Long-term oncological outcomes of robotic versus laparoscopic gastrectomy for gastric cancer: multicentre cohort study.

BACKGROUND: The aim of this multicentre cohort study was to compare the long-term oncological outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with gastric cancer. METHODS: Patients with gastric cancer who underwent radical gastrectomy by robotic or laparoscopic approaches from 1 March 2010 to 31 December 2018 at 10 high-volume centres in China were selected from institutional databases. Patients receiving RG were matched 1 : 1 by propensity score with patients undergoing LG. The primary outcome was 3-year disease-free survival. Secondary outcomes were overall survival and disease recurrence. RESULTS: Some 2055 patients who underwent RG and 4309 patients who had LG were included. The propensity score-matched cohort comprised 2026 RGs and 2026 LGs. Median follow-up was 41 (i.q.r. 39-58) months for the RG group and 39 (38-56) months for the LG group. The 3-year disease-free survival rates were 80.8% in the RG group and 79.5% in the LG group (log rank P = 0.240; HR 0.92, 95% c.i. 0.80 to 1.06; P = 0.242). Three-year OS rates were 83.9 and 81.8% respectively (log rank P = 0.068; HR 0.87, 0.75 to 1.01; P = 0.068) and the cumulative incidence of recurrence over 3 years was 19.3% versus 20.8% (HR 0.95, 0.88 to 1.03; P = 0.219), with no difference between groups. CONCLUSION: RG and LG in patients with gastric cancer are associated with comparable disease-free and overall survival.

Novel combined endoscopic and laparoscopic surgery for advanced T2 gastric cancer: Two case reports.

BACKGROUND: The standard treatment for advanced T2 gastric cancer (GC) is laparoscopic or surgical gastrectomy (either partial or total) and D2 lymphadenectomy. A novel combined endoscopic and laparoscopic surgery (NCELS) has recently been proposed as a better option for T2 GC. Here we describe two case studies demonstrating the efficacy and safety of NCELS. CASE SUMMARY: Two T2 GC cases were both resected by endoscopic submucosal dissection and full-thickness resection and laparoscopic lymph nodes dissection. This method has the advantage of being more precise and minimally invasive compared to current methods. The treatment of these 2 patients was safe and effective with no complications. These cases were followed up for nearly 4 years without recurrence or metastasis. CONCLUSION: This novel method provides a minimally invasive treatment option for T2 GC, and its potential indications, effectiveness and safety needs to be further evaluated in controlled studies.

Robotic Gastrectomy Versus Laparoscopic Gastrectomy for Gastric Cancer: A Multicenter Cohort Study of 5402 Patients in China.

OBJECTIVE: A large-scale multicenter retrospective cohort study was conducted to compare the short- and long-term outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer. SUMMARY OF BACKGROUND DATA: RG is being increasingly used worldwide, but data from large-scale multicenter studies on the short- and long-term oncologic outcomes of RG versus LG are limited. The potential benefits of RG compared with LG for gastric cancer remain controversial. METHODS: Data from eligible patients who underwent RG or LG for gastric cancer of 11 experienced surgeons from 7 centers in China between March 2010 and October 2019 were collected. The RG group was matched 1:1 with the LG group by using propensity score matching. The primary outcome was postoperative complications. RESULTS: After propensity score matching, a well-balanced cohort of 3552 patients was included for further analysis. The occurrence of overall complications (12.6% vs 15.2%, P = 0.023) was lower in the RG group than in the LG group. RG was associated with less blood loss (126.8 vs 142.5 mL, P < 0.001) and more retrieved lymph nodes in total (32.5 vs 30.7, P < 0.001) and in suprapancreatic areas (13.3 vs 11.6, P < 0.001).The long-term oncological outcomes were comparable between the two groups. CONCLUSIONS: The results of this multicenter study demonstrate that RG is a safe and effective treatment for gastric cancer when performed by experienced surgeons, although longer operation time and higher costs are still concerns about RG. This study provides evidence suggesting that RG may represent an alternative surgical treatment to LG.

Comparison of the Postoperative Complications Between Robotic Total and Distal Gastrectomies for Gastric Cancer Using Clavien-Dindo Classification: A Propensity Score-matched Retrospective Cohort Study of 726 Patients.

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.

Robotic total gastrectomy for carcinoma in the remnant stomach: a comparison with laparoscopic total gastrectomy.

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 < 0.001), and less estimated blood loss (229.2 vs 288.8 mL, P = 0.031). No significant differences were found between the robotic and laparoscopic groups in terms of conversion rate, time to first flatus, time to first soft diet, post-operative hospital stay, post-operative complications, R0 resection rate, and number of retrieved lymph nodes (all 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.

Short-Term Clinical Efficacy of Neoadjuvant Chemotherapy Combined With Laparoscopic Gastrectomy for Locally Advanced Siewert Type II and III Adenocarcinoma of the Esophagogastric Junction: A Retrospective, Propensity Score-Matched Study.

BACKGROUND: Laparoscopic 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. METHODS: This 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. RESULTS: After 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. CONCLUSION: NACT combined with LG for AEG does not increase the risk of postoperative morbidity and mortality compared with LG.

Laparoscopic versus open gastrectomy for serosa-invasive gastric cancer: A single-center retrospective cohort study.

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.

Incidence and risk factors of postoperative complications after robotic gastrectomy for gastric cancer: an analysis of 817 cases based on 10-year experience in a large-scale center.

BACKGROUND: In this study, we investigated the incidence and risk factors for postoperative complications after robotic gastrectomy (RG) in patients with gastric cancer. METHODS: 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. RESULTS: 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 < 0.001) and multiorgan resection (P = 0.031) were independent risk factors for the occurrence of overall complications. Multivariable analysis showed that an age of 70 years or older (P = 0.005) and surgeons' experience ≤ 25 cases (P = 0.004) were independent risk factors for severe complications. Regarding local complications, an age of 70 years or older (P < 0.001), multiorgan resection (P = 0.010) and surgeons' experience ≤ 25 cases (P = 0.005) were identified as independent risk factors. An age of 70 years or older (P < 0.001), a BMI of 25 or higher (P = 0.045) and the presence of comorbidity (P = 0.029) were identified as independent risk factors for systemic complications. CONCLUSIONS: The present study demonstrated that RG is a safe and feasible procedure for the treatment of gastric cancer, and it has an acceptable postoperative morbidity. Elderly patients and insufficient surgeon experience were two major risk factors for the occurrence of complications following RG. We suggest that surgeons choose patients in good condition during their RG learning phase to reduce learning-associated morbidity.

Long-term oncologic outcomes of robotic versus laparoscopic gastrectomy for locally advanced gastric cancer: a propensity score-matched analysis of 1170 patients.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSION: For patients with locally AGC, RG can result in comparable long-term survival outcomes without an increase in recurrence rate.

Reappraise role of No. 10 lymphadenectomy for proximal gastric cancer in the era of minimal invasive surgery during total gastrectomy: a pooled analysis of 4 prospective trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Safety and feasibility of laparoscopic spleen-preserving No. 10 lymph node dissection for locally advanced upper third gastric cancer: a prospective, multicenter clinical trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Is Preoperative Fibrinogen Associated with the Survival Prognosis of Gastric Cancer Patients? A Multi-centered, Propensity Score-Matched Retrospective Study.

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.

MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling.

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.

NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients.

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.

AEBP1 promotes epithelial-mesenchymal transition of gastric cancer cells by activating the NF-κB pathway and predicts poor outcome of the patients.

Adipocyte enhancer binding protein 1 (AEBP1) is a transcriptional repressor that plays a critical role in regulating adipogenesis. Recent studies have indicated that AEBP1 might function as a candidate oncogene and is overexpressed in several human malignancies. However, the role of AEBP1 in gastric cancer (GC) remains largely unknown. This study aimed to investigate the expression pattern, prognostic significance and biological function of AEBP1 in human gastric cancer and to explore the underlying mechanism. We found that both the mRNA and protein levels of AEBP1 were significantly increased in human GC tissues. Elevated AEBP1 expression was significantly correlated with poor overall survival in patients with both early-stage (Tumor, Node, Metastases (TNM) TNM I and II) and late-stage (TNM III and IV) GC. Silencing AEBP1 markedly suppressed the proliferation, migration, invasion, metastasis and epithelial-mesenchymal transition of GC cells. Moreover, we demonstrated that knockdown of AEBP1 in GC cells led to inhibition of the NF-κB pathway by hampering the degradation of IκBα. Thus, AEBP1 might be served as a promising prognostic indicator and a potential therapeutic target in human GC.

Superiority of Tumor Location-Modified Lauren Classification System for Gastric Cancer: A Multi-Institutional Validation Analysis.

BACKGROUND: The tumor location-modified Lauren classification (mLC) has been proposed recently, but its clinical significance remains under debate. This study aimed to elucidate the clinical relevance of mLC and evaluate its superiority to the Lauren classification (LC) for gastric cancer patients with gastrectomy. METHODS: This study retrospectively evaluated 2764 consecutive gastric cancer patients from three comprehensive medical institutions. The patients were categorized into training, inner-validation, and independent validation sets. The relationships between mLC and other clinicopathologic factors were analyzed, and independent prognostic factors were identified. Survival prognostic discriminatory ability and predictive accuracy were compared between mLC and LC using the concordance index (C-index) and Akaike's information criterion (AIC), and a nomogram based on mLC was constructed to compare its prognostic improvement with the tumor-node metastasis (TNM) staging system. RESULTS: A significant association between mLC and gender, age, histologic type, T stage, N stage, and M stage was found. The findings showed that mLC, not LC, is an independent prognostic factor, with a smaller AIC and a higher C-index than LC. The nomogram based on mLC showed a better predictive ability than TNM alone. CONCLUSIONS: Compared with LC, mLC, which could be considered a more reliable prognostic factor, may improve the prognostic discriminatory ability and predictive accuracy for gastric cancer patients with gastrectomy.

Overexpression of Tie2 is associated with poor prognosis in patients with gastric cancer.

Tunica Interna endothelial cell kinase (Tie2)-expressing macrophages (TEMs) are a subgroup of tumor-associated macrophages that are associated with a poor prognosis in numerous types of cancer. The present study aimed to assess the prognostic impact of Tie2 expression in gastric cancer tissues. Between January 2009 and December 2009, 76 newly diagnosed patients with gastric cancer at the Southwest Hospital, Third Military Medical University (Chongqing, China) were enrolled. TEMs were detected using immunohistochemistry. Tie2, cluster of differentiation (CD)68 and carbonic anhydrase IX (CAIX) were analyzed using immunohistochemistry and immunofluorescent microscopy. Tie2 protein expression was analyzed using western blot analysis in hypoxic and normoxic gastric cancer tissues. The number of TEMs positively staining for Tie2 increased with the tumor-node-metastasis (TNM) stage: 0, 53.9, 75.6 and 100% in stages I, II, III and IV, respectively (P<0.001). Tumor size and lymph node involvement were significantly associated with the presence of Tie2 in the tumor stroma (P<0.001). There was no significant difference between Tie2 and CAIX, irrespective of how the patients were grouped (tumor size, lymph node involvement, TNM stage or histological grade). Tie2 protein expression was increased in the hypoxic regions of gastric tumors.Tie2 and CD68 expression colocalized in hypoxic and normoxic gastric cancer tissues. The 1-, 2- and 3-year recurrence rates of the TEM-positive group were 31.4, 56.9 and 66.7%, respectively, as compared with 8, 28 and 48%, respectively, for the TEM-negative group (P<0.05). In the TEM-negative group, 2 patients succumbed to the disease, as compared with 21 patients in the TEM-positive group (P<0.05). Therefore, high quantities of TEMs, represented by Tie2 expression, in gastric tumors may be associated with poor survival.

High density of CD68+ tumor-associated macrophages predicts a poor prognosis in gastric cancer mediated by IL-6 expression.

The aim of the present study was to explore the potential role of cluster of differentiation CD68+ tumor-associated macrophages (TAMs) induced by interleukin (IL)-6 in the progression of gastric cancer (GC) and patient prognosis. The expression levels of IL-6 and CD68 were detected by immunohistochemical staining in 60 samples of tumor and non-tumor gastric tissues. CD14+ monocytes were isolated from peripheral blood mononuclear cells and stimulated with macrophage colony stimulation factor (M-CSF) and IL-6, and the expression levels of IL-10, IL-12, vascular endothelial growth factor (VEGF)-C and transforming growth factor (TGF)-ß were measured by reverse transcription polymerase chain reaction and ELISA. The GC MGC-803 cell line was co-cultured with monocytes stimulated by M-CSF and IL-6 and the invasion ability of the MGC-803 was evaluated by Transwell analysis. The levels of STAT3, P-STAT3 and interferon-regulatory factor 4 (IRF4) in the monocytes stimulated by M-CSF and IL-6 were detected by western blotting. The results demonstrated that the frequencies of IL-6+ macrophages (Mφs) and CD68+ Mφs were significantly higher in tumor regions compared with the corresponding non-tumor regions of GC tissues. Kaplan-Meier analysis revealed that the densities of tumor-infiltrating CD68+ or IL-6+ Mφs were inversely associated with the overall survival rates of the patients. In vitro, the expression levels of IL-10, VEGF-C and TGF-ß significantly increased in CD14+ monocytes subsequent to M-CSF and IL-6 stimulation. The invasion abilities of MGC-803 were increased by the monocytes stimulated with M-CSF and IL-6. The levels of STAT3, P-STAT3 and IRF4 proteins increased in the monocytes stimulated by M-CSF and IL-6. In conclusion, the results from the present study suggest that a high density of CD68+ TAMs predicts a poor prognosis in GC. IL-6 may polarize the Mφs and promote tumor invasion through the IL-6/STAT3/IRF4 signaling pathway.

The role and gene expression profile of SOCS3 in colorectal carcinoma.

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-ß/Smads, NF-κB, and HIF-MAPK pathways. Especially for the TGF-ß/Smads pathways, high SOCS3 expression could inhibit TGF-ß1 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.

Modulation of CD8+ memory stem T cell activity and glycogen synthase kinase 3ß inhibition enhances anti-tumoral immunity in gastric cancer.

The potential contributions of CD8+ memory stem T cells to anti-tumor immunity and immunotherapy responses in gastric cancer has not been demonstrated. We found that CD8+ memory stem T cell frequencies were increased in the peripheral blood of gastric cancer patients compared to healthy donors and declined in frequency with disease progression. Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8+ memory stem T cells into Rag1-/- tumor bearing mice enhanced tumor regression compared to CD8+ central or effector memory T cell counterparts. This effect was associated with an increase in splenic, draining lymph node and tumor infiltrating CD8+ T cell numbers and the development of an altered CD8+ T cell phenotype not seen during homeostasis. GSK-3ß inhibition is known to promote memory stem T cell accumulation by arresting effector T cell differentiation in vivo. Surprisingly however, GSK-3ß inhibition conversely increased the cytotoxic capacity of CD8+ memory stem T cells in vitro, and this was associated with the induction of effector T cell-associated effector proteins including FasL. Finally, FasL neutralization following GSK-3ß inhibition directly attenuated the anti-tumoral capacity of CD8+ memory stem T cells both in vitro and in vivo. Altogether, our findings identify the therapeutic potential of modulating CD8+ memory stem T cells for improved anti-tumoral responses against gastric cancer.