditional recurrence-free survival (cRFS) and restricted mean survival time (RMST) were used to assess the survival differences., Results: In total, 1,661 LAGC patients were included (ACT group, n = 1,236 and OBS group, n = 425). The recurrence hazard gradually declined; in contrast, cRFS increased with RFS already accrued. Following IPTW adjustment, the cRFS rates were higher in the ACT group than those in the OBS group for patients at baseline or with accrued RFS of 1 and 2 years (p˂0.05). However, the cRFS rates of the ACT group were comparable with those of the OBS group for patients with accrued RFS of 3 or more years (p > 0.05). Likewise, the 5-year △RMST between the ACT and OBS groups demonstrated a similar trend. Moreover, the hematological metastasis rate of the ACT group was significantly lower than that of the OBS group for patients at baseline or with accrued RFS of 1 and 2 years, respectively (p˂0.05)., Conclusions: Although ACT could provide substantial benefits for patients with LAGC, the differences in recurrence hazard between the ACT and OBS groups may attenuate over time, which could help guide surveillance and alleviate patients' anxiety. Further prospective large-scale studies are warranted., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Importance: It is largely unclear whether robotic distal gastrectomy (RDG) is cost-effective for locally advanced gastric cancer (LAGC)., Objective: To evaluate the cost-effectiveness of RDG, laparoscopic distal gastrectomy (LDG), and open distal gastrectomy (ODG) for patients with LAGC., Design, Setting, and Participants: Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. A decision-analytic model was constructed to evaluate the cost-effectiveness of RDG, LDG, and ODG., Exposures: RDG, LDG, and ODG., Main Outcomes and Measures: Incremental cost-effectiveness ratio (ICER) and quality-adjusted life year (QALY)., Results: This pooled analysis of two randomized controlled trials included 449 patients: 117, 254, and 78 patients in the RDG, LDG, and ODG groups, respectively. After IPTW, RDG demonstrated its priority in terms of less blood loss, postoperative length, and complication rate (all P < 0.05). RDG also showed higher QOL with more cost, representing an ICER of $85,739.73 per QALY and $42,189.53 per QALY compared to LDG and ODG, respectively. In probabilistic sensitivity analysis, RDG achieved the best cost-effectiveness for patients with LAGC only when the willingness-to-pay threshold was > $85,739.73 per QALY, which significantly exceeded 3 times Chinese per capita GDP. Furthermore, one of the most important factors was the indirect costs of robotic surgery in terms of the cost-effectiveness of RDG compared to that of LDG or ODG., Conclusions and Relevance: Although improved short-term outcomes and QOL were seen in patients underwent RDG, the economic burden should be considered in the clinical decision-making regarding robotic surgery use for patients with LAGC. Our findings may vary in different health care settings and affordability. Trial registration CLASS-01 trial (ClinicalTrials.gov, CT01609309) and FUGES-011 trial (ClinicalTrials.gov, NCT03313700)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To verify an intraoperative adverse event (iAE) classification (ClassIntra grade) to evaluate quality control and to predict the prognostic performance of laparoscopic radical surgery for gastric cancer., Background: Surgical quality control is a key factor in the evaluation of surgical treatment for tumors. And, there is no recognized iAE classification for gastric cancer., Methods: We performed a retrospective post hoc analysis of previously collected data from the FUGES-001 study (NCT02327481) and a subset of the CLASS-01 study (NCT01609309). Patients were classified into the iAE and non-iAE groups. And iAE was further classified into 5 subgrades according to the ClassIntra grade (with I-V severity categories). Technical performance was evaluated using the Objective Structured Assessment of Technical Skills tool and the Generic Error Rating Tool., Results: Overall, 528 gastric cancer patients were included in this study, with 105 patients (19.9%) in the iAE group and 423 (80.1%) in the non-iAE group. The survival curve showed that the overall, disease-specific, and recurrence-free survival of the non-iAE group were significantly better than those of the iAE group ( P =0.001). The prognosis of patients with ClassIntra grade ≥II was significantly worse than that of patients with ClassIntra grade ≤I. A higher ClassIntra grade, lower Objective Structured Assessment of Technical Skills score, and total gastrectomy were independent risk factors for severe postoperative complications. There was a significant increase in bleeding (grade IV) and injury with splenic hilar lymph node dissection during total gastrectomy., Conclusions: The ClassIntra grade is an effective prognostic and surgical quality control index for laparoscopic radical surgery for gastric cancer; therefore, it could be included in routine hospital care and surgical quality control., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The accuracy of the eighth AJCC ypTNM staging system on the prognosis of gastric cancer (GC) patients after neoadjuvant therapy (NAT) is controversial. This study aimed to develop and validate a novel staging system using the log odds of positive lymph nodes scheme (LODDS)., Methods: A retrospective analysis of 606 GC patients who underwent radical gastrectomy after neoadjuvant therapy was conducted as the development cohort. (Fujian Medical University Affiliated Union Hospital (n = 183), Qinghai University Affiliated Hospital (n = 169), Mayo Clinic (n = 236), Lanzhou University First Hospital (n = 18)). The validation cohort came from the SEER database (n = 1701). A novel ypTLoddsS (ypTLM) staging system was established using the 3-year overall survival. The predictive performance of two systems was compared., Results: Two-step multivariate Cox regression analysis in both cohorts showed that ypTLM was an independent predictor of overall survival of GC patients after neoadjuvant therapy (HR: 1.57, 95% CI: 1.30-1.88, p < 0.001). In the development cohort, ypTLM had better discrimination ability than ypTNM (C-index: 0.663 vs 0.633, p < 0.001), better prediction homogeneity (LR: 97.7 vs. 70.9), and better prediction accuracy (BIC: 3067.01 vs 3093.82; NRI: 0.36). In the validation cohort, ypTLM had a better prognostic predictive ability (C-index: 0.614 vs 0.588, p < 0.001; LR: 11,909.05 vs. 11,975.75; BIC: 13,263.71 vs 13,328.24; NRI: 0.22). The time-dependent ROC curve shows that the predictive performance of ypTLM is better than ypTNM, and the analysis of the decision curve shows that ypTLM achieved better net benefits., Conclusion: A LODDS-based ypTLM staging system based on multicenter data was established and validated. The predictive performance was superior to the eighth AJCC ypTNM staging system., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Laparoscopic D2 lymph node dissection (LND) for gastric cancer has a wide range and high difficulty. In the past, the quality of surgery was often judged by the time of the operation or the amount of blood loss, but the analysis based on surgical video was rarely reported. The purpose of this study was to analyze the relationship between the quality of laparoscopic D2 LND for gastric cancer and postoperative complications., Methods: The surgical video and clinicopathological data of 610 patients in two randomized controlled trials in our center from 2013 to 2016 were retrospectively analyzed. Klass-02-QC LND scale and general error score tool were used to quantitatively evaluate the intraoperative performance of D2 LND. Logistic regression was used to analyze the influencing factors of postoperative complications., Results: The overall incidence of complications (CD classification≥2) was 20.6%; the incidence of surgical complications was 6.9%. According to whether the LND score reached 44, patients were divided into a qualified group (73%) and a not-qualified group (27%). Event score (ES) by quartile was divided into grade 1 (21.7%), grade 2 (26%), grade 3 (28%), and grade 4 (24.3%) from low to high. Univariate logistic regression analysis showed that ES greater than or equal to 3, tumor size greater than or equal to 35 mm, and cTNM >II were independent risk factors for not-qualified LND. Male,tumor size greater than or equal to 35 mm and cTNM >II were independent risk factors for grade 4 ES. Not-qualified LND (OR=1.62, 95% CI: 1.16-3.89, P =0.021), grade 4 ES (OR=3.21, 95% CI: 1.52-3.90, P =0.035), and cTNM >II (OR=1.74, 95% CI: 1.39-7.33, P =0.041) were independent risk factors for postoperative surgical complications., Conclusions: The qualification of LND and intraoperative events based on surgical video are the independent influencing factors of postoperative complications of laparoscopic gastric cancer surgery. Specialist training and teaching based on surgical video may help to improve the surgical skills of specialists and improve the postoperative outcome of patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype-related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG-3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in-house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPS Low is characterized as immune-activated, and IPS High is immune-silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPS Low and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti-PD-1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The Global Leadership Initiative on Malnutrition released a new version of the malnutrition criteria (GLIM criteria). To investigate the influence of the GLIM criteria on the long-term efficacy of radical gastric cancer surgery and establish a nomogram to predict the long-term prognosis of patients with gastric cancer., Methods: A retrospective analysis of 1121 patients with gastric cancer in our department from 2010 to 2013 was performed. A nomogram was established to predict overall survival (OS) based on the GLIM criteria. Patients were divided into the low-risk group (LRG) and high-risk group (HRG) based on the established nomogram., Results: Multivariate Cox regression analyses showed that GLIM criteria was an independent risk factor for the 5-year OS (HR = 1.768, Cl:1.341-2.329, p < 0.001). The C index, AUC and Time-ROC of the nomogram were significantly better than that of GLIM criteria and traditional criteria. The 5-year OS of patients receiving adjuvant chemotherapy in the high-risk group was significantly higher than that of patients without chemotherapy (45.77% vs. 24.73%,p < 0.001)., Conclusions: The GLIM criteria independently influence the long-term outcome of patients after radical gastric cancer surgery. The established nomogram can predict the long-term survival of patients with gastric cancer, and postoperative adjuvant chemotherapy for HRG can significantly improve the 5-year OS of patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Totally laparoscopic total gastrectomy (TLTG) and laparoscopic-assisted total gastrectomy (LATG) are two types of minimally invasive radical gastrectomy procedures to treat gastric cancer (GC). This study compared the long-term prognosis and postoperative health-related quality of life (HRQoL) between TLTG and LATG., Methods: A total of 106 patients who underwent TLTG and 1,076 patients who underwent LATG at the Union Hospital of Fujian Medical University (Fuzhou, China) between January 2014 and April 2018 were included in the propensity score matching (PSM, 1:2). Patient-reported outcomes at 3, 6, and 12 months after gastrectomy were analyzed. The questionnaire referred to the European Organization for Research and Treatment of Cancer (EORTC) 30-item core QoL (QLQ-C30)and the GC module (QLQ-STO22) questionnaire., Results: After PSM, there were no significant differences in clinicopathological characteristics between the TLTG (n = 104) and the LATG groups (n = 208). Operative time and volume of blood loss were significantly lower in the TLTG group than in the LATG group. Kaplan-Meier survival analysis revealed similar 3-year survival rates between the TLTG and LATG groups (83.7 vs. 80.3%, respectively; P = 0.462). Tolerance to nonliquid diet, decrease in body weight, and albumin levels were also significantly lower in the TLTG group than in the LATG group (all P < 0.05). The HRQoL scale demonstrated that the overall score in the TLTG group was better than that in the LATG group at 3, 6, and 12 months after gastrectomy (all P < 0.05)., Conclusions: Patients with GC undergoing TLTG reported better HRQoL and experienced faster recovery of social function than those undergoing LATG, although the two groups demonstrated similar short-term outcomes and long-term prognosis., (© 2022. Society of Surgical Oncology.)

Importance: The survival benefit of laparoscopic total gastrectomy combined with spleen-preserving splenic hilar lymphadenectomy (LSTG) for locally advanced proximal gastric cancer (APGC) without invasion into the greater curvature remains uncertain., Objective: To compare the long-term and short-term efficacy of LSTG (D2 + No. 10 group) and conventional laparoscopic total gastrectomy (D2 group) for patients with APGC that has not invaded the greater curvature., Design, Setting, and Participants: In this open-label, prospective randomized clinical trial, a total of 536 patients with clinical stage cT2 to 4a/N0 to 3/M0 APGC without invasion into the greater curvature were enrolled from January 2015 to October 2018. The final follow-up was on October 31, 2021. Data were analyzed from December 2021 to February 2022., Interventions: Eligible patients were randomized to the D2 + No. 10 group or the D2 group., Main Outcomes and Measures: The primary outcome was 3-year disease-free survival (DFS). The secondary outcomes were 3-year overall survival (OS) and morbidity and mortality within 30 days after surgery., Results: Of 526 included patients, 392 (74.5%) were men, and the mean (SD) age was 60.6 (9.6) years. A total of 263 patients were included in the D2 + No. 10 group, and 263 were included in the D2 group. The 3-year DFS was 70.3% (95% CI, 64.8-75.8) for the D2 + No. 10 group and 64.3% (95% CI, 58.4-70.2; P = .11) for the D2 group, and the 3-year OS in the D2 + No. 10 group was better than that in the D2 group (75.7% [95% CI, 70.6-80.8] vs 66.5% [95% CI, 60.8-72.2]; P = .02). Multivariate analysis revealed that splenic hilar lymphadenectomy was not an independent protective factor for DFS (hazard ratio [HR], 0.86; 95% CI, 0.63-1.16) or OS (HR, 0.81; 95% CI, 0.59-1.12). Stratification analysis showed that patients with advanced posterior gastric cancer in the D2 + No. 10 group had better 3-year DFS (92.9% vs 39.3%; P < .001) and OS (92.9% vs 42.9%; P < .001) than those in the D2 group. Multivariate analysis confirmed that patients with advanced posterior gastric cancer could have the survival benefit from No. 10 lymph node dissection (DFS: HR, 0.10; 95% CI, 0.02-0.46; OS: HR, 0.12; 95% CI, 0.03-0.52)., Conclusions and Relevance: Although LSTG could not significantly improve the 3-year DFS of patients with APGC without invasion into the greater curvature, patients with APGC located posterior gastric wall may benefit from LSTG., Trial Registration: ClinicalTrials.gov Identifier: NCT02333721.

We have demonstrated that CDK5RAP3 exerts a tumour suppressor effect in gastric cancer, but its role in regulating tumour-associated macrophages (TAMs) has not yet been reported. Here, we show that CDK5RAP3 is related to the infiltration and polarization of macrophages. It inhibits the polarization of TAMs to M2 macrophages and promotes the polarization of the M1 phenotype. CDK5RAP3 reduces the recruitment of circulating monocytes to infiltrate tumour tissue by inhibiting the CCL2/CCR2 axis in gastric cancer. Blocking CCR2 reduces the growth of xenograft tumours and the infiltration of monocytes. CDK5RAP3 inhibits the nuclear transcription of NF-κB, thereby reducing the secretion of the cytokines IL4 and IL10 and blocking the polarization of M2 macrophages. In addition, the absence of CDK5RAP3 in gastric cancer cells allows macrophages to secrete more MMP2 to promote the epithelial-mesenchymal transition (EMT) process of gastric cancer cells, thereby enhancing the invasion and migration ability. Our results imply that CDK5RAP3 may be involved in the regulation of immune activity in the tumour microenvironment and is expected to become a potential immunotherapy target for gastric cancer., (© 2022. The Author(s).)

Background: Immune checkpoint inhibitors are increasingly used in neoadjuvant therapy for locally advanced gastric cancer. However, the effect of body composition on the efficacy of neoadjuvant therapy has not been reported., Methods: The computed tomography (CT) images and clinicopathological data of 101 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy (NCI) from 2019 to 2021 were collected. The CT image of L3 vertebral body section was selected, and the body composition before and after the neoadjuvant treatment was calculated using the SliceOmatic software, mainly including skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). The relationship between body composition and the efficacy and adverse events of NCI was analyzed., Results: Of the 101 patients, 81 with evaluable data were included in the analysis. Of the included patients, 77.8% were male; the median age of all the patients was 62 years, and the median neoadjuvant therapy cycle was three. After the neoadjuvant therapy, 62.9% of the tumors were in remission (residual tumor cells ≤ 50%), and 37.1% of the tumors had no remission (residual tumor cells>50%). Moreover, 61.7% of the patients had treatment-related adverse events (TRAEs), and 18.5% had immune-related adverse events (irAEs). After neoadjuvant therapy, the body mass index (from 23 to 22.6 cm 2 /m 2 , p=0.042), SAI (from 34.7 to 32.9 cm 2 /m 2 , p=0.01) and VAI (from 32.4 to 26.8 cm 2 /m 2 , p=0.005) were significantly lower than those before treatment, while the SMI had no significant change (44.7 vs 42.5 cm 2 /m 2 , p=0.278). The multivariate logistics regression analysis revealed that low SMI (odds ratio [OR]: 3.23,95% confidence interval [CI]: 1.06-9.81, p=0.047), SMI attenuation (△SMI) ≥ 1.8(OR: 1.45,95%CI: 1.20-3.48, p=0.048), and clinical node positivity (OR: 6.99,95%CI: 2.35-20.82, p=0.001) were independent risk factors for non-remission. Additionally, high SAI is an independent risk factor for irAEs (OR: 14, 95%CI: 1.73-112.7, p=0.013)., Conclusion: Low SMI and △SMI≥1.8 are independent risk factors for poor tumor regression in patients with advanced gastric cancer receiving NCI. Patients with a high SAI are more likely to develop irAEs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Huang, Lin, Lin, Xie, Wang, Lu, Zheng, Huang and Li.)

Objective: To investigate the effect of intraoperative lymph node (LN) dissection and postoperative adjuvant chemotherapy on the overall survival (OS) of gastric cancer (GC) patients and their reciprocity., Methods: LN noncompliance was defined as the absence of more than one LN station, as described in the protocol for D2 lymphadenectomy in the Japanese Gastric Cancer Association. The definition of adjuvant chemotherapy (AC) noncompliance was that the chemotherapy planned dose does not meet the requirements., Results: Kaplan-Meier survival curves showed that the OS of patients with major LN noncompliance was significantly lower than that of patients with nonmajor LN noncompliance, and the OS of AC noncompliance patients was significantly lower than that of AC compliance patients. If there was nonmajor LN noncompliance during surgery, the OS of patients with AC compliance was significantly higher than that of patients with AC noncompliance (P = 0.035). In the case of major LN noncompliance during surgery, there was no statistically significant difference in OS between those with AC compliance and those with AC noncompliance (P = 0.682). Multivariate Cox regression analysis including AC noncompliance indicated that major LN noncompliance was an independent prognostic factor for poor OS (P = 0.012), while AC noncompliance was not an independent prognostic factor for OS (P = 0.609)., Conclusion: Adequate lymph node dissection and adjuvant chemotherapy are both key steps to improve the awful prognosis of GC patients. Adjuvant chemotherapy may fail to remedy the poor prognosis caused by major LN noncompliance., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 of 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 2 groups (14.6% vs 16.7%, P = 0.748)., Conclusions: In complex total gastrectomy for GC, compared with traditional laparoscopic surgery, robotic surgery provides a technically superior operative environment and reduces surgeon workload at high-volume specialized institutions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Robotic surgery may be advantageous for complex surgery. We aimed to compare the intraoperative and postoperative short-term outcomes of spleen-preserving splenic hilar lymphadenectomy (SPSHL) during robotic and laparoscopic total gastrectomy., Methods: From July 2016 to December 2020, the clinicopathological data of 115 patients who underwent robotic total gastrectomy combined with robotic SPSHL (RSPSHL) and 697 patients who underwent laparoscopic total gastrectomy combined with laparoscopic SPSHL (LSPSHL) were retrospectively analyzed. A 1:2 ratio propensity score matching (PSM) was used to balance the differences between the two groups to compare their outcomes. The Generic Error Rating Tool was used to evaluate the technical performance., Results: After PSM, the baseline preoperative characteristics of the 115 patients in the RSPSHL and 230 patients in the LSPSHL groups were balanced. The dissection time of the region of the splenic artery trunk (5.4 ± 1.9 min vs. 7.8 ± 3.6 min, P < 0.001), the estimated blood loss during SPSHL (9.6 ± 4.8 ml vs. 14.9 ± 7.8 ml, P < 0.001), and the average number of intraoperative technical errors during SPSHL (15.1 ± 3.4 times/case vs. 20.7 ± 4.3 times/case, P < 0.001) were significantly lower in the RSPSHL group than in the LSPSHL group. The RSPSHL group showed higher dissection rates of No. 10 (78.3% vs. 70.0%, P = 0.104) and No. 11d (54.8% vs. 40.4%, P = 0.012) lymph nodes and significantly improved postoperative recovery results in terms of times to ambulation, first flatus, and first intake (P < 0.05). The splenectomy rates of the two groups were similar (1.7% vs. 0.4%, P = 0.539), and there was no significant difference in morbidity and mortality within postoperative 30 days (13.0% vs. 15.2%, P = 0.589)., Conclusion: Compared to LSPSHL, RSPSHL has more advantages in terms of surgical qualities and postoperative recovery process with similar morbidity and mortality. For complex SPSHL, robotic surgery may be a better choice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: There is insufficient evidence to evaluate the long-term outcomes of robotic radical gastrectomy. The aim of this study was to compare the radical results and long-term outcomes of robotic and laparoscopic radical gastrectomy., Methods: We prospectively collected and retrospectively analyzed the general clinicopathological data of gastric cancer patients treated with robotic radical gastrectomy (RG) and laparoscopic radical gastrectomy (LG) from July 2016 to July 2018 at Fujian Medical University Union Hospital. The RG cohort was matched 1:3 with the LG cohort by using propensity score matching (PSM). The primary endpoints of the study were 3-year overall survival (OS) and 3-year relapse-free survival (RFS)., Results: The study included 221 patients treated with RG and 1106 patients treated with LG for gastric cancer. After PSM, 211 patients were included in the RG cohort, and 663 patients were included in the LG cohort. The 3-year OS rate was 81.0% in the robotic cohort and 79.3% in the laparoscopic cohort (log-rank test, P = 0.516). The 3-year RFS rate was 78.7% in the robotic cohort and 75.6% in the laparoscopic cohort (log-rank test, P = 0.600). In the subgroup analyses, no significant differences were noted between the RG and LG cohorts in terms of 3-year OS and 3-year RFS (all P > 0.05). The therapeutic value index of each lymph node station dissection in the robotic cohort was comparable to that in the laparoscopic cohort., Conclusion: Robotic radical gastrectomy can achieve radical results and long-term outcomes comparable to laparoscopic surgery, and further multicenter prospective studies can be conducted to assess the clinical efficacy of robotic radical gastrectomy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To develop and validate a simple metabolic score (Metabolic score, MS) for use in evaluating the prognosis of gastric cancer (GC) patients and dynamically monitor for early recurrence., Methods: We retrospectively collected general clinicopathological data of patients who underwent radical gastrectomy for GC between September 2012 and December 2017 in the Department of Gastric Surgery of the Fujian Medical University Union Hospital. Using a random forest algorithm to screen preoperative blood indicators into the Least absolute shrinkage and selection operator (LASSO) model, we developed a novel MS to predict prognosis., Results: Data of 1974 patients were used to develop and validate the model. Total cholesterol (TCHO), bilirubin (TBIL), direct bilirubin (DBIL), and 15 other metabolic indicators had significant predictive value for the prognosis using the random forest algorithm. In the overall population, 533 patients (27.0%) had high and 1441 (73%) had low MS status. High MS status was related to tumor progression. The KM curves of 3-year OS and RFS for training set patients showed low MS had a better prognosis than high MS (OS: 79.4% vs 59.7%, P < 0.001; RFS: 76.0% vs 56.2%, P < 0.001)., Conclusions: We have developed and validated MS to predict the long-term survival of GC patients and allow early monitoring of recurrence. This will provide physicians with simple, economical, and dynamic tumor monitoring information., (Copyright © 2022. Published by Elsevier Ltd.)

Background: This study aims to analyze the effect of textbook outcome (TO) on the long-term prognosis and adjuvant chemotherapy (AC) compliance of patients with gastric cancer (GC) in a single institute., Materials and Methods: Consecutive patients who underwent radical gastrectomy with pathological stage I-III at Union Hospital of Fujian Medical University from January 2010 to June 2017 were included. TO was defined as receiving a complete-potentially curative status, ≥15 lymph nodes examined, hospital stay ≤21 days, and freedom from intraoperative and postoperative complications, re-intervention in 30 days, 30-day readmission to the hospital or intensive care unit, and 30-day postoperative mortality., Results: Totally 3993 patients were included, of which 3361 (84.2%) patients achieved TO. The overall, disease-specific, and recurrence-free survival of patients achieving TO were significantly better than those of patients without achieving TO (all P < 0.05). The total number of AC cycles was greater and the interval from surgery to first AC was shorter in the TO group compared with the Non-TO group. Age >65 years old, open surgery, pT3-4 stage, and total radical gastrectomy (TG) were identified as related high-risk factors for failure to achieve TO. Laparoscopic surgery facilitated TO achievement in high-risk groups., Conclusion: TO is a reliable indicator of favorable prognosis of patients with GC and contributes to postoperative chemotherapy compliance. Age ≤65 years old, non-TG, pT1-2 stage, and laparoscopic surgery may promote the achievement of TO., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Few studies have reported the association between the pattern and time point of recurrence in different groups stratified by age in postoperative survival of patients with gastric cancer., Methods: The clinicopathological data and recurrence data of 2028 patients with GC who underwent curative surgery from January 2010 to March 2015 were enrolled in this study. Patients were grouped according to age: young group (YG) (≤45 years old) (n = 180) and non-young group (OG) (&gt;45 years old) (n = 1848)., Results: A total of 2028 patients were enrolled. The young group had better 5-year OS and DFS than the non-young group. In peritoneal recurrence, the cumulative incidence of recurrence in YG was higher than that in OG (P &lt; 0.001). In distant recurrence, the cumulative incidence of recurrence YG was always lower than that of OG (P = 0.004). Recurrence hazard function varied over time between the two groups:in the peritoneal metastasis, the recurrence hazard for YG was higher and earlier than that of OG and the YG was observed during five years after surgery with two recurrence peaks in 8.5 months and in 41.5 months. In distant recurrence, the recurrence hazard for OG had an earlier and higher single peak than that of YG (6.0 months)., Conclusion: The recurrence characteristics of patients with gastric cancer after curative resection between young group and older group are different. Personalized follow-up strategies should be developed according to the age and time point after operation for the early detection of recurrence and making decision for further treatment., Competing Interests: Declaration of competing interest All authors such as Wen-Wu Qiu,Qi-Yue Chen, Wen-Ze Zheng,Qi-Chen He,Ze-Ning Huang, Jian Wei Xie, Jia-Bin Wang, Jian-Xian Lin, Jun Lu, Long-Long Cao, Mi Lin, Ru-Hong Tu, Ju-Li Lin, Hua-Long Zheng, Guang-Tan Lin,Guo-Sheng Lin,Chao-Hui Zheng,Chang-Ming Huang, Ping Li have no conflict of interest and no potential benefits. The institutional review boards of all the participating institutions approved the study.The authors have no other disclosures to report., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Effective classifiers for the prediction of individual adjuvant chemotherapy (AC) benefits are scarce., Purpose: This study aimed to construct a useful classifier to predict the AC benefit and recurrence hazard based on preoperative hematological indices through a multicenter database., Methods and Results: Multivariate analysis revealing GCRF (comprehensive deep learning classifier) as an independent prognostic factor associated with overall survival (OS) and disease-free survival (DFS). Locally advanced gastric cancer (LAGC) patients are categorized into the high-risk group (HRG) and low-risk group (LRG). In HRG, OS and DFS of the AC group are significantly higher than those of the non-AC group (all p˂0.05), whereas in LRG, OS and DFS of the AC group are comparable to those of the non-AC group (all p &gt; 0.05). Furthermore, combined GCRF with 8th AJCC TNM staging system, only 650 (51.1%) patients can benefit most from AC among 1273 patients with pStage II-III. From the perspective of recurrence pattern, the recurrence rate of HRG is significantly higher than that of LRG in any recurrence type, including local recurrence, peritoneal recurrence, and distant recurrence (all p˂0.05). Furthermore, the mean time to peritoneal recurrence and lung metastasis in HRG is earlier than that in the LRG (p = 0.028 and 0.011, respectively)., Conclusion: In summary, our novel classifier based on deep learning preoperative hematological indices can predict not only the AC benefit of LAGC patients, but also the recurrence hazard after surgery. This classifier is expected to be an effective supplement to the 8th AJCC TNM staging system for the prediction of AC benefits and is helpful for clinical decision in AC individual administration. Further large-scale western studies are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The tumor immunosuppressive microenvironment can influence treatment response and outcomes. A previously validated immunosuppression scoring system (ISS) assesses multiple immune checkpoints in gastric cancer (GC) using tissue-based assays. We aimed to develop a radiological signature for non-invasive assessment of ISS and treatment outcomes., Methods: A total of 642 patients with resectable GC from three centers were divided into four cohorts. Radiomic features were extracted from portal venous-phase CT images of GC. A radiomic signature for predicting ISS (RISS) was constructed using the least absolute shrinkage and selection operator (LASSO) regression method. Moreover, we investigated the value of the RISS in predicting survival and chemotherapy response., Results: The RISS, which consisted of 10 selected features, showed good discrimination of immunosuppressive status in three independent cohorts (area under the curve = 0.840, 0.809, and 0.843, respectively). Multivariate analysis revealed that the RISS was an independent prognostic factor for both disease-free survival (DFS) and overall survival (OS) in all cohorts (all p < 0.05). Further analysis revealed that stage II and III GC patients with low RISS exhibited a favorable response to adjuvant chemotherapy (OS: hazard ratio [HR] 0.407, 95% confidence interval [CI] 0.284-0.584); DFS: HR 0.395, 95% CI 0.275-0.568). Furthermore, the RISS could predict prognosis and select stage II and III GC patients who could benefit from adjuvant chemotherapy independent of microsatellite instability status and Epstein-Barr virus status., Conclusion: The new, non-invasive radiomic signature could effectively predict the immunosuppressive status and prognosis of GC. Moreover, the RISS could help identify stage II and III GC patients most likely to benefit from adjuvant chemotherapy and avoid overtreatment., (© 2022. Society of Surgical Oncology.)

Background: Laparoscopic surgical approaches for gastric cancer after neoadjuvant chemotherapy are increasing, yet there is limited evidence of their safety and effectiveness., Methods: This prospective single-armed clinical trial enrolled 80 neoadjuvant chemotherapy patients who underwent laparoscopic gastrectomy. In addition, to better analyze the outcomes of this study, 1:2 propensity score matching was performed, and a contemporaneous historic control group containing 160 laparoscopic gastrectomy patients without neoadjuvant chemotherapy was established., Results: Analyses were performed to compare the neoadjuvant chemotherapy group (n = 80) and the control group (n = 160). The general clinical data of both groups were comparable. The neoadjuvant chemotherapy group showed less intraoperative bleeding (P = .029) and recovered more quickly than the control group (all P < .05). The 2 groups did not exhibit major differences in terms of postoperative complications (P = .679) or severe complications (P = .055). The proportion of patients with ypT4 stage and ypN3 stage disease in the neoadjuvant chemotherapy group totaled 20.7% and 23.8%, respectively, which was significantly lower than that observed in the control group (P < .05). The number of metastatic lymph nodes was 4.8 ± 7.0 in the neoadjuvant chemotherapy group, which was lower than that in the control group (P < .001). In the neoadjuvant chemotherapy group, the major pathological regression rate was 27.5%, while the objective radiologic response rate (complete response + partial response) was 64.0%. In contrast to nonresponding patients, the patients who experienced an objective response had a shorter operation time (P < .001), less intraoperative bleeding (P < .001), and fewer metastatic lymph nodes (P = .005). The short-term effects observed in the nonresponding patients were similar to those observed in the control group., Conclusion: Laparoscopic gastrectomy could achieve improved short-term outcomes through NACT tumor downstaging without increasing the incidence of postoperative complications. Further multicenter and prospective clinical trials are warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 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. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. 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. Together, our findings suggest that LHPP 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., (© 2022. The Author(s).)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: Neoadjuvant chemotherapy (NAC) is a standard treatment option for locally advanced gastric cancer (LAGC); however, the indications for adjuvant chemotherapy (AC) in patients with LAGC who received NAC remain controversial., Objective: To compare survival rates between patients with LAGC who received AC and those who did not after NAC followed by surgery., Design, Setting, and Participants: This multicenter, international cohort study included 353 patients with LAGC undergoing curative-intent gastrectomy after NAC at 2 tertiary referral teaching hospitals in China between June 1, 2008, and December 31, 2017. To externally validate the findings in the Chinese patients, 109 patients from the US and Italy between June 1, 2006, and June 30, 2013, were reviewed. The follow-up period of the Chinese patients was completed in December 2020, and the follow-up period of the Western patients was completed between February and July 2017. Data analysis was performed from December 1, 2020, to February 28, 2021., Exposures: Patients who received AC and those who did not were propensity score matched to evaluate the association of AC with survival., Main Outcomes and Measures: Overall survival (OS), disease-free survival, and disease-specific survival., Results: Of 353 patients from China (275 [78.1%] male; mean [SD] age, 58.0 [10.7] years), 262 (74.1%) received AC and 91 (25.9%) did not. After propensity score matching, the 3-year OS was significantly higher in patients who received AC (60.1%; 95% CI, 53.1%-68.1%) than in those who did not (49.3%; 95% CI, 39.8%-61.0%) (P = .02). Lymph node ratio (LNR) was significantly associated with AC benefit (P < .001 for interaction), and a plot of the interaction between LNR and AC demonstrated that AC was associated with improved OS in patients with higher (≥9%) LNRs (3-year OS: 46.6% vs 21.7%; P < .001), but not in patients with LNRs less than 9% (3-year OS: 73.9% vs 71.3%; P = .30). When stratified by AC cycles, only those patients who completed at least 4 AC cycles exhibited a significant survival benefit in the 6-month (hazard ratio, 0.56; 95% CI, 0.33-0.96; P = .03) and 9-month landmark analysis (hazard ratio, 0.50; 95% CI, 0.27-0.94; P = .03). In the external cohort, improved OS with AC administration was also found in patients with LNRs of 9% or greater (3-year OS: 53.0% vs 26.3%; P = .04)., Conclusions and Relevance: In this cohort study, the administration of AC after NAC and resection of LAGC was associated with improved prognosis in patients with LNRs of 9% or greater. These findings suggest that LNR might be valuable in AC selection in future decision-making processes.

Background: It remains inconclusive whether laparoscopic gastrectomy (LG) has better long-term outcomes when compared with open gastrectomy (OG) for elderly gastric cancer (EGC). We attempted to explore the influence of the immune prognostic index (IPI) on the prognosis of EGCs treated by LG or OG to identify a population among EGC who may benefit from LG., Methods: We included 1539 EGCs treated with radical gastrectomy from January 2007 to December 2016. Propensity score matching was applied at a ratio of 1:1 to compare the LG and OG groups. The IPI based on dNLR ≥ cut-off value (dNLR) and sLDH ≥ cut-off value (sLDH) was developed, characterizing two groups (IPI = 0, good, 0 factors; IPI = 1, poor, 1 or 2 factors)., Results: Of the 528 EGCs (LG: 264 and OG: 264), 271 were in the IPI = 0 group, and 257 were in the IPI = 1 group. In the entire cohort, the IPI = 0 group was associated with good 5-year overall survival (OS) (p = 0.001) and progression-free survival (PFS) (p = 0.003) compared to the IPI = 1 group; no significant differences in 5-year OS and PFS between the LG and OG groups were observed. In the IPI = 1 cohort, there was no significant difference in OS or PFS between the LG and OG groups across all tumor stages. However, in the IPI = 0 cohort, LG was associated with longer OS (p = 0.015) and PFS (p = 0.018) than OG in stage II EGC, but not in stage I or III EGC. Multivariate analysis showed that IPI = 0 was an independent protective factor for stage II EGC receiving LG, but not for those receiving OG., Conclusion: The IPI is related to the long-term prognosis of EGC. Compared with OG, LG may improve the 5-year survival rate of stage II EGC with a good IPI score. This hypothesis needs to be further confirmed by prospective studies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The oncologic efficacy of laparoscopic versus open surgery for advanced distal gastric cancer (ADGC) beyond 3 years after surgery remain obscure., Methods: A total of 1256 patients with ADGC at two teaching institutions in China from April 2007 to December 2014 were enrolled. The general data of the two groups were identified to enable rigorous estimation of propensity scores. Restricted mean survival time (RMST) and Landmark analysis was used to compare survival., Results: After matching 461 patients each in the open distal gastrectomy (ODG) and laparoscopic distal gastrectomy (LDG) groups, they were included into analysis. The 3- and 5-year overall survival (OS) and disease-free survival were comparable in two groups. RMST-stratified analysis showed that the 3-year RMST of ODG group was similar to that of LDG group in patients with cT4a (- 1.38 years, p = 0.163) or with cT4a and tumor size > 5 cm, whereas the 5-year RMST had significant differences between groups in cT4a patients(- 8.36 years, P = 0.005) or cT4a and tumor size > 5 cm patients(4.67 years, P = 0.042). In patients with cT4a and tumors > 5 cm, the number of peritoneal recurrences was significantly fewer in the ODG group than in the LDG group (4 vs. 17, P = 0.033), and the peritoneal recurrence time and multiple-site recurrence time were both later in the ODG group., Conclusion: By reducing recurrence, ODG achieves a better survival for GC patients with serous infiltration and tumors larger than 5 cm beyond 3 years after surgery. The present findings can serve as a reference for surgical options and the setting of follow-up time point for clinical studies., (© 2021. The Author(s).)

Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo . Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To investigate the safety and efficacy of camrelizumab in combination with nab-paclitaxel plus S-1 for the treatment of gastric cancer with serosal invasion., Method: Two hundred patients with gastric cancer with serosal invasion who received neoadjuvant therapy from January 2012 to December 2020 were retrospectively analyzed. According to the different neoadjuvant therapy regimens, the patients were divided into the following three groups: the SOX group (S-1 + oxaliplatin) (72 patients), SAP group (S-1 + nab-paclitaxel) (95 patients) and C-SAP group (camrelizumab + S-1 + nab-paclitaxel) (33 patients)., Result: The pathological response (TRG 1a/1b) in the C-SAP group (39.4%) was not significantly different from that in the SAP group (26.3%) and was significantly higher than that in the SOX group (18.1%). The rate of ypT0 in the C-SAP group (24.2%) was higher than that in the SAP group (6.3%) and the SOX group (5.6%). The rate of ypN0 in the C-SAP group (66.7%) was also higher than that in the SAP group (38.9%) and the SOX group (36.1%). The rate of pCR in the C-SAP group (21.2%) was higher than that in the SAP group (5.3%) and the SOX group (2.8%). The use of an anti-PD-1 monoclonal antibody was an independent protective factor for TRG grade (1a/1b). The use of camrelizumab did not increase postoperative complications or the adverse effects of neoadjuvant therapy., Conclusion: Camrelizumab combined with nab-paclitaxel plus S-1 could significantly improve the rate of tumor regression grade (TRG 1a/1b) and the rate of pCR in gastric cancer with serosal invasion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Lin, Lin, Zheng, Li, Xie, Wang, Lu, Chen and Huang.)