Yanfeng Hu

Morbidity and Mortality of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: A Randomized Controlled Trial

PURPOSE The safety and efficacy of radical laparoscopic distal gastrectomy (LG) with D2 lymphadenectomy for the treatment of advanced gastric cancer (AGC) remain controversial. We conducted a randomized controlled trial to compare laparoscopic and conventional open distal gastrectomy with D2 lymph node dissections for AGC. PATIENTS AND METHODS Between September 2012 and December 2014, 1,056 patients with clinical stage T2-4aN0-3M0 gastric cancer were eligible for inclusion. They were randomly assigned to either the LG with D2 lymphadenectomy group (n = 528) or the open gastrectomy (OG) with D2 lymphadenectomy group (n = 528). Fifteen experienced surgeons from 14 institutions in China participated in the study. The morbidity and mortality within 30 days after surgery between the LG (n = 519) and the OG (n = 520) groups were compared on the basis of the modified intention-to-treat principle. Postoperative complications were stratified according to the Clavien-Dindo classification. RESULTS The compliance rates of D2 lymphadenectomy were similar between the LG and OG groups (99.4% v 99.6%; P = .845). The postoperative morbidity was 15.2% in the LG group and 12.9% in OG group with no significant difference (difference, 2.3%; 95% CI, -1.9 to 6.6; P = .285). The mortality rate was 0.4% for the LG group and zero for the OG group (difference, 0.4%; 95% CI, -0.4 to 1.4; P = .249). The distribution of severity was similar between the two groups (P = .314). CONCLUSION Experienced surgeons can safely perform LG with D2 lymphadenectomy for AGC.

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.

Perirectal fascia and spaces: annular distribution pattern around the mesorectum.

PURPOSE: In view of debate on the optimal surgical planes for total mesorectal excision, this study was designed to explore the regional anatomy of the perirectal fascia and spaces. METHODS: Twenty-one cadavers (15 male and 6 female) were embalmed and their vessels visualized by injection with color dye. From the cadavers, 30 hemipelves and 6 three-quarter pelves were harvested. The perirectal fascia and spaces and the pelvic autonomic nerves were dissected and examined. RESULTS: Three tissue layers were dissected from the inside to the periphery: the proper rectal fascia enveloping the mesorectum, the presacral fascia, and the piriformis fascia fused with the sacral periosteum. The mesorectum comprised 2 parts: posterior, with the classical posterolateral fat covered by the proper rectal fascia; and anterior, with the anterior fat covered by the posterior layer of Denonvilliers fascia. Extending anteriorly to the anterior layer of Denonvilliers fascia, the presacral fascia bisected the space between the mesorectum and the piriformis fascia into the retrorectal space and the presacral space. The retrorectal space extended cranially to the left Toldts space, anterior to the space between the 2 layers of Denonvilliers fascia. CONCLUSIONS: From the inside to the periphery, the proper rectal fascia, the presacral fascia, and the muscular fascia are distributed in an annular pattern around the mesorectum. The presacral fascia divides the perirectal space into 2 annular parts: the central retrorectal space and the peripheral presacral space. The retrorectal space is the ideal surgical plane for the total mesorectal excision.

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.

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.

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.

A new order of D2 lymphadenectomy in laparoscopic gastrectomy for cancer: Live anatomy-based dissection

Abstract It was the aim of this study to develop a methodology for dissection in laparoscopic distal gastrectomy with D2 lymphadenectomy (D2 LDG) for gastric cancer. One-hundred and thirty-two patients with distal gastric cancer underwent D2 LDG with a novel sequence of lymph node dissection between August 2004 and June 2008. Live anatomy in each step was observed simultaneously to ensure and confirm the newly developed methodology. Dissections in LDG were standardized as sequential steps: Dividing the gastrocolic ligament and getting access to the prepancreatic space – lymph node dissection in the lower left area – lymph node dissection in the lower right area – lymph node dissection in the upper right area – lymph nodes dissection centrally – lymph node dissection between liver and stomach. All dissections were successfully performed in peripancreatic spaces and their extensions. Gastric vessels were located by special landmarks, traced along vascular trunks and bifurcations, and identified by fine dissection technique in vaginavasorum. Sequential dissection around the pancreas was an effective method for D2 LDG. It was ensured by anatomical knowledge in each step: Vessels and fascial spaces around a central landmark, the pancreas.

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.