Newly discovered mechanisms that mediate tumorigenesis and tumour progression: circRNA-encoded proteins.

Proteins produced by cap-independent translation mediated by an internal ribosome entry site (IRES) in circular RNAs (circRNAs) play important roles in tumour progression. To date, numerous studies have been performed on circRNAs and the proteins they encode. In this review, we summarize the biogenesis of circRNAs and the mechanisms regulating circRNA-encoded proteins expression. We also describe relevant research methods and their applications to biological processes such as tumour cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), apoptosis, autophagy and chemoresistance. This paper offers deeper insights into the roles that circRNA-encoded proteins play in tumours. It also provides a theoretical basis for the use of circRNA-encoded proteins as biomarkers of tumorigenesis and for the development of new targets for tumour therapy.

Preserving or peeling the inferior mesenteric arterial sheath during laparoscopic rectal cancer surgery: a prospective study of surgical outcomes.

BACKGROUND: We mainly evaluated whether preserving the inferior mesenteric artery (IMA) sheath to dissecting IMA root lymph nodes (also called No.253 lymph nodes) would benefit patients in terms of comparable lymph-node yield removed during operation and postoperative complications in laparoscopic radical resection of rectal cancer. METHODS: This is a prospective study included 141 rectal cancer patients who received laparoscopic radical resection during September 2018 to December 2020. All patients were randomly assigned to the preserved group (n = 71) and the peeled group (n = 70). The baseline characteristics, pathological features, intraoperative and postoperative data outcomes and complications were analyzed by independent samples t test, chi-square test or Fisher's exact test between the 2 groups. RESULTS: The baseline characteristic and pathological features had no statistical difference between the 2 groups. The preserved group had a shorter operative time (P = 0.002), a shorter lymph node dissection time (P < 0.001), less intraoperative bleeding (P = 0.004), an earlier time to first flatus (P = 0.013), an earlier time to fluid intake (P = 0.033) and a shorter length of hospitalization (P = 0.012) than the peeled group. The differences between the 2 groups were not statistically significant (P > 0.05) in regard to the total number of lymph nodes cleared, positive lymph nodes, bleeding, anastomotic leakage, pneumonia, wound infection, abscess, ileus, urinary retention, urinary tract infection and chyle leakage. CONCLUSION: Preserving of the IMA sheath in laparoscopic radical surgery for rectal cancer will reduce the total operation time and the length of hospitalization. This surgical method could lead to lower complication rate and faster recovery. TRIAL REGISTRATION: The study was approved by the Ethics Committee of The First Affiliated Hospital of Wannan Medical College and registered by the China Clinical Trials Registry (ChiCTR2200060830, Date of Registration:2022-06-12 -retrospective registration) http://www.chictr.org.cn/index.aspx .

A novel circular RNA circFN1 enhances cisplatin resistance in gastric cancer via sponging miR-182-5p.

Cisplatin (CDDP) is commonly used for gastric cancer (GC) chemotherapy. However, after several CDDP-based treatment cycles, patients always acquire chemotherapy resistance, which limits the overall clinical efficacy of the treatment. Clarification of the mechanisms responsible for CDDP resistance is required to improve therapeutic outcomes for patients. Circular RNAs (circRNAs) are noncoding RNAs involved in the pathogenesis of cancer, although their role in the mechanism underlying CDDP resistance in GC remains unknown. In the present study, we explored the underlying roles of circRNAs in the modulation of CDDP resistance in CDDP-sensitive and CDDP-resistant human GC cells. Using RNA sequencing and quantitative reverse transcription polymerase chain reaction, expression of circFN1 (originating from exons 10, 11, and 12 of the FN1 gene hsa_circ_0058147) was higher in CDDP-resistant GC cells and tissues. CircFN1 upregulation in GC patients treated by CDDP was significantly correlated with aggressive biological behavior. CircFN1 promoted viability and inhibited apoptosis of GC cells exposed to CDDP in vivo and in vitro. Furthermore, circFN1 suppressed GC cell apoptosis by "sponging" miR-182-5p. These findings demonstrate the involvement of circFN1 in CDDP resistance of GC and implicate circFN1 as a therapeutic target for GC patients treated with CDDP. It provides novel evidence of the function of circRNAs as microRNA sponges and highlight a potential therapeutic target for extinguishing CDDP resistance in patients with GC.

CircRNACCDC66 regulates cisplatin resistance in gastric cancer via the miR-618/BCL2 axis.

Gastric cancer (GC) remains a serious threat to human health with a high cancer-related death rate and unsatisfactory treatment effects after curative resection, especially with advanced GC. Thus, exploration of the molecular mechanism of cisplatin (CDDP) resistance in GC is crucial. circCCDC66 (hsa_circ_0001313) expression was detected by quantitative reverse-transcription PCR in GC cell lines and tissues. The characteristics of circCCDC66 in CDDP resistance in GC were evaluated in vivo and vitro. We performed luciferin reporter assays, biotin-coupled RNA pull-downs and fluorescence in situ hybridization (FISH) to assess the relationship of miR-618 to circCCDC66. Function was determined by cytotoxicity assay, western immunoblotting and TUNEL. CircCCDC66 was overexpressed in CDDP-resistant cells and tissues. The circCCDC66 expression was significantly associated with malignancy and was an independent risk factor for disease-free survival (DFS) in GC patients treated by CDDP based chemotherapy. Data from in vitro and vivo experiments demonstrated that circCCDC66 inhibited apoptosis by targeting miR-618 and release of B-cell lymphoma-2 (BCL2). CircCCDC66 is an essential regulator in the development of CDDP resistance and may serve as a promising therapeutic target for GC patients. Otherwise, our study adds more evidence of circRNA functioning as a sequestering agent for miRNA.

Natural orifice specimen extraction with a modified reverse puncture device technique for total laparoscopic colorectal resection: feasibility and efficacy.

Objective: To evaluate the feasibility and efficacy of the modified reverse puncture device (mRPD) technique for transanal anastomosis in total laparoscopic colorectal resection with natural orifice specimen extraction surgery (NOSES).Methods: From August 2015 to September 2017, 34 patients underwent laparoscopic colorectal resection using the mRPD technique to place the anvil in the abdominal cavity and complete transanal anastomosis.Results: All patients who underwent total laparoscopic colorectal resection with NOSES were analyzed. The anvil placement time was 5-14 min, with an average of 6.7 min. The postoperative pain visual analogue scale (VAS) score was 1-4 points, with an average of 2.2 points. The postoperative hospital stay was 7-13 days, with an average of 8.7 days. No complications, such as anastomotic bleeding or stenosis, occurred. During a 14- to 28-month follow-up period (average, 19.5 months), no cases of long-term complications were observed.Conclusion: Total laparoscopic colorectal resection using mRPD is a technically feasible and safe procedure with satisfactory short-term efficacy.

Reverse puncture device technique: an innovation of esophagojejunostomy in radical laparoscopic total gastrectomy.

Aim: To evaluate the feasibility, safety, short- and long-term efficacy of a reverse puncture device (RPD) technique for esophagojejunostomy in laparoscopic-assisted total gastrectomy. Patients & methods: This retrospective study analyzed outcome data of 104 patients in propensity score matching whom were divided into the RPD and the purse-string suture technique group. Results: The RPD group had a shorter anvil placement time, shorter operative time, longer resected esophageal length, shorter incision length, shorter postoperative drainage time, shorter postoperative hospital stay and anastomotic complications than the purse-string suture technique group (p < 0.05). Multivariate analysis showed that BMI (odds ratio: 6.285, 1.446-27.322) and anvil placement time (odds ratio: 5.645, 1.089-29.321) were independent risk factors for anastomotic complications (p < 0.05). Conclusion: Laparoscopic-assisted total gastrectomy using an RPD technique is feasible, safe and effective.

The Therapeutic Effectiveness of Laparoscopic Sleeve Gastrectomy Among Individuals with Low BMI Obesity (30-35 Kg/m2) and the Relationship of BMI to Weight Loss.

Purpose: Investigating the therapeutic efficacy of Laparoscopic Sleeve Gastrectomy (LSG) in low BMI (30-35 kg/m2) patients with obesity, and exploring the correlation between patients' preoperative BMI and postoperative weight loss. Methods: Comparing the weight loss, remission of comorbidities, occurrence of complications, and quality of life among the different BMI patients who underwent LSG. Analyzing the relationship between BMI and percentage of excess weight loss (%EWL) by using Spearman correlation analysis and linear regression analysis. Results: The %EWL at 12 months after the surgical procedure was (104.26±16.41)%, (90.36±9.98)%, and (78.30±14.64)% for patients with Class I, II, and III obesity, respectively, P<0.05. Spearman correlation coefficients between %EWL and BMI at 1, 3, 6, and 12 months after surgery were R=-0.334 (P<0.001), R=-0.389 (P<0.001), and R=-0.442 (P<0.001), R=-0.641 (P<0.001), respectively. The remission of hypertension, diabetes and dyslipidaemia did not differ significantly between groups (P>0.05). Conclusion: Individuals with obesity for varying BMI can experience favorable outcomes following LSG surgery. It is advisable to consider LSG treatment for patients with Class I obesity.

Hyperinsulinemia Influences the Short-Term Efficiency of Laparoscopic Sleeve Gastrectomy for Patients with Obesity and Insulin Resistance.

Purpose: The effect of hyperinsulinemia on short-term outcomes after laparoscopic sleeve gastrectomy (LSG) in patients with obesity combined with insulin resistance is unclear. Material and Methods: This was a retrospective analysis of patients who underwent LSG at our center between January 1, 2020, and December 31, 2021. Patients were divided into hyperinsulinemia (HINS) and nonhyperinsulinemia (NHINS) groups based on fasting insulin levels. The primary endpoint was weight change. Metabolic disease outcomes, postoperative complications, and quality of life score changes were secondary endpoints. Results: A total of 92 patients were included in this study, with 59 in the HINS group and 33 in the NHINS group. At 6 months postoperatively, the median (P25, P75) %EWL was 76.01 (64.40, 86.99)% in the HINS group and 92.02 (86.78, 100.88)% in the NHINS group (P<0.001). The mean %TWL (SD) was 23.26 (7.14)% in the HINS group and 26.80 (6.55)% in the NHINS group (P=0.021). The remission of dyslipidemia and hypertension in the NHINS group and the HINS group were not significantly different (P>0.05 for all). The differences in QOL between groups were not statistically significant (P=0.788). In terms of postoperative complications, there was no statistically significant difference between the groups (P>0.05 for all). Conclusion: HINS negatively influences weight change in patients with obesity and insulin resistance, and the NHINS group had better postoperative weight loss. In terms of hypertension, dyslipidemia, and postoperative complications, there was no significant effect of HINS.

NPRA promotes fatty acid metabolism and proliferation of gastric cancer cells by binding to PPARα.

Among cancers, gastric cancer (GC) ranks third globally in morbidity and mortality, particularly in East Asia. Natriuretic peptide receptor A (NPRA), a receptor for guanylate cyclase, plays important roles in regulating water and sodium balance. Recent studies have suggested that NPRA is involved in tumorigenesis, but its role in GC development remains unclear. Herein, we showed that the expression level of NPRA was positively correlated with gastric tumor size and clinical stage. Patients with high NPRA expression had a lower five-year survival rate than those with low expression, and NPRA was identified as an independent predictor of GC prognosis. NPRA knockdown suppressed GC cell proliferation, migration and invasion. NPRA overexpression enhanced cell malignant behavior. Immunohistochemistry of collected tumor samples showed that tumors with high NPRA expression had higher peroxisome proliferator-activated receptor α (PPARα) levels. In vivo and in vitro studies showed that NPRA promotes fatty acid oxidation and tumor cell metastasis. Co-IP showed that NPRA binds to PPARα and prevents PPARα degradation. PPARα upregulation under NPRA protection activates arnitine palmitoyl transferase 1B (CPT1B) to promote fatty acid oxidation. In this study, new mechanisms by which NPRA promotes the development of GC and new regulatory mechanisms of PPARα were identified.

Current status and progress of laparoscopic inguinal hernia repair: A review.

After 30 years of development, laparoscopic inguinal hernia repair (LIHR) has become the main method for treating adult inguinal hernia. LIHR is more standardized, the approach of single-port laparoscopic hernioplasty, the advantages of robotic inguinal hernioplasty, the application of new patches and the selection of surgical methods for different populations have become the focus and difficulty of current research. This article summarized the research progress of LIHR in recent years. Different keywords and phrases including inguinal hernia, LIHR, transabdominal laparoscopic preperitoneal hernia repair, and total extraperitoneal hernia repair were used to search the PubMed, China National Knowledge Infrastructure, and Web of Science databases for related original and review articles that serve the aim of this article well, which was to perform a nonsystematic review of the development, progress, and current status of LIHR.

A prospective study of specimen eversion to lateral rectum and valgus resection for low rectal cancer.

Purpose: To investigate the safety and efficacy of a reverse puncture device (RPD) and specimen eversion of the rectum for resection in total laparoscopic proctectomy. Methods: In a prospective study from August 2019 to March 2021, 40 patients underwent a procedure with an RPD and specimen eversion of the rectum for total laparoscopic low rectal cancer resection, that is natural orifice specimen extraction surgery (NOSES), were included in the NOSES group. Forty patients in the control group underwent conventional laparoscopic radical resection for low rectal cancer and were included in the LAP group. Intraoperative- and postoperative-related indicators, recovery and inflammatory factors, quality of life (QOL) and mental health were compared. Results: All operations were successfully completed. Compared with the LAP group, the NOSES group showed better short-term outcomes, such as time to eating, postoperative pain, and especially postoperative incision-related complications. At the same time, postoperative inflammatory factor levels, psychological trauma, life-related anxiety and depression scores, and QOL were better in the NOSES group than in the LAP group. Conclusions: The application of an RPD and specimen eversion of the rectum for total laparoscopic low rectal cancer resection is a technically feasible and safe approach with a short-term curative effect.

Advances in the Study of CircRNAs in Tumor Drug Resistance.

Recent studies have revealed that circRNAs can affect tumor DNA damage and repair, apoptosis, proliferation, and invasion and influence the transport of intratumor substances by acting as miRNA sponges and transcriptional regulators and binding to proteins in a variety of ways. However, research on the role of circRNAs in cancer radiotherapy and chemoresistance is still in its early stages. Chemotherapy is a common approach to oncology treatment, but the development of tumor resistance limits the overall clinical efficacy of chemotherapy for cancer patients. The current study suggests that circRNAs have a facilitative or inhibitory effect on the development of resistance to conventional chemotherapy in a variety of tumors, suggesting that circRNAs may serve as a new direction for the study of antitumor drug resistance. In this review, we will briefly discuss the biological features of circRNAs and summarize the recent progression of the involvement of circRNAs in the development and pathogenesis of cancer chemoresistance.

The role of noncoding RNAs in cancer lipid metabolism.

Research on noncoding ribonucleic acids (ncRNAs) is mostly and broadly focused on microRNAs (miRNAs), cyclic RNAs (circRNAs), and long ncRNAs (lncRNAs), which have been confirmed to play important roles in tumor cell proliferation, invasion, and migration. Specifically, recent studies have shown that ncRNAs contribute to tumorigenesis and tumor development by mediating changes in enzymes related to lipid metabolism. The purpose of this review is to discuss the characterized ncRNAs involved in the lipid metabolism of tumors to highlight ncRNA-mediated lipid metabolism-related enzyme expression in malignant tumors and its importance to tumor development. In this review, we describe the types of ncRNA and the mechanism of tumor lipid metabolism and analyze the important role of ncRNA in tumor lipid metabolism and its future prospects from the perspectives of ncRNA biological function and lipid metabolic enzyme classification. However, several critical issues still need to be resolved. Because ncRNAs can affect tumor processes by regulating lipid metabolism enzymes, in the future, we can study the unique role of ncRNAs from four aspects: disease prevention, detection, diagnosis, and treatment. Therefore, in the future, the development of ncRNA-targeted therapy will become a hot direction and shoulder a major task in the medical field.

MiRNA-339 targets and regulates ZNF689 to inhibit the proliferation and invasion of gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is the most common malignant tumor of the digestive system, and its mortality rate ranks first among malignant tumors. However, the pathogenesis of GC has not yet been fully elucidated. This study found that microRNA (miRNA)-339 is abnormally expressed in GC tissues. However, the role and molecular mechanism of miRNA-339 in the occurrence and development of GC are still unclear. METHODS: Fluorescence quantitative polymerase chain reaction (qPCR) was used to detect the expression level of miRNA-339 in GC tissues and adjacent tissues and analyze the correlation with the clinicopathological characteristics of GC patients. Cell counting kit-8 (CCK-8) and Transwell experiments detected the effect of overexpression of miRNA-339 on the proliferation, invasion, and migration of GC cells. The luciferase reporter gene detected the downstream target molecules regulated by miRNA-339, and western blot was employed to detect the effect of overexpression of miRNA-339 on the expression of ZNF689. RESULTS: The results of fluorescence qPCR showed that miRNA-339 was less expressed in GC tissues compared with adjacent tissues, and it was correlated with the patient's clinical tumor, node, metastasis (TNM) grade and lymph node metastasis. Cell function experiments showed that overexpression of miRNA-339 can significantly inhibit the proliferation, invasion, and migration of GC cells. The luciferase reporter gene showed that miRNA-339 can bind to the 3'-UTR region of ZNF689, and overexpression of miRNA-339 can significantly inhibit the expression of ZNF689 in GC cells. Overexpression of ZNF689 can significantly block the ability of overexpression of miRNA-339 to inhibit the proliferation and migration of GC cells. CONCLUSIONS: miRNA-339 inhibits the proliferation and invasion of GC cells through targeted regulation of the expression of ZNF689. In addition, the expression level of miRNA-339 can be used as a biomarker for the prognosis of GC.

Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer.

BACKGROUND: Many studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (lncRNAs) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear. METHODS: In PC cells, the expression levels of lncRNAs in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 (ZEB1-AS1) antisense lncRNA on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence in situ hybridization and luciferase reporter assays in addition to in vivo studies were utilized to explore the adaptive mechanisms of ZEB1-AS1 in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of ZEB1-AS1 and its associated targets or pathways were investigated in both PC and pancreatic normal tissues. RESULTS: RNA-seq revealed that ZEB1-AS1 was significantly upregulated in PC cells under hypoxia conditions. The ZEB1-AS1 expression level was closely associated with poor prognosis of PC patients. Knockdown of ZEB1-AS1 suppressed the proliferation, migration, and invasion of PC cells in vitro as well as PC xenograft tumor growth in vivo. In PC cells, RNAi-mediated reduction of ZEB1-AS1 inhibited zinc finger E-box-binding homeobox 1 (ZEB1), while ZEB1-AS1 overexpression rescued ZEB1 expression, indicating that ZEB1-AS1 promotes ZEB1 expression. Moreover, hypoxia-inducible factor-1α (HIF-1α)induced the expression of ZEB1-AS1 by binding to the ZEB1-AS1 promoter, which contains a putative hypoxia response element (HRE). Mechanistically, ZEB1-AS1 scaffolded the interaction among HIF-1α, ZEB1, and histone deacetylase 1 (HDAC1), leading to deacetylation-mediated stabilization of HIF-1α. We further revealed that ZEB1 induced the deacetylase capacity of HDAC1 to suppress the acetylation or degradation of HIF-1α, improving HIF-1α assembly. Thus, hypoxia-induced ZEB1-AS1 facilitated ZEB1 transcription and the stability of HIF-1α, which promoted the metastasis of PC cells. Clinically, dysregulated ZEB1 and HIF-1α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients. CONCLUSIONS: Our results emphasized that the positive reciprocal loop of HIF-1α/ZEB1-AS1/ZEB1/HDAC1 contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.

Corrigendum: Positive Reciprocal Feedback of LncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer.

[This corrects the article DOI: 10.3389/fonc.2021.761979.].

Three-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer.

Whether extensive intraoperative peritoneal lavage (EIPL) after gastrectomy is beneficial to patients with locally advanced gastric cancer (AGC) is not clear. This phase 3, multicenter, parallel-group, prospective randomized study (NCT02745509) recruits patients between April 2016 and November 2017. Eligible patients who had been histologically proven AGC with T3/4NxM0 stage are randomly assigned (1:1) to either surgery alone or surgery plus EIPL. The results of the two groups are analyzed in the intent-to-treat population. A total of 662 patients with AGC (329 patients in the surgery alone group, and 333 in the surgery plus EIPL group) are included in the study. The primary endpoint is 3-year overall survival (OS). The secondary endpoints include 3-year disease free survival (DFS), 3-year peritoneal recurrence-free survival (reported in this manuscript) and 30-day postoperative complication and mortality (previously reported). The trial meets pre-specified endpoints. Estimated 3-year OS rates are 68.5% in the surgery alone group and 70.6% in the surgery plus EIPL group (log-rank p = 0.77). 3-year DFS rates are 61.2% in the surgery alone group and 66.0% in the surgery plus EIPL group (log-rank p = 0.24). The pattern of disease recurrence is similar in the two groups. In conclusion, EIPL does not improve the 3-year survival rate in AGC patients.

Longnon-coding RNA BLACAT2 promotes gastric cancer progression via the miR-193b-5p/METTL3 pathway.

Gastric cancer is one of the leading prevalent and malignant cancers worldwide, especially in east Asia. However, the in-depth molecular mechanism underlying gastric cancer progression remains uncertain. Recently, studies have identified that long non-coding RNA (lncRNA) could play critical roles in the tumorigenesis of multiple types of cancer. Studies on long non-coding RNA BLACAT2 have proven that it participates in bladder cancer and colorectal cancer regulation and was identified as highly expressed using the cBioPortal for Cancer Genomics in gastric cancer. However, the precise function of lncRNA-BLACAT2 in the carcinogenesis and progression of gastric cancer remains largely unexplored. Our study discovered that lncRNA-BLACAT2 was significantly upregulated in gastric cancer. Different studies have illustrated that BLACAT2 promoted gastric cancer progression through regulating proliferation, migration, invasion, and apoptosis in terms of biological function. Furthermore, BLACAT2 was verified to perform its function through interaction with miR-193b-5p using a luciferase reporter assay. On the other hand, MiR-193b-5p specific inhibitor treatment reversed the inhibitory effect of BLACAT2 on cell biological functions. Additional studies also discovered that Methyltransferase Like 3 (METTL3) was the downstream target of miR-193b-5p. Subsequently, restoration of METTL3 eliminated the suppressive effect of proliferation or the promotive effect of apoptosis caused by BLACAT2 knockdown. To sum up, these experimental results demonstrated that BLACAT2 acted as an oncogene in gastric cancer progression through the regulation of the miR-193b-5p/METTL3 pathway, hence providing new insights regarding the pathogenesis of gastric cancer.

Combined Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery Alone for Treatment of Locally Advanced Gastric Cancer: The SEIPLUS Randomized Clinical Trial.

Importance: Peritoneal metastasis is the most frequent pattern of postoperative recurrence in patients with gastric cancer. Extensive intraoperative peritoneal lavage (EIPL) is a new prophylactic strategy for treatment of peritoneal metastasis of locally advanced gastric cancer; however, the safety and efficacy of EIPL is currently unknown. Objective: To evaluate short-term outcomes of patients with advanced gastric cancer who received combined surgery and EIPL or surgery alone. Design, Setting, and Participants: From March 2016 to November 2017, 662 patients with advanced gastric cancer receiving D2 gastrectomy were enrolled in a large, multicenter, randomized clinical trial from 11 centers across China. In total, 329 patients were randomly assigned to receive surgery alone, and 333 patients were randomly assigned to receive surgery plus EIPL. Clinical characteristics, operative findings, and postoperative short-term outcomes were compared between the 2 groups in the intent-to-treat population. Main Outcomes and Measures: Short-term postoperative complications and mortality. Results: The present analysis included data from 550 patients, 390 men and 160 women, with a mean (SD) age of 60.8 (10.7) years in the surgery alone group and 60.6 (10.8) in the surgery plus EIPL group. Patients assigned to the surgery plus EIPL group exhibited reduced mortality (0 of 279 patients) compared with those assigned to surgery alone (5 of 271 patients [1.9%]) (difference, 1.9%; 95% CI, 0.3%-3.4%; P = .02). A significant difference in the overall postoperative complication rate was observed between patients receiving surgery alone (46 patients [17.0%]) and those receiving surgery plus EIPL (31 patients [11.1%]) (difference, 5.9%; 95% CI, 0.1%-11.6%; P = .04). Postoperative pain occurred more often following surgery alone (48 patients [17.7%]) than following surgery plus EIPL (30 patients [10.8%]) (difference, 7.0%; 95% CI, 0.8%-13.1%; P = .02). Conclusions and Relevance: Inclusion of EIPL can increase the safety of D2 gastrectomy and decrease postoperative short-term complications and wound pain. As a new, safe, and simple procedure, EIPL therapy is easily performed anywhere and does not require any special devices or techniques. Our study suggests that patients with advanced gastric cancer appear to be candidates for the EIPL approach. Trial Registration: ClinicalTrials.gov identifier: NCT02745509.