Tingyu Mou

Laparoscopic vs open D2 gastrectomy for locally advanced gastric cancer: a meta-analysis.

AIM To conduct a meta-analysis comparing laparoscopic (LGD2) and open D2 gastrectomies (OGD2) for the treatment of advanced gastric cancer (AGC). METHODS Randomized controlled trials (RCTs) and non-RCTs comparing LGD2 with OGD2 for AGC treatment, published between 1 January 2000 and 12 January 2013, were identified in the PubMed, Embase, and Cochrane Library databases. Primary endpoints included operative outcomes (operative time, intraoperative blood loss, and conversion rate), postoperative outcomes (postoperative analgesic consumption, time to first ambulation, time to first flatus, time to first oral intake, postoperative hospital stay length, postoperative morbidity, incidence of reoperation, and postoperative mortality), and oncologic outcomes (the number of lymph nodes harvested, tumor recurrence and metastasis, disease-free rates, and overall survival rates). The Cochrane Collaboration tools and the modified Newcastle-Ottawa scale were used to assess the quality and risk of bias of RCTs and non-RCTs in the study. Subgroup analyses were conducted to explore the incidence rate of various postoperative morbidities as well as recurrence and metastasis patterns. A Beggs test was used to evaluate the publication bias. RESULTS One RCT and 13 non-RCTs totaling 2596 patients were included in the meta-analysis. LGD2 in comparison to OGD2 showed lower intraoperative blood loss [weighted mean difference (WMD) = -137.87 mL, 95%CI: -164.41--111.33; P < 0.01], lower analgesic consumption (WMD = -1.94, 95%CI: -2.50--1.38; P < 0.01), shorter times to first ambulation (WMD = -1.03 d, 95%CI: -1.90--0.16; P < 0.05), flatus (WMD = -0.98 d, 95%CI: -1.30--0.66; P < 0.01), and oral intake (WMD = -0.85 d, 95%CI: -1.67--0.03; P < 0.05), shorter hospitalization (WMD = -3.08 d, 95%CI: -4.38--1.78; P < 0.01), and lower postoperative morbidity (odds ratio = 0.78, 95%CI: 0.61-0.99; P < 0.05). No significant differences were observed between LGD2 and OGD2 for the following criteria: reoperation incidence, postoperative mortality, number of harvested lymph nodes, tumor recurrence/metastasis, or three- or five-year disease-free and overall survival rates. However, LGD2 had longer operative times (WMD = 57.06 min, 95%CI: 41.87-72.25; P < 0.01). CONCLUSION Although a technically demanding and time-consuming procedure, LGD2 may be safe and effective, and offer some advantages over OGD2 for treatment of locally AGC.

Immunoscore Signature: A Prognostic and Predictive Tool in Gastric Cancer

Objective: We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). Summary Background Data: A prediction model for GC patients was developed using data from 879 consecutive patients. Methods: The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5-feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. Results: Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P <0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P <0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stage II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. Conclusions: The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stage II and III GC patients who would benefit from adjuvant chemotherapy.

Circular RNAs signature predicts the early recurrence of stage III gastric cancer after radical surgery

Tumor recurrence is usually detected within one year after radical resection of stage III gastric cancer. This study aimed to establish the expression profile and determine potential circular RNAs (circRNAs) and predict the early recurrence of stage III gastric cancer. We identified 46 differently expressed circRNAs between cancer and adjacent normal tissues through circRNA microarray. We further screened eight indicators related to early recurrence. We subsequently divided the remaining cases into two cohorts. qRT-PCR results demonstrated a significantly different outcome between low and high expressed groups of four circRNAs in the training cohort. We then constructed a four-circRNA-based classifier to evaluate the risk of early recurrence and distinguished patients with a high risk from those with a low risk. The areas under the receiver operator characteristic curve (ROC) of this classifier were 0.763 and 0.711 in the two cohorts, respectively. A new formula could be established by combined the circRNA classifier with TNM stages. The areas under the ROC curve were 0.866 and 0.818 of the two cohorts, respectively. Our study suggested that this four-circRNA-based classifier yielded a predictive ability to the early recurrence of stage III gastric cancer after radical surgery.

Interleukin-17-producing neutrophils link inflammatory stimuli to disease progression by promoting angiogenesis in gastric cancer.

Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking. Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivo. Results: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer. Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 23(6); 1575–85. ©2016 AACR.

Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: Relevance to therapy response

AIM To evaluate the epithelial-to-mesenchymal transition (EMT) of circulating tumor cells (CTCs) in gastric cancer patients. METHODS We detected tumor cells for expression of four epithelial (E(+)) transcripts (keratins 8, 18, and 19 and epithelial cell adhesion molecule) and two mesenchymal (M(+)) transcripts (Vimentin and Twist) by a quantifiable, dual-colorimetric RNA-in situ hybridization assay. Between July 2014 and October 2014, 44 patients with gastric cancer were recruited for CTC evaluation. Blood samples were obtained from selected patients during the treatment course [before surgery, after surgery and at the 6(th) cycle of XELOX based chemotherapy (about 6 mo postoperatively)]. RESULTS We found the EMT phenomenon in which there were a few biphenotypic E(+)/M(+) cells in primary human gastric cancer specimens. Of the 44 patients, the presence of CTCs was reported in 35 (79.5%) patients at baseline. Five types of cells including from exclusively E(+) CTCs to intermediate CTCs and exclusively M(+) CTCs were identified (4 patients with M(+) CTCs and 10 patients with M(+) or M(+) > E(+) CTCs). Further, a chemotherapy patient having progressive disease showed a proportional increase of mesenchymal CTCs in the post-treatment blood specimens. We used NCI-N87 cells to analyze the linearity and sensitivity of CanPatrol(TM) system and the correlation coefficient (R(2)) was 0.999. CONCLUSION The findings suggest that the EMT phenomenon was both in a few cells of primary tumors and abundantly in CTCs from the blood of gastric cancer patients, which might be used to monitor therapy response.

Overexpression of the Receptor for Advanced Glycation Endproducts (RAGE) is associated with poor prognosis in gastric cancer.

Background The receptor for advanced glycation endproducts (RAGE) is an oncogenic multidisciplinary trans-membranous receptor, which is overexpressed in multiple human cancers. Recently, it has been shown that RAGE is also involved in carcinogenesis and tumor invasion. In this study, we investigated the expression levels and prognostic value of RAGE in primary gastric cancers (GC). Methods We investigated RAGE expression in primary GC and paired normal gastric tissue by real-time quantitative RT-PCR (n = 30) and Western blotting analysis (n = 30). Additionally, we performed immunohistochemistry on 180 paraffin-embedded GC specimens, 69 matched normal specimens. Results RAGE was overexpressed in GC compared with the adjacent noncancerous tissues (P＜0.001), and higher RAGE expression significantly correlated with the histological grade (P = 0.002), nodal status(P = 0.025), metastasis status(P = 0.002), and American Joint Committee on Cancer stage (P = 0.020). Furthermore, upregulation of RAGE expression is an independent prognostic factor in multivariate analysis using the Cox regression model (P = 0.001). Conclusions RAGE Overexpression may be a useful marker to predict GC progression and poor prognosis.

Is early oral feeding after gastric cancer surgery feasible? A systematic review and meta-analysis of randomized controlled trials.

Aim To assess the feasibility and safety of early oral feeding (EOF) after gastrectomy for gastric cancer through a systematic review and meta-analysis based on randomized controlled trials. Methods A literature search in PubMed, Embase, Web of Science and Cochrane library databases was performed for eligible studies published between January 1995 and March 2014. Systematic review was carried out to identify randomized controlled trials comparing EOF and traditional postoperative oral feeding after gastric cancer surgery. Meta-analyses were performed by either a fixed effects model or a random effects model according to the heterogeneity using RevMan 5.2 software. Results Six studies remained for final analysis. Included studies were published between 2005 and 2013 reporting on a total of 454 patients. No significant differences were observed for postoperative complication (RR = 0.95; 95%CI, 0.70 to 1.29; P = 0.75), the tolerability of oral feeding (RR = 0.98; 95%CI, 0.91 to 1.06; P = 0.61), readmission rate (RR = 1; 95%CI, 0.30 to 3.31; P = 1.00) and incidence of anastomotic leakage (RR = 0.31; 95%CI, 0.01 to 7.30; P = 0.47) between two groups. EOF after gastrectomy for gastric cancer was associated with significant shorter duration of the hospital stay (WMD = −2.36; 95%CI, −3.37 to −1.34; P<0.0001) and time to first flatus (WMD = −19.94; 95%CI, −32.03 to −7.84; P = 0.001). There were no significant differences in postoperative complication, tolerability of oral feeding, readmission rates, duration of hospital stay and time to first flatus among subgroups stratified by the time to start EOF or by partial and total gastrectomy or by laparoscopic and open surgery. Conclusions The result of this meta-analysis showed that EOF after gastric cancer surgery seems feasible and safe, even started at the day of surgery irrespective of the extent of the gastric resection and the type of surgery. However, more prospective, well-designed multicenter RCTs with more clinical outcomes are needed for further validation.

Laparoscopic splenic hilum lymph node dissection for advanced proximal gastric cancer: A modified approach for pancreas- and spleen-preserving total gastrectomy

AIM To investigate the feasibility and optimal approach for laparoscopic pancreas- and spleen-preserving splenic hilum lymph node dissection in advanced proximal gastric cancer. METHODS Between August 2009 and August 2012, 12 patients with advanced proximal gastric cancer treated in Nanfang Hospital, Southern Medical University, Guangzhou, China were enrolled and subsequently underwent laparoscopic total gastrectomy with pancreas- and spleen-preserving splenic hilum lymph node (LN) dissection. The clinicopathological characteristics, surgical outcomes, postoperative course and follow-up data of these patients were retrospectively collected and analyzed in the study. RESULTS Based on our anatomical understanding of peripancreatic structures, we combined the characteristics of laparoscopic surgery and developed a modified approach (combined supra- and infra-pancreatic approaches) for laparoscopic pancreas- and spleen-preserving splenic hilum LN dissection. Surgery was completed in all 12 patients laparoscopically without conversion. Only one patient experienced intraoperative bleeding when dissecting LNs along the splenic artery and was handled with laparoscopic hemostasis. The mean operating time was 268.4 min and mean number of retrieved splenic hilum LNs was 4.8. One patient had splenic hilum LN metastasis (8.3%). Neither postoperative morbidity nor mortality was observed. Peritoneal metastasis occurred in one patient and none of the other patients died or experienced recurrent disease during the follow-up period. CONCLUSION Laparoscopic total gastrectomy with pancreas- and spleen-preserving splenic hilum LN dissection using the modified approach for advanced proximal gastric cancer could be safely achieved.

Gastric cancer cells inhibit natural killer cell proliferation and induce apoptosis via prostaglandin E2

ABSTRACT Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we showed, in detailed studies of NK cells from 235 untreated patients with gastric cancer (GC), the NK cell density in GC tissues could predict improved survival of patients. However, NK cells were significantly decreased in number with advanced-stage GC. A multivariate Cox analysis revealed that the intratumoral NK cell density was an independent prognostic factor for overall survival and disease-free survival in the GC patients. Most of the intratumoral NK cells exhibited a normal phenotype and secreted normal levels of cytokines, but the expression of Ki67 was decreased compared with NK cells from nontumoral regions. Moreover, the levels of intratumoral NK cells were negatively correlated with the intratumoral expression of cyclooxygenase-2. Furthermore, we found that PGE2 derived from GC cells suppressed NK cell proliferation and increased apoptosis in vitro. These data reveal that tumor-derived PGE2 is critical for inducing NK cell dysfunction in GC and demonstrate that an extensive infiltration of NK cells predicts a good prognosis in patients with GC. Our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression.

Staging laparoscopy improves treatment decision-making for advanced gastric cancer.

AIM To evaluate the clinical value of staging laparoscopy in treatment decision-making for advanced gastric cancer (GC). METHODS Clinical data of 582 patients with advanced GC were retrospectively analyzed. All patients underwent staging laparoscopy. The strength of agreement between computed tomography (CT) stage, endoscopic ultrasound (EUS) stage, laparoscopic stage, and final stage were determined by weighted Kappa statistic (Kw). The number of patients with treatment decision-changes was counted. A χ(2) test was used to analyze the correlation between peritoneal metastasis or positive cytology and clinical characteristics. RESULTS Among the 582 patients, the distributions of pathological T classifications were T2/3 (153, 26.3%), T4a (262, 45.0%), and T4b (167, 28.7%). Treatment plans for 211 (36.3%) patients were changed after staging laparoscopy was performed. Two (10.5%) of 19 patients in M1 regained the opportunity for potential radical resection by staging laparoscopy. Unnecessary laparotomy was avoided in 71 (12.2%) patients. The strength of agreement between preoperative T stage and final T stage was in almost perfect agreement (Kw = 0.838; 95% confidence interval (CI): 0.803-0.872; P < 0.05) for staging laparoscopy; compared with CT and EUS, which was in fair agreement. The strength of agreement between preoperative M stage and final M stage was in almost perfect agreement (Kw = 0.990; 95% CI: 0.977-1.000; P < 0.05) for staging laparoscopy; compared with CT, which was in slight agreement. Multivariate analysis revealed that tumor size (≥ 40 mm), depth of tumor invasion (T4b), and Borrmann type (III or IV) were significantly correlated with either peritoneal metastasis or positive cytology. The best performance in diagnosing P-positive was obtained when two or three risk factors existed. CONCLUSION Staging laparoscopy can improve treatment decision-making for advanced GC and decrease unnecessary exploratory laparotomy.