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Summary Background The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. Methods We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40–60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. Findings Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5–56·3) in the adjuvant-CapOx group, 56·5% (51·0–61·7) in the adjuvant-SOX group, and 59·4% (53·8–64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61–0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68–1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3–4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. Interpretation Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. Funding National Key Research and Development Program of China, Beijing Scholars Program 2018–2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Background Total gastrectomy for carcinoma in the remnant stomach (CRS) remains a technically demanding procedure. Whether robotic surgery is superior, equal, or inferior to laparoscopic surgery in patients with CRS is unclear. This study was designed to compare the efficacy and safety of robotic total gastrectomy (RTG) and laparoscopic total gastrectomy (LTG) for the treatment of CRS. Methods In this cohort study, we retrospectively analysed the data from patients who underwent RTG or LTG for CRS at Southwest Hospital (Chongqing, China) between May 2006 and October 2019. The surgical outcomes, post-operative complications, and survival outcomes between the two groups were compared. Results Compared with LTG, RTG was associated with similar effective operation time (272.0 vs 297.9 min, P = 0.170), higher total costs (105,967.2 vs 81,629.5 RMB, P 0.05). The 3-year disease-free survival and 3-year overall survival rates were comparable between the two groups (65.5% vs 57.5%, P = 0.918; 69.0% vs 60.0%, P = 0.850, respectively). Conclusions RTG is a safe and feasible procedure for the treatment of CRS and could serve as an optimal treatment for CRS.

Background Whether laparoscopic gastrectomy is suitable for patients with serosa-invasive gastric cancer remains controversial. We performed this study to evaluate the short- and long-term outcomes after laparoscopic gastrectomy compared with after open gastrectomy. Methods We retrospectively analyzed 906 consecutive patients with serosa-invasive gastric cancer from January 2004 to December 2014 in our center, who underwent laparoscopic gastrectomy or open gastrectomy with D2 lymphadenectomy. After propensity score matching, 334 patients were included in each group. Surgical conditions and short- and long-term results were compared. Results Laparoscopic gastrectomy was associated with less estimated blood loss and longer operation time, while the number of harvested lymph nodes was not significantly different between laparoscopic gastrectomy and open gastrectomy. Patients who underwent laparoscopic gastrectomy had an earlier time to first flatus, first diet, and first ambulation and were discharged earlier. Overall and pulmonary postoperative complication rates were lower in the laparoscopic gastrectomy group. With a minimum follow-up of 60 months, the 5-year overall survival was 39.3% in the laparoscopic gastrectomy group and 34.3% in the open gastrectomy group, and the 5-year disease-free survival was 36.4% in the laparoscopic gastrectomy group and 32.7% in the open gastrectomy group. Laparoscopic gastrectomy was associated with better 5-year overall survival in patients aged ≥60 years. The overall recurrence rates and patterns were not significantly different between the 2 groups. Conclusion Laparoscopic gastrectomy is an alternative surgical approach for patients with serosa-invasive gastric cancer in terms of short-term outcomes and long-term survival, and it might be more advantageous for certain populations.

Background: We aimed to evaluate the association between the vascular endothelial growth factor (VEGF) gene +936C>T polymorphism and digestive system tumors using a meta-analysis. Methods: Studies ...

Background The efficacy of pelvic floor peritoneum closure (PC) during endoscopic low anterior resection (E-LAR) of rectal cancer remains unclear. This study aimed to clarify whether pelvic floor PC affected short-term outcomes. Methods The study group comprised patients with the pathologically confirmed diagnosis of rectal cancer who underwent E-LAR with pelvic floor PC or with no PC (NPC) between January 2013 and December 2018 in Southwest Hospital. After propensity score matching (PSM), 584 patients (292 who underwent PC and 292 who underwent NPC) were evaluated. Postoperative indicators, including the rates of complications, anastomotic leakage (AL), reoperation, and inflammation, were observed in the two groups. Results No significant difference was observed in the rates of postoperative complications between the PC and NPC groups. The rates of AL were similar (11.3% vs. 9.2%, p = .414). However, the reoperation rate of patients in the PC group was significantly lower than that of patients in the NPC group after AL (36.4% vs. 11.1%, p = .025). The hospital costs were higher in the NPC leakage subgroup (p = .001). Additionally, the serum C-reactive protein levels were lower in the PC group on postoperative days (PODs) 1, 3, and 5, whereas procalcitonin levels on POD 1 and 3 were lower in the PC group but did not differ significantly on POD 5. Conclusion Pelvic peritonization did not affect the rate of complications, especially AL; however, it effectively reduced the reoperation and inflammation rates and reduced hospitalization costs. Other short-term outcomes were similar, which warrant the increased use of pelvic peritonization in endoscopic surgery.

Background Few studies have been designed to evaluate the short-term outcomes between robotic-assisted total gastrectomy (RATG) and laparoscopy-assisted total gastrectomy (LATG) for advanced gastric cancer (AGC). The purpose of this study was to assess the short-term outcomes of RATG compared with LATG for AGC. Methods We retrospectively evaluated 126 and 257 patients who underwent RATG or LATG, respectively. In addition, we performed propensity score matching (PSM) analysis between RATG and LATG for clinicopathological characteristics to reduce bias and compared short-term surgical outcomes. Results After PSM, the RATG group had a longer mean operation time (291.14 ± 59.18 vs. 270.34 ± 52.22 min, p = 0.003), less intraoperative bleeding (154.37 ± 89.68 vs. 183.77 ± 95.39 ml, p = 0.004) and more N2 tier RLNs (9.07 ± 5.34 vs. 7.56 ± 4.50, p = 0.016) than the LATG group. Additionally, the total RLNs of the RATG group were almost significantly different compared to that of the LATG group (34.90 ± 13.05 vs. 31.91 ± 12.46, p = 0.065). Moreover, no significant differences were found between the two groups in terms of the length of incision, proximal resection margin, distal resection margin, residual disease and postoperative hospital stay. There was no significant difference in the overall complication rate between the RATG and LATG groups after PSM (23.8% vs. 28.6%, p = 0.390). Grade II complications accounted for most of the complications in the two cohorts after PSM. The conversion rates were 4.55 and 8.54% in the RATG and LATG groups, respectively, with no significant difference (p = 0.145), and the ratio of splenectomy were 1.59 and 0.39% (p = 0.253). The mortality rates were 0.8 and 0.4% for the RATG and LATG groups, respectively (p = 1.000). Conclusion This study demonstrates that RATG is comparable to LATG in terms of short-term surgical outcomes.

BackgroundIt is unclear whether the dissection of pyloric lymph nodes (PLNs, No. 5 and No. 6 lymph nodes) is necessary for adenocarcinoma of the esophagogastric junction (AEG) with a tumor diameter >4 cm based on current guidelines. This study aimed at evaluating whether pyloric node lymphadenectomy is essential for patients with Siewert type II/III AEG according to different tumor diameters.MethodsThis study included 300 patients on whom transabdominal total gastrectomy was performed for Siewert type II/III AEG at a high-volume center in China from January 2006 to December 2015. The index of estimated benefit from lymph node dissection (IEBLD) was used to analyze the priority of pyloric lymphadenectomy.ResultsIn Siewert type II AEG, the 5-year overall survival (OS) and the 5-year disease-free survival (DFS) were similar between patients with PLN-positive cancer and patients of stage III AEG without PLN metastasis (23.1% vs. 30.6%, p = 0.505; 23.1% vs. 27.1%, p = 0.678). However, in Siewert type III AEG, the OS and the DFS of patients with PLN-positive cancer were significantly lower than that of patients with stage III without PLN metastasis (7.9% vs. 27.8%, p = 0.021; 0 vs. 26.8%, p = 0.005). According to the IEBLD, the dissection of PLNs did not appear to be beneficial in either Siewert type II AEG or type III AEG, whereas a stratified analysis revealed that PLN dissection yielded a high therapeutic benefit for Siewert type II AEG with tumor diameters >4 cm.ConclusionWe recommended that the PLNs be dissected in Siewert type II AEG when a tumor diameter is >4 cm. Total gastrectomy should be optional for Siewert type II AEG with a tumor diameter >4 cm and Siewert type III AEG.

Background This study was designed to compare the postoperative complications after Robotic total gastrectomy (RTG) and robotic distal gastrectomy (RDG) and to systematically evaluate the safety and feasibility of RTG for the treatment of gastric cancer (GC). Methods Patients with GC who underwent RTG or RDG for curative intent between March 2010 and August 2019 were analyzed. We used propensity score matching (PSM) to reduce selection bias. The morbidity and mortality within 30 days after surgery between the RTG and the RDG groups were compared. Results According to Clavien–Dindo (C–D) classification, the morbidity and mortality of the RTG group were comparable to those of the RDG group. Subgroup analyses showed no significant difference between the RTG and RDG groups in all stratified parameters (all P > .05). Multivariate analysis revealed that age ≥70 years ( P = .002) and surgeons’ experience ≤25 cases ( P = .013) were independent risk factors for overall complication. Surgeons’ experience ≤25 cases ( P = .010) was identified as an independent risk factor for severe complication. Conclusion RTG is a safe and feasible surgical procedure for the treatment of GC with acceptable morbidity and mortality. More complications were observed for RTG, indicating that RTG is more invasive than RDG.

BackgroundLaparoscopic gastrectomy (LG) has been increasingly used for the treatment of locally advanced Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). However, whether LG can achieve the same short-term efficacy in the treatment of patients who receive neoadjuvant chemotherapy (NACT) remains controversial. Thus, the aim of this study was to investigate the clinical outcomes of NACT combined with LG for Siewert type II and III AEG.MethodsThis retrospective study identified patients with locally advanced Siewert type II and III AEG diagnosed between May 2011 and October 2020 using the clinical tumor-node-metastasis (cTNM) staging system. The short-term outcomes were compared between the matched groups using a 1:3 propensity score matching (PSM) method, which was performed to reduce bias in patient selection.ResultsAfter PSM, 164 patients were selected, including 41 in the NACT group and 123 in the LG group. The baseline characteristics were similar between the two groups. Compared with the LG group, the NACT group exhibit a smaller tumor size and significantly less advanced pathological tumor classification and nodal classification stages. The time to first flatus of the NACT group was significantly shorter, but the hospital stay was significantly longer than that of the LG group. The NACT group showed similar overall (29.3% vs 25.2%, P=0.683), systemic (24.4% vs 21.1%, P=0.663), local (12.2% vs 9.8%, P=0.767), minor (19.5% vs 19.5%, P=1.000) and major (9.8% vs 5.7%, P=0.470) complications as the LG group. Subgroup analyses showed no significant differences in most stratified parameters. Operation time≥ 300 minutes was identified as an independent risk factor for overall complications. Age≥ 60 years was identified as an independent risk factor for major complications.ConclusionNACT combined with LG for AEG does not increase the risk of postoperative morbidity and mortality compared with LG.

Background The prognostic significance of preoperative plasma fibrinogen in patients with operable gastric cancer remains under debate. This study aimed to elucidate the prognostic value of fibrinogen in gastric cancer patients underwent gastrectomy. Methods A total of 4351 patients with gastric cancer collected from three comprehensive medical centers were retrospectively evaluated. Patients were categorized by minimum P value using X-tile, while the baseline confounders for fibrinogen was balanced through propensity score matching (PSM). The relationships between fibrinogen and other clinicopathologic features were evaluated, and nomogram was constructed to assess its prognostic improvement compared with TNM staging system. Results Fibrinogen was significantly correlated with macroscopic type, tumor differentiation, tumor size, and T and N stage. The factors, fibrinogen and T stage as well as N stage, were identified to be independent prognostic factors after PSM. Nomogram based on fibrinogen demonstrated a smaller Akaike information criterion (AIC) and a larger concordance index (C-index) than TNM staging system, illustrating that fibrinogen might be able to improve the prognostic accuracy. Conclusions Preoperative plasma fibrinogen levels in gastric cancer patients were significantly correlated with tumor progression, which could be regarded as a reliable marker for survival prognostic prediction.

Background The aberrant expression of myotubularin-related protein 2 (MTMR2) has been found in some cancers, but little is known about the roles and clinical relevance. The present study aimed to investigate the roles and clinical relevance of MTMR2 as well as the underlying mechanisms in gastric cancer (GC). Methods MTMR2 expression was examined in 295 GC samples by using immunohistochemistry (IHC). The correlation between MTMR2 expression and clinicopathological features and outcomes of the patients was analyzed. The roles of MTMR2 in regulating the invasive and metastatic capabilities of GC cells were observed using gain-and loss-of-function assays both in vitro and in vivo. The pathways involved in MTMR2-regulating invasion and metastasis were selected and identified by using mRNA expression profiling. Functions and underlying mechanisms of MTMR2-mediated invasion and metastasis were further investigated in a series of in vitro studies. Results MTMR2 was highly expressed in human GC tissues compared to adjacent normal tissues and its expression levels were significantly correlated with depth of invasion, lymph node metastasis, and TNM stage. Patients with MTMR2high had significantly shorter lifespan than those with MTMR2low. Cox regression analysis showed that MTMR2 was an independent prognostic indicator for GC patients. Knockdown of MTMR2 significantly reduced migratory and invasive capabilities in vitro and metastases in vivo in GC cells, while overexpressing MTMR2 achieved the opposite results. MTMR2 knockdown and overexpression markedly inhibited and promoted the epithelial-mesenchymal transition (EMT), respectively. MTMR2 mediated EMT through the IFNγ/STAT1/IRF1 pathway to promote GC invasion and metastasis. Phosphorylation of STAT1 and IRF1 was increased by MTMR2 knockdown and decreased by MTMR2 overexpression accompanying with ZEB1 down-regulation and up-regulation, respectively. Silencing IRF1 upregulated ZEB1, which induced EMT and consequently enhanced invasion and metastasis in GC cells. Conclusions Our findings suggest that MTMR2 is an important promoter in GC invasion and metastasis by inactivating IFNγ/STAT1 signaling and may act as a new prognostic indicator and a potential therapeutic target for GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1186-z) contains supplementary material, which is available to authorized users.

Aberrant expression of neuropilin and tolloid-like 2 (NETO2) has been observed during the progression of some human carcinomas. However, the expression pattern and clinical relevance of NETO2 in gastric cancer (GC) remain to be elucidated. In this study, we found that NETO2 expression was higher in GC tissues compared with paired non-cancerous tissues. Moreover, the expression of NETO2 was positively correlated with clinical stage, invasion depth, lymph node metastasis, and tumor size, but inversely correlated with overall and disease-free survival rates. Cox regression analysis identified NETO2 as an independent prognostic indicator for GC patients. Overexpression of NETO2 facilitated migration and invasion of GC cells in vitro and metastasis in vivo in association with induction of epithelial-mesenchymal transition. Conversely, knockdown of NETO2 had the opposite effects. Mechanistically, silencing NETO2 reduced the phosphorylation of PI3K, AKT, and NF-κB p65 as well as the expression of Snail, whereas NETO2 overexpression achieved the opposite results. Furthermore, we identified TNFRSF12A as a mediator for NETO2 to activate PI3K/AKT/NF-κB/Snail axis. Collectively, our results demonstrate that NETO2 promotes invasion and metastasis of GC cells and represents a novel prognostic indicator as well as a potential therapeutic target in GC.

Robotic surgery has been increasingly used worldwide owing to its advanced features. However, the significant benefits of robotic total gastrectomy (RTG) over laparoscopic total gastrectomy (LTG) have yet to be demonstrated. We conducted a prospective cohort study to compare the safety and efficacy of robotic and laparoscopic total gastrectomy (LTG) with D2 lymphadenectomy for AGC.Between March 26, 2018 and July 30, 2021, 155 patients between 18 and 80 years of age with locally advanced gastric cancer (cT2-4a, N0/+, M0) were enrolled. The perioperative outcomes within 30 days after surgery were compared between the RTG (n = 69) and LTG (n = 73) groups on a per-protocol (PP) basis. Postoperative complications were evaluated according to the Clavien-Dindo classification.The overall postoperative morbidity rate was 21.74% in the RTG group and 28.77% in the LTG group with no significant difference (P = 0.44), RTG was associated with a lower incidence of pneumonia (4.35% vs. 15.07%, P = 0.047). No mortality was observed in either group. There was no significant difference in the total operative time (284.48 vs. 271.73 min, P = 0.171), but RTG was associated with a lower estimated volume of blood loss (110 vs. 150 ml, P 0.001) and more total retrieved lymph nodes (LNs) (41.36 vs 35.1, P = 0.019), more extraperigastric LNs (14.91 vs. 12.19, P = 0.024) and more LNs in the suprapancreatic areas (14.68 vs. 11.82, P = 0.017). The laboratory data (amylase, inflammatory, Albumin and T lymphocyte levels) of the RTG group were better than those of the LTG group.According to the results of this prospective cohort study, for patients with locally advanced gastric cancer, Robotic surgery has advantages over laparoscopic surgery for radical total gastrectomy with D2 lymphadenectomy performed by well-trained doctors.

Importance The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains uncertain given the lack of high-level clinical evidence. Objective To compare the safety of LTG for clinical stage I gastric cancer with that of conventional open total gastrectomy (OTG). Design, Setting, and Participants The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group CLASS02 study was a prospective, multicenter, open-label, noninferiority, randomized clinical trial that compared the safety of LTG vs OTG with lymphadenectomy for patients with clinical stage I gastric cancer. From January 2017 to September 2018, a total of 227 patients were enrolled. Final follow-up was in October 2018. Interventions Eligible patients were randomized to LTG (n = 113) or OTG (n = 114) by an interactive web response system. Main Outcomes and Measures The primary outcome was the morbidity and mortality within 30 days following surgeries between LTG and OTG with a noninferiority margin of 10%. The secondary outcomes were recovery courses and postoperative hospital stays. Results A total of 214 patients were analyzed for morbidity and mortality (105 patients in the LTG group and 109 patients in the OTG group). The mean (SD) age was 59.8 (9.4) years in the LTG group and 59.4 (9.2) years in the OTG group, and most were male (LTG group, 75 of 105 [71.4%]; OTG group, 80 of 109 [73.4%]). The overall morbidity and mortality rates were not significantly different between the groups (rate difference, −1.1%; 95% CI, −11.8% to 9.6%). Intraoperative complications occurred in 3 patients (2.9%) in the LTG group and 4 patients (3.7%) in the OTG group (rate difference, −0.8%; 95% CI, −6.5% to 4.9%). In addition, there was no significant difference in the overall postoperative complication rate of 18.1% in the LTG group and 17.4% in the OTG group (rate difference, 0.7%; 95% CI, −9.6% to 11.0%). One patient in the LTG group died from intra-abdominal bleeding secondary to splenic artery hemorrhage. However, there was no significant difference in mortality between the LTG group and the OTG group (rate difference, 1.0%; 95% CI, −2.5% to 5.2%), and the distribution of complication severity was similar between the 2 groups. Conclusions and Relevance The results of the CLASS02 trial showed that the safety of LTG with lymphadenectomy by experienced surgeons for clinical stage I gastric cancer was comparable to that of OTG. Trial Registration ClinicalTrials.gov Identifier:NCT03007550

The robotic surgical system has several technical advantages over laparoscopic instruments. The technical feasibility and safety of robotic gastrectomy (RG) for gastric cancer have been reported by increasing number of studies. However, the long-term survival and recurrence outcomes after RG for locally advanced gastric cancer (AGC) have seldom been reported. This study aimed to compare long-term oncologic outcomes for patients with locally AGC after RG or laparoscopic gastrectomy (LG). This study comprised 1170 patients underwent RG or LG, respectively, for locally AGC between March 2010 and February 2017. The primary outcome was the 3-year disease-free survival (DFS). The secondary endpoint included 3-year overall survival (OS) and recurrence patterns. One-to-one propensity score matching (PSM) was performed to reduce confounding bias. The outcomes were compared in PSM cohort. After PSM, a well-balanced cohort of 816 patients (408 in each group) were included in the analysis. The 3-year DFS rate was 76.2% in the robotic group and 70.1% in the laparoscopic group (P = 0.076). The 3-year OS rates was 76.7% in the robotic group and 73.3% in the laparoscopic group (P = 0.246). In the subgroup analyses for potential confounding variables, neither 3-year DFS nor 3-year OS survival were significantly different between the two groups (all P > 0.05). The two groups showed similar recurrence patterns within 3 years after surgery (P > 0.05). For patients with locally AGC, RG can result in comparable long-term survival outcomes without an increase in recurrence rate.

In this study, we investigated the incidence and risk factors for postoperative complications after robotic gastrectomy (RG) in patients with gastric cancer. A total of 817 patients who underwent RG for gastric cancer between March 2010 and August 2019 were analyzed retrospectively. Postoperative complications were categorized according to the Clavien–Dindo classification, and possible risk factors were evaluated. Among 817 patients who underwent RG, overall, severe, local and systemic complication rates were 13.8, 4.2, 7.0 and 6.9%, respectively. Multivariable analysis revealed that an age of 70 years or older (P

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.

For patients with locally advanced proximal gastric cancer (LAPGC), the individualized selection of patients with highly suspected splenic hilar (No. 10) lymph node (LN) metastasis to undergo splenic hilar lymphadenectomy, is a clinical dilemma. This study aimed to re-evaluate the feasibility and safety of laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) and to identify the population who would benefit from it. A total of 1068 patients (D2 group = 409; D2 + No. 10 group = 659) who underwent laparoscopic total gastrectomy from four prospective trials between January 2015 and July 2019 were analyzed. No significant difference in the incidence (16.9% vs. 16.4%; P = 0.837) of postoperative complications were found between the two groups. The metastasis rate of No. 10 LN among patients in the D2 + No. 10 group was 10.3% (68/659). Based on the decision tree, patients with LAPGC with tumor invading the greater curvature (Gre), patients with non-Gre-invading LAPGC with a tumor size > 5 cm and clinical positive locoregional LNs were defined as the high-priority No. 10 dissection group. The metastasis rate of No. 10 LNs in the high-priority group was 19.4% (41/211). In high-priority group, the 3-year overall survival of the D2 + No. 10 group was better than that of the D2 group (74.4% vs. 42.1%; P = 0.005), and the therapeutic index of No. 10 was higher than the indices of most suprapancreatic stations. LSPSHL for LAPGC is safe and feasible when performed by experienced surgeons. LSPSHL could be recommended for the high-priority group patients even without invasion of the Gre.

Presence of cancer stem cells (CSCs) contributes to tumor outgrowth, chemo-resistance and relapse in some cancers including colorectal carcinoma (CRC). The current characterization methods of CSCs in CRC only allows enrichment of CSCs but not their purification. Recent reports showed that ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-I) plays an essential role in protecting tumor cells against harsh environment like oxidative stress and nutrient deprivation. Therefore, whether ST6Gal-I may be highly expressed in CSCs or whether it may enhance resistance of tumor cells to chemotherapy deserves exploration. ST6Gal-I levels were determined in CRC specimens, compared to paired normal colorectal tissue, and examined in CD133+ vs CD133− CRC cells, and CD44+ vs CD44− CRC cells. ST6Gal-I levels and their association with patient survival were examined. In vivo, 2 CRC cell lines Caco-2 and SW48 were transduced with two lentiviruses, one lentivirus carrying a green fluorescent protein reporter and a luciferase reporter under a cytomegalovirus promoter to allow tracing tumor cells by both fluorescence and luciferase activity, and one lentivirus carrying a nuclear red fluorescent protein under the control of ST6Gal-I promoter to allow separation of ST6Gal-I+ vs ST6Gal-I− CRC cells. Tumor sphere formation, resistance to fluorouracil-induced apoptosis, and frequency of tumor formation after serial adoptive transplantation were done on ST6Gal-I+ vs ST6Gal-I− CRC cells. ST6Gal-I levels were significantly upregulated in clinically obtained CRC specimens, compared to paired normal colorectal tissue. Poorer patient survival was detected in ST6Gal-I-high CRC, compared to ST6Gal-I-low subjects. Higher levels of ST6Gal-I were detected in CD133+ CRC cells than CD133− CRC cells, and in CD44+ CRC cells than in CD44− CRC cells. Compared to ST6Gal-I− CRC cells, ST6Gal-I+ CRC cells generated significantly more tumor spheres in culture, were more resistant to fluorouracil-induced apoptosis likely through upregulating cell autophagy, and generated tumor more frequently after serial adoptive transplantation. ST6Gal-I may be highly expressed in the cancer stem-like cells in CRC and enhances cancer cell resistance to chemotherapy.

SOCS3 has been postulated to play a role in the occurrence and progression of malignancies. However, the relationship of SOCS3 with colorectal carcinoma remains poorly understood. The purpose of the study was to explore the role of SOCS3 in colorectal carcinoma and its underlying mechanisms. Protein and mRNA expression of SOCS3 in colorectal carcinoma and normal colorectal mucosa was detected using immunohistochemistry and real-time quantitative PCR. SOCS3 expression was significantly lower in colorectal carcinoma tissue than in normal colorectal mucosa, and was negatively correlated with tumor invasion depth, lymph node metastasis, differentiation degree, and TNM stage. A stably transfected colorectal carcinoma cell line (8348SOCS3) with high expression of SOCS3 was established. The effects of SOCS3 overexpression on the growth, proliferation, invasion and tumor formation of colorectal carcinoma cells were examined by CCK-8 assay, transwell method and tumorigenicity assays in nude mice. Then we found SOCS3 overexpression significantly decreased proliferation and invasion capability of 8348 cells in vitro and in vivo. Furthermore, the effect of SOCS3 overexpression on the gene expression profile of colorectal carcinoma cells was analyzed using human genome arrays. The results revealed 369 genes that were differentially expressed in 8348SOCS3 cells. 193 genes was significantly increased and 176 genes was significantly decreased. Bioinformatics analysis demonstrated that high SOCS3 expression affected multiple signaling pathways in colorectal carcinoma including TGF-β/Smads, NF-κB, and HIF-MAPK pathways. Especially for the TGF-β/Smads pathways, high SOCS3 expression could inhibit TGF-β1 expression and activate Smad4 expression. These data suggested that low expression of SOCS3 was associated with the occurrence and progression of colorectal carcinoma. SOCS3 protein may be a useful indicator for malignancy and prognosis of colorectal carcinoma and also a new target for gene therapy.

Laparoscopy-assisted gastrectomy (LAG) has gained acceptance as one of the best treatments for early gastric cancer. However, the application of LAG with D2 lymph node dissection in patients with locally advanced gastric cancer (AGC) remains controversial. We launched a prospective randomized controlled trial comparing laparoscopic and open gastrectomy with D2 lymph node dissection for locally AGC to evaluate technical safety and oncologic feasibility. The postoperative morbidity and mortality rates were based on the modified intention-to-treat analysis. Between January 2010 and June 2012, a total of 328 patients with preoperative clinical stage T2–3N0–3M0 gastric cancer were enrolled in the trial. Six patients with unresected AGC were excluded, and the remaining 322 patients were randomized to the laparoscopic group (162 patients) or the open group (160 patients) for radical surgery. All patients underwent D2 lymph node dissection including 18 (5.59%) proximal gastrectomies, 196 (60.87%) distal gastrectomies, and 108 (33.54%) total gastrectomies. Six patients (3.70%) in the LAG group were converted to open procedures. The overall complication rate was 11.72% in the LAG group and 14.38% in the open group (P = 0.512). No mortality occurred in either group. The short-term results of the current study suggest that LAG with D2 lymph node dissection is a safe and feasible procedure in treating patients with locally AGC in experienced centers.

Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163+CD206+ M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163+CD206+ M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10highTGF-βhighIL-12 p35low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.

The feasibility and safety of laparoscopic-assisted gastrectomy as a first-line treatment for advanced gastric cancer is controversial, especially for patients with serous membrane invasion. This study was designed to evaluate and compare the clinical effect of laparoscopy-assisted and open radical gastrectomy for stage T4a gastric cancer.We performed a retrospective analysis of the clinical data of 230 patients with stage T4a gastric cancer in our hospital from October 2006 to October 2008. A total of 111 patients with stage T4a gastric cancer underwent laparoscopic radical gastrectomy (LARG group), and 119 patients with stage T4a gastric cancer underwent open radical gastrectomy (ORG group). Clinical parameters, including incision length, operation time, blood loss, time to first flatus, time to first defecation, length of hospital stay, postoperative complications, one-year, three-year, and five-year disease-free survival rates, and the overall survival rate were analyzed via t-tests and chi-squared tests.The incision length, blood loss, time to first flatus, time to first defecation, and length of hospital stay in the LARG group were significantly less than in the ORG group (P 0.05). The mean operation time in the LARG group was similar to that in the ORG group (P 0.05). Postoperative complications were significantly less in the LARG group than in the ORG group (P 0.05). The one-year, three-year, and five-year disease-free survival rates were 83.8%, 67.6%, and 37.8% in the LARG group, respectively, and 81.5%, 65.5%, and 35.3% in the ORG group, respectively (P 0.05). The one-year, three-year, and five-year survival rates were 89.2%, 72.1%, and 47.7% in the LARG group, respectively, and 87.4%, 68.1%, and 40.3% in the ORG group, respectively (P 0.05).LARG for stage T4a gastric cancer not only has the advantage of being minimally invasive, but the postoperative complication rate is low and the clinical effects are satisfactory.

Colorectal cancer (CRC) causes high morbidity and mortality worldwide, and noninvasive gut microbiome (GM) biomarkers are promising for early CRC diagnosis. However, the GM varies significantly based on ethnicity, diet and living environment, suggesting varied GM biomarker performance in different regions. We performed a metagenomic association analysis on stools from 52 patients and 55 corresponding healthy family members who lived together to identify GM biomarkers for CRC in Chongqing, China. The GM of patients differed significantly from that of healthy controls. A total of 22 microbial genes were included as screening biomarkers with high accuracy in additional 46 cases and 40 randomly selected healthy adults in Chongqing (area under the receive-operation curve (AUC) = 0.905, 95% CI 0.832-0.977). The classifier based on the identified 22 biomarkers also performed well in the cohort from Hong Kong (AUC = 0.811, 95% CI 0.715-0.907) and French (AUC = 0.859, 95% CI 0.773-0.944) populations. Quantitative PCR was applied for measuring three selected biomarkers in the classification of CRC patients in independent Chongqing population containing 30 cases and 30 controls and the best biomarker from Coprobacillus performed well with high AUC (0.930, 95% CI 0.904-0.955). This study revealed increased sensitivity and applicability of our GM biomarkers compared with previous biomarkers significantly promoting the early diagnosis of CRC.

Background: The objective of this study is to identify independent risks and protective factors and to construct a mortality prediction model for gastrectomy in the Chinese population. Study design: This is a population-based prospective cohort at an institutional level. Seventy-two participating hospitals reported their annual gastrectomy data between 2014 and 2016, while 44 variables covering the institution and surgical information were included in the analysis. We used R software to encode and complete data pre-processing. The first difference model was applied to build the risk model. Data from 2014 and 2015 were assigned to risk model development, while data from 2016 was used for validation. Results: In the included centers with 94,277 gastric cancer cases, the in-hospital mortality rate was 0.32%. The regression model revealed that provinces with low-middle GDP, hospitals with annual gastrectomy volume between 100 and 500, greater volume of urgent surgeries performed, larger proportion of males, and a higher proportion of liver metastasis were independent risk factors for mortality following gastric surgeries, while higher laparoscopic resection volume, greater volume of distal gastrectomy with B2 reconstruction, and larger proportion of palliative surgery were independent protective factors (p < 0.05, respectively). In the prediction test, the mean square error of the training set was 0.948, while that of the test set was 0.728, demonstrating the effectiveness of this model. Conclusions: We constructed the first mortality risk prediction model for gastric cancer surgery in the Chinese population. The identified risk factors will help with the therapy selection, while further informing Chinese medical policy decision-makers.

Peritoneal metastasis is one of the most important causes of postoperative death in patients with gastric cancer, and the exact mechanism remains unclear. The proliferation of multicellular aggregates of exfoliated malignant gastric cells in the abdominal cavity is the focus of current research. However, the mechanism how gastric cancer multicellular aggregates survive remains unclear. In this study, we demonstrated that multicellular aggregates of exfoliated gastric cancer cells in the abdominal cavity expressed a stem cell-Like phenotype. We found that Integrin αvβ3 not only mediated adhesion of gastric cancer multicellular aggregates to form independent functional units, but also maintained their stem cell-like phenotype by the non-classical pathway Integrin αvβ3/ERK1/2/GLI1. In addition, ERK1/2 directly regulates the transcriptional activity of GLI1. GLI1 is a key effector of the Integrin αvβ3 pathway in regulating stem cell-like phenotype in multicellular aggregates. Our data indicates that although there is a crosstalk between the non-classical Integrin αvβ3 pathway and the classical Hedgehog pathway, the activation of GLI1 is almost independent of the Hedgehog pathway in multicellular aggregates of gastric cancer cells. Our study provides a basis for blocking GLI1 activity in the prevention and treatment of peritoneal metastases of gastric cancer.

Previous retrospective studies have shown that laparoscopic spleen-preserving D2 total gastrectomy (LSTG) for advanced upper third gastric cancer (AUTGC) is safe. However, all previous studies were underpowered. We therefore conducted a prospective, multicenter study to evaluate the technical safety and feasibility of LSTG for patients with AUTGC. Patients diagnosed with AUTGC (cT2-4a, N−/+, M0) underwent LSTG at 19 institutions between September 2016 and October 2017 were included. The number of No. 10 lymph node (LN) dissections, metastasis rates, intraoperative and postoperative complications were investigated. A total of 251 patients were enrolled in the study, and 242 patients were eligible for the per protocol analysis. The average numbers of No. 10 LN dissections and metastases were 2.4 and 0.1, respectively. Eighteen patients (7.4%) had No. 10 LN metastases, and among patients with advanced gastric cancer, the rate of No. 10 LN metastasis was 8.1% (18/223). pN3 status was an independent risk factor for No. 10 LN metastasis. Intraoperative complications occurred in 7 patients, but no patients required conversion to open surgery or splenectomy. The overall postoperative complication rate was 13.6% (33/242). The major complication and mortality rates were 3.3% (8/242) and 0.4% (1/242), respectively. The number of retrieved No. 10 LNs, No. 10 LN metastasis and TNM stage had no significant influence on postoperative complication rates. LSTG for AUTGC was safe and effective when performed by very experienced surgeons, this technique could be used in patients who needed splenic hilar lymph node dissection.

// Shi-wei Yang 1, * , Zhi-gang Zhang 1, * , Ying-xue Hao 1 , Yong-liang Zhao 1 , Feng Qian 1 , Yan Shi 1 , Ping-ang Li 1 , Chun-yang Liu 1 , Pei-wu Yu 1 1 Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China * These authors contributed equally to this work Correspondence to: Pei-Wu Yu, email: yupeiwu01@vip.sina.com.cn Ying-xue Hao, email: haoyingxue@hotmail.com Keywords: cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), hypoxia inducible factor-1α (HIF-1α), Snail Received: March 09, 2016 Accepted: December 16, 2016 Published: January 04, 2017 ABSTRACT Substantial evidence suggests that the epithelial-mesenchymal transition (EMT) phenotype is associated with the invasive characteristics of cancer stem cells (CSCs),which possess an EMT phenotype that may predominate in tumor invasion and metastasis. However, the mechanisms for the generation and regulation of these CSCs have not been clearly defined. As hypoxia and EMT-related factors may have important functions in EMT-like CSCs, the aim of this study was to investigate the effects of hypoxia on these cells. CSCs were established from the gastric cancer cell lines MGC-803 and SGC7901, and the relationship between hypoxia and EMT-like CSCs was investigated in gastric cancer. After hypoxia treatment, some gastric CSCs exhibited a marked increase in hypoxia-inducible factor-1α (HIF-1α)expression and increased migration and invasion capabilities compared with the normoxic control. These CSCs were defined by activation of the mesenchymal cell marker Vimentin and by inhibition of the epithelial cell marker E-cadherin. Our analyses also show that HIF-1α was responsible for activating EMT via increased expression of the transcription factor Snail in gastric CSCs. Moreover, inhibition of Snail by shRNA reduced HIF-1α-induced EMT in gastric CSCs. The results demonstrated that hypoxia-induced EMT-like CSCs rely on HIF-1αto activate Snail, which may result in recurrence and metastasis of gastric cancer.

Robotic total mesorectal excision (RTME) for rectal cancer has recently been increasingly used; technical feasibility and short-term outcomes have been reported in detail. Few studies have presented clinical efficacy and mid-term outcomes for a large sample size. The aim of this study is to present oncologic efficacy and mid-term outcomes of robotic total mesorectal excision for rectal cancer and to provide our experiences regarding these surgically challenging issues. Three hundred ninety-two patients received RTME between March 2010 and June 2015. Patient characteristics, perioperative clinical results, complications, pathologic details, recurrence, and mid-term outcomes were evaluated. Duration of surgery ranged from 80 to 388 min (median 224 min). There were no deaths during surgery and no anesthesiology complications in our series. The conversion rate was 1.1% (4/392). The postoperative complication rate was 10.2%; anastomosis leakage was the most common complication with an incidence of 4.1% (16/392). The median blood loss was 67.5±34.3 (20-600). The mean postoperative hospital stay was 12.1±6.1 (6–64). Circumferential resection margins were negative in 387 out of 392 cases (98.7%). The mean number of harvested lymph nodes was 14.6. Two deaths occurred during 30-day mortality. At a mean follow-up of 24 months (range 3–66 months), there were 35 deaths. Our results suggest that RTME is technically feasible for rectal cancer and can yield good short- and mid-term oncologic outcomes.

p53 mutations in tumors can induce the loss of wild-type tumor-suppressing p53 function, which results in the increase in proliferation, migration and invasion ability in cancer cells. Studies have shown that the expression of p53 is regulated by several microRNAs (miRNAs). In the present study, we found that miR-300 and p53 were significantly increased in colorectal cancer (CRC) tissues when compared with levels noted in adjacent colorectal tissues. Both miR-300 and p53 were significantly correlated with lymphatic metastasis and TNM stage. Both miR-300 and p53 promoted CRC cell (SW480 and HT29) proliferation, migration, and invasion, respectively, in vitro. In addition, we found that miR-300 is a direct positive regulator of p53 through binding to the binding site in the 3'UTR of the p53 gene in human CRC cells. Moreover, both miR-300 and p53 induced CRC cell epithelial‑mesenchymal transition (EMT) respectively. Taken together, we demonstrated that miR-300 promoted proliferation and EMT-mediated CRC migration and invasion by targeting p53. These findings provide a new theoretical basis and potential therapeutic targets, and thus lays the foundation for exploring the pathogenesis of CRC.

Postoperative recurrence and metastasis have crucial roles in the poor prognosis of gastric cancer patients. Previous studies have indicated that gastric cancer originates from cancer stem cells (CSCs), and some investigators have found that a particular subset of CSCs possesses higher metastatic capacity. However, the specific mechanism remains uncertain. In the present study, we aimed to explore the biological functions of the inflammatory cytokine interleukin-17 (IL-17) in gastric cancer metastasis and the distinct IL-17-induced transformation of quiescent gastric CSCs. Our results showed that invasive gastric CSCs were CD26+ and CXCR4+ and were closely associated with increased metastatic ability. The quiescent gastric CSCs, which were CD26- and CXCR4-, were exposed to appropriate concentrations of IL-17; this resulted in the decreased expression of E-cadherin and the increased expression of vimentin and N-cadherin. In addition, the upregulation of IL-17 both in vitro and in vivo resulted in a significant induction of invasion, migration and tumor formation ability in gastric CSCs compared with the control group, which was not treated with IL-17. Further experiments indicated that the activation of the downstream phosphorylated signal transducer and activator of transcription 3 (STAT3) transcription factor pathway was facilitated by IL-17. On the contrary, the downregulation of STAT3 by the specific inhibitor Stattic significantly reversed the IL-17-induced epithelial-mesenchymal transition (EMT)-associated properties of quiescent gastric CSCs. Moreover, tumorigenesis and metastasis were suppressed. Taken together, we suggest that IL-17 is positively correlated with the transformation of quiescent gastric CSCs into invasive gastric CSCs and that targeting IL-17 may emerge as a possible novel therapeutic strategy for gastric cancer.

Currently, whether laparoscopic or open splenectomy is a gold standard option for spleen abnormalities remains in controversy. There is in deficiency of academic evidence concerning the surgical efficacy and safety of both comparative managements. In order to surgically appraise the applied potentials of both approaches, we hence performed this comprehensive meta-analysis on the basis of 15-year literatures.Via searching of PubMed, EMBASE, Web of Science, and Cochrane Library databases, overall 37 original articles were eligibly incorporated into our meta-analysis and subdivided into six sections. In accordance with the Cochrane Collaboration protocol, all statistical procedures were mathematically conducted in a standard manner. Publication bias was additionally evaluated by funnel plot and Egger's test.Irrespective of the diversified splenic disorders, laparoscopic splenectomy was superior to open technique owing to its fewer estimated blood loss, shorter postoperative hospital stay as well as lower complication rate (P 0.05). As for operative duration and perioperative mortality, a statistical similarity was observed amid both surgical measures (P 0.05).Technically, laparoscopic splenectomy should be recommended as a prior remedy with its advantage of rapid recovery and minimally physical damage, in addition to its comparably surgical efficacy against that of open manipulation.

378 Background: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The aim of this study was to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG). Methods: From January 2017 to September 2018, a total of 227 patients with clinical stage T1N0-1M0/T2N0M0 gastric cancer were enrolled in this clinical trial and randomly assigned to Laparoscopic Gastrectomy group (LG, n=113) or Open Gastrectomy group (OG, n=114). The morbidity and mortality within 30 days following surgery, the recovery course, and the postoperative hospital stay between LG group (n=105) and OG group (n=109) were compared. Clavien-Dindo classification system was used to stratify surgical complications. Results: The overall morbidity rate was not significantly different in each group (LG group: 19.05%; OG group: 20.18%; Rate difference [RD]: -1.14%, 95%CI, -11.75%-9.58%). Intraoperative complications occurred in 3 (2.86%) patients in LG group and 4 (3.67%) patients in OG group (RD: -0.81%, 95%CI, -6.52%-4.85%). In addition, there was no significant difference in the overall postoperative complication rate of 18.10% in LG group and 17.43% in OG group (RD: 0.66%, 95%CI, -9.61%-11.01%). Each subtypes of postoperative complication were not significantly different between groups. One patient in LG group died of intra-abdominal bleeding from splenic artery, and there was no significant difference in mortality between LG group and OG group (RD: 0.95%, 95%CI, -2.54%-5.20%). The distribution of severity was similar between the two groups. Conclusions: Experienced surgeons can safely perform LTG with lymphadenectomy for clinical stage I gastric cancer. Clinical trial information: NCT03007550.

Background Laparoscopy-assisted gastrectomy is a feasible and safe procedure for treating advanced gastric cancer in terms of short-term outcomes. However, concern about long-term oncologic outcomes has limited the adoption of laparoscopy-assisted gastrectomy for advanced gastric cancer. Methods We launched a prospective randomized controlled trial comparing laparoscopic and open gastrectomy with D2 lymph node dissection for locally advanced gastric cancer to evaluate long-term oncologic feasibility. The 5-year overall survival, disease-free survival, and tumor recurrences have been determined on an intention-to-treat basis. Results Between January 2010 and June 2012, a total of 328 patients with preoperative clinical stage T2-4aN0-3M0 gastric cancer were enrolled in the trial. We excluded 6 patients with unresected tumor, and the remaining 322 patients were randomized to the laparoscopic group (162 patients) or the open group (160 patients) for radical surgery. One patient in laparoscopy-assisted gastrectomy and 4 patients in open gastrectomy were lost to follow-up immediately after discharge, leaving 317 patients (161 in laparoscopy-assisted gastrectomy and 156 in open gastrectomy) eligible for long-term analysis. The 5-year overall survival rate was 49.0% in the laparoscopic group and 50.7% in the open group, and the 5-year disease-free survival rate was 47.2% and 49.6% in the 2 groups, respectively. Kaplan–Meier curves for overall survival and disease-free survival showed no differences between the 2 groups. There was no difference in the 5-year tumor recurrence rate between the 2 procedures. Conclusion Laparoscopy-assisted gastrectomy can provide comparable long-term survival without an increase in recurrence and metastasis in treating advanced gastric cancer.

Peritoneal metastasis is one of the most important causes of postoperative death in patients with gastric cancer, and the exact mechanism remains unclear. The proliferation of multicellular aggregates of exfoliated malignant gastric cells in the abdominal cavity is the focus of current research. However, the mechanism how gastric cancer multicellular aggregates survive remains unclear. In this study, we demonstrated that multicellular aggregates of exfoliated gastric cancer cells in the abdominal cavity expressed a stem cell-Like phenotype. We found that Integrin αvβ3 not only mediated adhesion of gastric cancer multicellular aggregates to form independent functional units, but also maintained their stem cell-like phenotype by the non-classical pathway Integrin αvβ3/ERK1/2/GLI1. In addition, ERK1/2 directly regulates the transcriptional activity of GLI1. GLI1 is a key effector of the Integrin αvβ3 pathway in regulating stem cell-like phenotype in multicellular aggregates. Our data indicates that although there is a crosstalk between the non-classical Integrin αvβ3 pathway and the classical Hedgehog pathway, the activation of GLI1 is almost independent of the Hedgehog pathway in multicellular aggregates of gastric cancer cells. Our study provides a basis for blocking GLI1 activity in the prevention and treatment of peritoneal metastases of gastric cancer.