Randomized clinical trial on D2 lymphadenectomy versus D2 lymphadenectomy plus complete mesogastric excision in patients undergoing gastrectomy for cancer (DCGC01 study).

BACKGROUND: It is unknown whether D2 lymphadenectomy + complete mesogastric excision for gastric cancer improves survival compared with just D2 lymphadenectomy. METHODS: Between September 2014 and June 2018, patients with advanced gastric cancer were randomly assigned (1 : 1) to laparoscopic D2 lymphadenectomy or D2 lymphadenectomy + complete mesogastric excision gastrectomy. The modified intention-to-treat population was defined as patients who had pathologically confirmed gastric adenocarcinoma (pT1 N1-3 M0 and pT2-4 N0-3 M0). The primary endpoint was 3-year disease-free survival. Secondary endpoints were the recurrence pattern and overall survival. RESULTS: The median follow-up of patients in the D2 lymphadenectomy group (169 patients) and patients in the D2 lymphadenectomy +complete mesogastric excision group (169 patients) was 55 (interquartile range 37-60) months and 51 (interquartile range 40-60) months respectively. Recurrence occurred in 50 patients in the D2 lymphadenectomy group (29.6%) versus 33 patients in the D2 lymphadenectomy + complete mesogastric excision group (19.5%) (P = 0.032). The 3-year disease-free survival was 75.5% (95% c.i. 68.3% to 81.3%) in the D2 lymphadenectomy group versus 85.0% (95% c.i. 78.7% to 89.6%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.042). The HR for recurrence in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 0.99) by Cox regression (P = 0.045). The 3-year overall survival rate was 77.5% (95% c.i. 70.4% to 83.1%) in the D2 lymphadenectomy group versus 85.8% (95% c.i. 79.6% to 90.2%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.058). The HR for death in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 1.02) (P = 0.058). CONCLUSION: Compared with conventional D2 dissection, D2 lymphadenectomy + complete mesogastric excision is associated with better disease-free survival, but there is no statistically significant difference in overall survival. REGISTRATION NUMBER: NCT01978444 (http://www.clinicaltrials.gov).

DAB2IP suppresses invadopodia formation through destabilizing ALK by interacting with USP10 in breast cancer.

Invadopodia, being actin-rich membrane protrusions, play a vital role in tumor cell invasion and metastasis. Our previous studies have revealed some functions of the DOC-2/DAB2 interacting protein (DAB2IP) as a tumor suppressor. Nevertheless, the specific role and mechanism of DAB2IP in invadopodia formation remain unclear. Here, we find that DAB2IP effectively suppresses invadopodia formation and metastasis in breast cancer, both in vitro and in vivo. Additionally, DAB2IP could downregulate anaplastic lymphoma kinase (ALK), resulting in the inhibition of tyrosine phosphorylation of Cortactin and the prevention of invadopodia formation. DAB2IP competitively antagonizes the interaction between the deubiquitinating enzyme Ubiquitin-specific peptidase 10 (USP10) and ALK, leading to a decrease in the abundance of ALK protein. In summary, DAB2IP impairs the stability of ALK through USP10-dependent deubiquitination, suppressing Cortactin phosphorylation, thereby inhibiting invadopodia formation and metastasis of breast cancer cells. Furthermore, this study suggests a potential therapeutic strategy for breast cancer treatment.

Surgical and oncological outcomes of laparoscopic right hemicolectomy (D3 + CME) for colon cancer: A prospective single-center cohort study.

BACKGROUND: Complete mesocolic excision (CME) or D3 lymphadenectomy led to survival benefits for locally advanced right colon cancer, but with vague definitions in anatomy and debated surgical hazard in clinic. Aiming to achieve a precise definition of it in anatomy, we proposed laparoscopic right hemicolectomy (D3 + CME) as a novel procedure for colon cancer. However, the surgical and oncological results of this procedure in clinic were uncertain. METHODS: We performed a cohort study involving prospective data collected from a single-center in China. Data from all patients who underwent right hemicolectomy between January 2014 and December 2018 were included. We compared the surgical and oncological outcomes between D3 + CME and conventional CME. RESULTS: After implementation of exclusion criteria, a total of 442 patients were included. D3 + CME group performed better in lymph nodes harvested (25.0 [17.0, 33.8] vs. 18.0 [14.0, 25.0], P < 0.001) and the proportion of intraoperative blood loss ≥ 50 mL (31.7% vs. 51.8%, P < 0.001); no significant difference was observed in the complication rates between two groups. Kaplan-Meier analysis demonstrated that a better cumulative 5-year disease-free survival (91.3% vs. 82.2%, P = 0.026) and a better cumulative 5-year overall survival (95.2% vs. 86.1%, P = 0.012) were obtained in the D3 + CME group. Multivariate COX regression revealed that D3 + CME was an independent protective factor for disease-free survival (P = 0.026). CONCLUSION: D3 + CME could improve surgical and oncological outcomes simultaneously for right colon cancer compared to conventional CME. Large-scale randomized controlled trials were further required to confirm this conclusion, if possible.

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer.

Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1-TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.

Short-term outcomes of D2 lymphadenectomy plus complete mesogastric excision for gastric cancer: a propensity score matching analysis.

BACKGROUND: Our previous study has demonstrated the surgical advantages of D2 lymphadenectomy plus complete mesogastric excision (D2 + CME) in gastric cancer surgery. To further verify the safety of D2 + CME procedure, we conducted this large-scale, observational cohort study and applied propensity score matching (PSM) approach to compare D2 + CME with conventional D2 in terms of short-term outcomes in gastric cancer patients. METHODS: Data on 855 patients from Tongji Hospital who underwent laparoscopic-assisted distal gastrectomy (LADG) with R0 resection (496 in the conventional D2 cohort and 359 in the D2 + CME cohort) between Dec 12, 2013 and Dec 28, 2017 were retrieved from prospectively maintained clinical database. After PSM analysis at a 1:1 ratio, each cohort included 219-matched patients. Short-term outcomes, including surgical results, morbidity, and mortality within 30 days after the operation, were collected and analyzed. RESULTS: In this large-scale, observational cohort study based on PSM analysis, the D2 + CME procedure showed less intra-laparoscopic blood loss, more lymph node harvest, and faster postoperative flatus than the conventional D2 procedure. However, both the overall and severe postoperative adverse events (Clavien-Dindo classification grade ≥ III a) seemed comparable between two cohorts. CONCLUSION: The present study showed that D2 + CME was associated with better short-term outcomes than conventional D2 dissection for patients with resectable gastric cancer.

DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer.

Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.

Complete mesogastric excision for locally advanced gastric cancer: short-term outcomes of a randomized clinical trial.

Implementation of complete mesogastric excision in gastric cancer surgery, named D2 lymphadenectomy plus complete mesogastric excision (D2+CME), has recently been proposed as an optimal procedure. However, the safety and efficacy of D2+CME remain uncertain. In this randomized controlled trial, patients receiving D2+CME exhibit less intraoperative blood loss, more lymph node harvesting, and earlier postoperative flatus than patients receiving conventional D2 radical surgery. Univariate Cox regression analysis reveals that the risk ratio for postoperative flatus in D2+CME group is 1.247 (p = 0.044). Overall postoperative complications are comparable between the two groups, but complications are significantly less severe in the D2+CME group than the D2 group (Clavien-Dindo classification grade ≥ IIIa: 4 D2+CME patients [11.8%] versus 9 D2 patients [33.3%]; p = 0.041). In conclusion, our work shows that D2+CME is associated with better short-term outcomes and surgical safety than conventional D2 dissection for patients with advanced gastric cancer.

Genome-wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most fatal cancers in the world. Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with GC prognosis are conflicting and mainly based on selected CIMP markers. The current study attempted to comprehensively assess the association between CIMP status and GC survival and to develop a CIMP-related prognostic gene signature of GC. METHODS: We used a hierarchical clustering method based on 2,082 GC-related methylation sites to stratify GC patients from the cancer genome atlas into three different CIMP subgroups according to the CIMP status. Gene set enrichment analysis, tumor-infiltrating immune cells, and DNA somatic mutations analysis were conducted to reveal the genomic characteristics in different CIMP-related patients. Cox regression analysis and the least absolute shrinkage and selection operator were performed to develop a CIMP-related prognostic signature. Analyses involving a time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to assess the performance of the prognostic signature. RESULTS: We found a positive relationship between CIMP and prognosis in GC. Gene set enrichment analysis indicated that cancer-progression-related pathways were enriched in the CIMP-L group. High abundances of CD8+ T cells and M1 macrophages were found in the CIMP-H group, meanwhile more plasma cells, regulatory T cells and CD4+ memory resting T cells were detected in the CIMP-L group. The CIMP-H group showed higher tumor mutation burden, more microsatellite instability-H, less lymph node metastasis, and more somatic mutations favoring survival. We then established a CIMP-related prognostic gene signature comprising six genes (CST6, SLC7A2, RAB3B, IGFBP1, VSTM2L and EVX2). The signature was capable of classifying patients into high-and low-risk groups with significant difference in overall survival (OS; p < 0.0001). To assess performance of the prognostic signature, the area under the ROC curve (AUC) for OS was calculated as 0.664 at 1 year, 0.704 at 3 years and 0.667 at 5 years. When compared with previously published gene-based signatures, our CIMP-related signature was comparable or better at predicting prognosis. A multivariate Cox regression analysis indicated the CIMP-related prognostic gene signature was an independent prognostic indicator of GC. In addition, Gene ontology analysis indicated that keratinocyte differentiation and epidermis development were enriched in the high-risk group. CONCLUSION: Collectively, we described a positive association between CIMP status and prognosis in GC and proposed a CIMP-related gene signature as a promising prognostic biomarker for GC.

An Optimal Surgical Approach for Suprapancreatic Area Dissection in Laparoscopic D2 Gastrectomy with Complete Mesogastric Excision.

BACKGROUND: During the radical operation, the suprapancreatic area is featured by anatomical complexity, and the lymph node dissection for this area is technically difficult and demanding.1-4 Previously, we have demonstrated the presence of disseminated cancer cells in the mesogastrium5,6 and presented a mesogastrium model for gastrectomy.7 As a consequence, laparoscopic D2 lymphadenectomy plus complete mesogastric excision (D2+CME) was proposed as a new concept in the surgical treatment of advanced gastric cancer.8 D2+CME procedure has been shown to be associated to lower number of free intraperitoneal cancer cells and with a better disease-free survival than conventional D2 gastrectomy.9 Under the concept of mesogastrium model, the proposed D2+CME procedure could help surgeons better define the anatomical boundaries of suprapancreatic mesogastrium, thus using it to achieve a complete and standard excision of the suprapancreatic area dissection. Here, we briefly present perioperative results of our case series with the laparoscopic curative subtotal gastrectomy and D2+CME with a R0 resection and present a video to detail the technical aspects of a laparoscopic D2+CME approach for suprapancreatic area dissection. METHODS: All patients in this study underwent laparoscopic subtotal gastrectomy (D2+CME) with a curative R0 resection. This study was approved by the Tongji Hospital Ethics Committee (Unique Reference Number: TJ-IRB20180811). The procedures in the video are described as follows. Based on our previous mesogastrium model (also named "Table model", Supplemental Figure 1), the suprapancreatic mesogastrium is attached to the lesser curvature or the posterior gastric wall and extended to the suprapancreatic area, respectively.7 Surgeon stands on patient left side, and the assistant lifts the stomach upward and cephalic to expose the suprapancreatic mesogastrium including left gastric mesentery (LGM), right gastric mesentery (RGM) and posterior gastric mesentery (PGM). First of all, towards to the left side of the suprapancreatic area, the "tri-junction" point of LGM is exposed. Using an energy devise, surgeon opens serosa layer and identifies the retrogastric space. The LGM and PGM are mobilized bluntly, between which a fusion retrogastric space is revealed. Both the LGM and PGM are covered by smooth and shiny surfaces of fascial propria and regarded as the "meso-bed" mutually. Secondly, at the inner side of duodenum, surgeon bluntly separates the adjuvant tissues along gastro-duodenal artery (GDA) upward and exposes right gastric mesentery (RGM). Next, after mobilizing the left gastric mesentery, surgeon removes the adipose tissue adherent to the common hepatic artery (CHA) and exposes the root of the left gastric artery after dissecting the perivascular sheath with triple-clips. Then, surgeon dissects RGM along the CHA and portal vein (HPV) towards the right side of the suprapancreatic area; afterwards, the right gastric vessels and RGM are identified and ligated. Lastly, the superior border of splenic vessels is dissected. The anterior lobe of the PGM is raised up with ligated posterior gastric vessels. Remarkably, posterior gastric vessels may be absent in some cases. Reconstruction of the alimentary tract is Roux-en-Y method. Standard recovery protocols are followed in postoperative treatments. RESULTS: Between August 28th 2017 and December 27th 2018, 107 patients receiving laparoscopic curative subtotal gastrectomy (D2+CME) with a R0 resection were retrospective collected in this study. After exposing the suprapancreatic mesogastrium including RGM, PGM and LGM with D2+CME procedure, the LNs and fat tissues around 7, 9, 8a, 12a and 11p were removed en bloc in all patients. This study recruited 67 males and 40 females. The median age was 55 years, with body mass index (BMI) 23.0 kg/m2 (Supplemental Table 1). The median number of retrieved regional lymph nodes was 31 (range 25-41), including 22 (range 17-27.5) suprapancreatic lymph nodes. The median volume of blood loss was 14 ml (range 6-34). The median total operation time was 287 min (range 265.5-313.5) and laparoscopic surgery time was 132 min (range 116-142) (Supplemental Table 2). Postoperative morbidity occurred at a rate of 9.3 %, and the mortality rate was 0% (Supplemental Table 3). The median follow-up was 10 months (range 8-13). No patient was lost during follow-up (Supplemental Table 4). CONCLUSION: A laparoscopic subtotal gastrectomy with D2+CME procedure provides for a complete and standardized en bloc excision of the suprapancreatic area dissection.

Prospective randomized controlled trial to compare laparoscopic distal gastrectomy (D2 lymphadenectomy plus complete mesogastrium excision, D2 + CME) with conventional D2 lymphadenectomy for locally advanced gastric adenocarcinoma: study protocol for a randomized controlled trial.

BACKGROUND: Although radical gastrectomy with D2 lymph node dissection has become the standard surgical approach for locally advanced gastric cancer, patients still have a poor prognosis after operation. Previously, we proposed laparoscopic distal gastrectomy (D2 lymphadenectomy plus complete mesogastrium excision [D2 + CME]) as an optimized surgical procedure for locally advanced gastric cancer. By dissection along the boundary of the mesogastrium, D2 + CME resected proximal segments of the dorsal mesogastrium completely with less blood loss, and it improved the short-term surgical outcome. However, the oncologic therapeutic effect of D2 + CME has not yet been confirmed. METHODS/DESIGN: A single-center, prospective, parallel-group, randomized controlled trial of laparoscopic distal gastrectomy with D2 + CME versus conventional D2 was conducted for patients with locally advanced gastric cancer at Tongji Hospital, Wuhan, China. In total, 336 patients who met the following eligibly criteria were included and were randomized to receive either the D2 + CME or D2 procedure: (1) pathologically proven adenocarcinoma; (2) 18 to 75 years old; cT2-4, N0-3, M0 at preoperative evaluation; (3) expected curative resection via laparoscopic distal gastrectomy; (4) no history of other cancer, chemotherapy, or radiotherapy; (5) no history of upper abdominal operation; and (6) perioperative American Society of Anesthesiologists class I, II, or III. The primary endpoint is 3 years of disease-free survival. The secondary endpoints are overall survival, recurrence pattern, mortality, morbidity, postoperative recovery course, and other parameters. DISCUSSION: Previous studies have demonstrated the safety and feasibility of D2 + CME for locally advanced gastric cancer; however, there is still a lack of evidence to support its therapeutic effect. Thus, we performed this randomized trial to investigate whether D2 + CME can improve oncologic outcomes of patients with locally advanced gastric cancer. The findings from this trial may potentially optimize the surgical procedure and may improve the prognosis of patients with locally advanced gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01978444 . Registered on October 31, 2013.

Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer.

BACKGROUND: Focal adhesion plays an essential role in tumour invasiveness and metastasis. Hippo component YAP has been widely reported to be involved in many aspects of tumour biology. However, its role in focal adhesion regulation in breast cancer remains unexplored. METHODS: Tissue microarray was used to evaluate YAP expression in clinical breast cancer specimens by immunohistochemical staining. Cell migration and invasion abilities were measured by Transwell assay. A cell adhesion assay was used to measure the ability of cell adhesion to gelatin. The focal adhesion was visualized through immunofluorescence. Phosphorylated FAK and other proteins were detected by Western blot analysis. Gene expression profiling was used to screen differently expressed genes, and gene ontology enrichment was performed using DAVID software. The gene mRNA levels were measured by quantitative real-time PCR. The activity of the THBS1-promoter was evaluated by dual luciferase assay. Chromatin immunoprecipitation (ChIP) was used to verify whether YAP could bind to the THBS1-promoter region. The prediction of potential protein-interaction was performed with the String program. The ChIP sequence data of TEAD was obtained from the ENCODE database and analysed via the ChIP-seek tool. The gene expression dataset (GSE30480) of purified tumour cells from primary breast tumour tissues and metastatic lymph nodes was used in the gene set enrichment analysis. Prognostic analysis of the TCGA dataset was performed by the SurvExpress program. Gene expression correlation of the TCGA dataset was analysed via R2: Genomics Analysis and Visualization Platform. RESULTS: Our study provides evidence that YAP acts as a promoter of focal adhesion and tumour invasiveness via regulating FAK phosphorylation in breast cancer. Further experiments reveal that YAP could induce FAK phosphorylation through a TEAD-dependent manner. Using gene expression profiling and bioinformatics analysis, we identify the FAK upstream gene, thrombospondin 1, as a direct transcriptional target of YAP-TEAD. Silencing THBS1 could reverse the YAP-induced FAK activation and focal adhesion. CONCLUSION: Our results unveil a new signal axis, YAP/THBS1/FAK, in the modulation of cell adhesion and invasiveness, and provides new insights into the crosstalk between Hippo signalling and focal adhesion.

Detection of metastatic cancer cells in mesentery of colorectal cancer patients.

AIM: To detect the existence of isolated cancer cells in the mesentery of colorectum (named as Metastasis V), and investigate its clinical significance in colorectal cancer (CRC) patients. METHODS: Sixty-three CRC patients who received radical excision between January 2012 and September 2015 were included. All the patients underwent laparoscopy-assisted radical colorectomy or proctectomy [with complete mesocolic excision (CME) or total mesorectal excision (TME)] with R0 dissections at the Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The location and size of the primary lesions were recorded immediately after the tumor was removed, with the surrounding mesenterium completely separated along the intestinal wall. Each dissected mesentery sample was analyzed for hematoxylin-eosin staining and immunohistochemistry using cytokeratin 19 antibody. Image Pro Plus Software 6.0 (Media Cybernetics, CA, United States) was used to semi-quantitatively measure the concentration of the cytokeratin 19 immunohistochemistry. The correlation between metastasis found in mesentery and clinicopathological characteristics was examined. The prognosis of patients was also evaluated by preoperative serum CEA level. RESULTS: Metastasis V was detected in 14 of 63 (22.2%) CRC patients who underwent laparoscopy-assisted radical colorectomy or proctectomy (with CME or TME) with R0 dissection in our hospital between January 2012 and September 2015. There was no significant difference in age, gender, tumor size, and tumor location in patients with Metastasis V (P > 0.05). Metastasis V was more likely to occur in poorly differentiated tumor (5/11; 45.5%) than moderately (8/46; 17.4%) and well- differentiated one (1/6; 16.7%). The Metastasis V in N2 stage (9/14; 64.3%) was more frequent that in the N0 stage (3/35; 8.6%) or N1 stages (2/14; 14.3%). In addition, Metastasis V was positively related to the tumor invasive depth (T1:0/1, 0%; T2:1/12, 8.3%; T3:7/39, 17.9%; T4:6/11, 54.5%). Furthermore, preoperative serum CEA level in Metastasis V-positive patients was significantly higher than in Metastasis V-negative patients (4.27 ng/mL vs 3.00 ng/mL). CONCLUSION: Metastasis V might be associated with a poor prognosis of CRC patients.

The length and complexity of mesentery are related to the locoregional recurrence of the carcinoma in gut.

Local-regional relapse is the main recurrence pattern of the carcinoma in gut, and leads to poor prognosis. With the development of the total mesorectal and complete mesocolic excision (TME/CME), the local relapse rate of colorectal cancer has significantly decreased. People attributed it to the improvement of lymphadenectomy, but lymphatic metastasis is difficult to explain the local relapse in N0 patients. Previously, we have proven the existence of "Metastasis V" in mesogastrium and mesocolorectum, and supposed that it is one of the major risk factors in local recurrence. Therefore, we think complete mesentery excision can effectively reduce "Metastasis V", prevent cancer leak and improve patients' outcome. Due to the different length and complexity of mesentery, the difficulty of mesentery excision varies. Meanwhile, there is an obvious distinction of local relapse rate in different alimentary tract, even in different segment of a same organ. Thus we assume that the length and complexity of mesentery may be a risk factor of the locoregional recurrence of the carcinoma in gut.

An Optimal Approach for Laparoscopic D3 Lymphadenectomy Plus Complete Mesocolic Excision (D3+CME) for Right-Sided Colon Cancer.

BACKGROUND: It is common knowledge that high ligation of blood vessels at the D3 level and complete mesocolic excision (CME) are two critical points of right hemicolectomy for right colon cancer (RCC). 1-5 To date, a safe strategy for completing these two procedures under laparoscopic surgery has not been extensively described. The authors provide a video to demonstrate laparoscopic right hemicolectomy (D3 + CME) with an optimal mesentery-defined approach. By identifying three "tri-junctions," this approach facilitates dissection of the entire mesocolon along the embryologic planes as far centrally as possible and enables the high tie of feeding vessels at bifurcation. The authors propose that this approach is safe, decreases blood loss, and is a secure method for right colon cancer intervention. METHODS: Between June 2014 and June 2015, the study recruited 36 patients with informed consent, and these patients underwent laparoscopic D3+CME for right colon cancer by a single surgeon. All the participants provided informed written consent to participate in the study. This study was approved by the Tongji Hospital Ethics Committee. The patients' demographics, oncologic charac- teristics, postoperative outcomes within 30 days, and follow-up data were collected. The perioperative outcomes included blood lost, number of retrieved lymph nodes, postoperative hospital length of stay, and morbidity. The postoperative 30-day morbidity included cardiovascular, pulmonary, and urinary complications, as well as wound infection, anastomotic leakage, and postoperative ileus. The complications were diagnosed and categorized based on relevant clinical manifestations. For this procedure, all patients are placed in the Trendelenburg position, with five trocars inserted. Carbon dioxide (CO2) is inflated through the intraumbilical trocar, maintaining steady intraabdominal pressure. The operating surgeon stands between the patient's legs, with the camera holder on the left and the assistant on the right. The operation table will be rotated left side up to redistribute the small bowels. The standard surgical procedures shown in the video are as follows. First, the surgeon identifies the first "tri-junction" (TJ1) in the ileocolic area (TJ1 is the fusion point of the mesocolon, the visceral peritoneum, and the intestinal mesentery). The surgeon then incises along the fusion fascia and separates the loose connective tissues with an ultrasonically activated device. Mobilization is continued to the origins of the ileocolic vessels, which are clipped and cut. The posterior mesocolic fascia is bluntly separated from the inferior mesentery bed, which is formed by duodenum, Gerota's fascia, and nearby structures. The second part of duodenum and the head of pancreas are exposed. Next, the surgeon mobilizes along the superior mesentery vein (SMV) and superior mesentery artery (SMA), with blunt dissection of the covering fascia and loose connective tissue to preserve the entire mesocolon completely and as far centrally as possible. Careful dissection is continued until the middle colic vessels (middle colic vein and middle colic artery) are reached. Afterward, the superior right colic vein of Henle's trunk is exposed and divided at the root. One pack of gauze is inserted beneath the mobilized mesocolon. Second, the surgeon divides the greater omentum. Entrance to the omental bursa is established after the second "tri-junction" (TJ2) is identified (TJ2 is the fusion point of the transverse mesocolon, the mesogastrium and the greater omentum). The fusion plane is bluntly separated between the transverse mesocolon (TM) and the right gastroepiploic mesentery (RGEM) until the previously placed gauze is exposed. Finally, the third "tri-junction" (TJ3) is identified (TJ3 is the fusion point of the retroperitoneum, the mesocolon, and the lateral peritoneum) at the inferior attachments of cecum. The ascending colon is freed up with mobilization of the lateral retroperitoneal attachments from the cecum to the hepatic flexture. Special attention should be paid to avoid breaking the fascia renalis. The tumor carrying the colon is exteriorized through an abdominal incision with a wound protector. Continuity of the digestive tract is performed extracorporeally with side-to-side ileotransverse colon anastomosis using a linear stapler. All the treatments follow standardized recovery protocols. RESULTS: This study recruited 20 males and 16 females. The median age was 56.5 years, and the median body mass index (BMI) was 22.1 kg/m2. Twelve patients had experienced previous abdominal surgery. No intraoperative complications occurred. The tumor was located in the ileocecus of 14 patients and in the hepatic flexture of 22 patients (Supplemental Table 1). The median number of retrieved lymph nodes was 20 (interquartile range [IQR], 14.8-27 (Supplemental Table 2). The median volume of blood lost was 5 ml (IQR 5-10 ml). The median postoperative hospital stay was 10 days (IQR 9-12.3 days). One patient received treatments from the intensive care unit (ICU). One patient underwent reoperation for incision dehiscence. Seven patients had a postoperative complication diagnosed within 30 days (Supplemental Table 3). The median follow-up period was 12 months (IQR 3-20) months. All the patients received adjuvant chemotherapy, with no case of recurrence (Supplemental Table 4). CONCLUSION: An optimal mesentery-defined approach for laparoscopic D3 + CME allows for ligation of feeding vessels at their bifurcation and for CME to be performed simultaneously with technical efficiency. This procedure is safe and strongly practical for advanced right colon cancer intervention.

Short-term outcomes of laparoscopic D2 lymphadenectomy with complete mesogastrium excision for advanced gastric cancer.

BACKGROUND: D2 lymphadenectomy has been widely accepted as a standard procedure of surgical treatment for local advanced gastric cancer [1, 2]. However, neither the dissection boundary nor the extent of the excision for perigastric soft tissues has been described [3-7]. Our previous researches demonstrate the existence of disseminated cancer cells in the mesogastrium [8, 9] and present an understandable mesogastrium model for gastrectomy [10]. Hence, the D2 lymphadenectomy plus complete mesogastrium excision (D2 + CME) is firstly proposed in this study, aiming to assess the safety, feasibility and corresponding short-term surgical outcomes. METHODS: All of these patients underwent laparoscopy assisted D2 + CME radical gastrectomy with a curative R0 resection, and all the operations were performed by Prof. Jianping Gong, chief of GI surgery of Tongji Hospital, Huazhong University of Science and Technology. All participants provided informed written consent to participate in the study. This study was approved by the Tongji Hospital Ethics Committee. The standard surgical procedures in the video are described as follows. Dissect along the gastrocolic ligament and then toward the left colic flexture with special made gauze. Bluntly separate the adipose tissues to find fascia plane. Expose along the plane toward the splenic inferior polar area. Precede to the origins of left gastroepiploic vessels (LGEVs), clip and cut. All the mobilized adipose tissues in this area are defined as left gastroepiploic mesentery (LGEM) [10]. Next, turn to infra-pyloric area. Dissect the fascia plane between right gastroepiploic mesentery (RGEM) and transverse mesocolon. Turn to the pancreas head, remove the covering adipose tissues, identify the superior mesentery vein and expose the origins of right gastroepiploic vessels (RGEVs). Clip and cut. All the surrounding mobilized adipose tissues are defined as RGEM [10]. Move to the superior boarder of pancreas with the stomach reflected cephalad, incise the serosa and bluntly mobilize through the plane with gauze. Turn to the common hepatic artery (CHA), remove the adherent adipose tissue. Expose the root of left gastric vein, clip and cut. Dissect the thick sheath of left gastric artery, expose at the root, trip clip and cut. All mobilized lateral adipose tissues and dorsal parts are defined as left gastric mesentery (LGM) [10]. Toward right, dissect follow the CHA and hepatic portal vein (HPV). Next, move toward the left side of LGM and dissect along the splenic artery until reaching the posterior gastric wall. Move to the anterior area of stomach and divide the lesser omentum. Clean up the adipose tissue and nerves along the lesser curvature up to the gastroesophageal junction. Expose and cut the right gastric vessels (RGVs) where the mobilized adipose tissues are defined as right gastric mesentery (RGM) [10]. Reconstruction of the alimentary tract was done by extracorporeal anastomosis. Standard recovery protocols were followed in postoperative treatments. RESULTS: Fifty-four patients between September 2014 and March 2015 have been recruited with informed consent and underwent laparoscopic D2 + CME by a single surgeon. The mean number of retrieved regional lymph nodes was 35.04 ± 10.70 (range 14-55). The mean volume of blood loss was 12.44 ± 22.89 ml (range 5-100). The mean laparoscopic surgery time was 127.82 ± 17.63 min (range 110-165). The mean hospitalization time was 11.09 ± 4.28 days (range 8-28). No operative complication was observed during the hospitalization. CONCLUSION: The anatomical boundary of mesogastrium is well described and dissected within D2 + CME surgical process. It proves to be safely feasible and repeatable with less blood lost, qualified lymph nodes retrieval results and other improved short-term surgical outcomes in advanced gastric cancer. Meanwhile, potential disseminated cancer cells fall into the mesogastrium can be eradicated by D2 + CME.

DAB2IP in cancer.

DOC-2/DAB2 is a member of the disable gene family that features tumor-inhibiting activity. The DOC-2/DAB2 interactive protein, DAB2IP, is a new member of the Ras GTPase-activating protein family. It interacts directly with DAB2 and has distinct cellular functions such as modulating different signal cascades associated with cell proliferation, survival, apoptosis and metastasis. Recently, DAB2IP has been found significantly down regulated in multiple types of cancer. The aberrant alteration of DAB2IP in cancer is caused by a variety of mechanisms, including the aberrant promoter methylation, histone deacetylation, and others. Reduced expression of DAB2IP in neoplasm may indicate a poor prognosis of many malignant cancers. Moreover, DAB2IP stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of DAB2IP in cancer progression; the mechanisms underlying the dysregulation of DAB2IP; the gene functional mechanism and the prospects of DAB2IP in the future cancer research.

Absence of DAB2IP promotes cancer stem cell like signatures and indicates poor survival outcome in colorectal cancer.

Metastasis is a critical factor for the high mortality of colorectal cancer (CRC), but its mechanism is not completely understood. Epithelial-mesenchymal transition (EMT) is thought to play a key role in metastasis and also increases the cancer stem cell (CSC) feature that facilitates metastatic colonization. In this study, we investigated the biological roles of DAB2IP regulating EMT and stem cell-like features in human CRC. We demonstrate that DAB2IP suppresses NF-κB-mediated EMT and CSC features in CRC cells. In DAB2IP knockout mice, we discovered the hyperplasia in colonic epithelium which aberrantly represents the mesenchymal feature and NF-κB pathway activation. In clinic CRC tissue, we also reveal that reduced DAB2IP can enrich the CD133(+) subpopulation. DAB2IP expression was inversely correlated with tumor differentiation and metastasis, and patients with lower DAB2IP expression had shorter overall survival time. Taken together, our study demonstrates that DAB2IP inhibits NF-κB-inducing EMT and CSC to suppress the CRC progression, and also suggests that DAB2IP is a beneficial prediction factor for CRC patient prognosis.