Clinical Gastric Cancer Research Articles

Convenience of Adding a Needle Grasper in Single-Incision Laparoscopic Distal Gastrectomy With Billroth I Anastomosis for Clinical Early Gastric Cancer

PurposeTo overcome the technical difficulties of single-incision laparoscopic distal gastrectomy (SILDG), needle grasper (Endo ReliefTM)-assisted SILDG (NASILDG) was developed. Here, we compared the operative convenience and postoperative outcomes between SILDG and NASILDG.Materials and MethodsA needle grasper was inserted into the right upper abdomen and used in the NASILDG. We retrospectively reviewed patients who underwent D1 + dissection and delta-shaped Billroth I anastomosis with SILDG or NASILDG performed by a single surgeon between September 2015 and August 2018.ResultsThe SILDG (male, 50.0%) and NASILDG (male, 60.0%) groups included 10 and 15 patients, respectively. The operative time without combined operation and anastomosis was significantly shorter in the NASILDG group. Early complications and scar characteristics were not significantly different between the two groups.ConclusionsBy adding a needle grasper, SILDG became more convenient without decreasing cosmetic results. NASILDG could be a recommended method to reduce the technical difficulty of SILDG.

Outcomes of Laparoscopic Total Gastrectomy Combined With Spleen-Preserving Hilar Lymphadenectomy for Locally Advanced Proximal Gastric Cancer

The long-term survival of patients with laparoscopic total gastrectomy combined with spleen-preserving splenic hilar lymphadenectomy (LSTG) for advanced upper-third gastric cancer (AUTGC) and the association of splenic hilar lymph node (LN-10) metastasis with survival remain controversial. To evaluate the long-term outcomes of LSTG and the value index of LN-10 metastasis for patients with AUTGC. The Chinese Laparoscopic Gastrointestinal Surgery Study 4 (CLASS-04) was a prospective, multicenter, single-arm trial that involved 19 centers in China. A total of 251 eligible patients with clinical stage T2, T3, or T4a upper-third gastric cancer without distant metastases were enrolled from September 1, 2016, to October 31, 2017. The final follow-up was on December 31, 2020. All patients were enrolled to undergo LSTG. The main outcomes were the 3-year overall survival (OS) and disease-free survival (DFS). Multivariate analyses were used to explore the association of LN-10 metastasis with survival. Among the 251 patients, 246 (98.0%; mean [SD] age, 60.1 [9.4] years; 197 [80.1%] male) underwent LSTG and completed the study. The 3-year OS was 79.1% (95% CI, 74.0%-84.2%), and the 3-year DFS was 73.1% (95% CI, 67.4%-78.8%). In addition, the 3-year therapeutic value index of LN-10 dissection was 4.5, exceeding the indexes for the partial D2 LN group (including LNs 5, 6, 11d, and 12a). Nineteen patients (7.7%) with LN-10 metastasis had significantly worse survival than the nonmetastasis group, and multivariate analysis revealed that splenic LN-10 metastasis was an independent risk factor (OS: hazard ratio [HR], 2.38; 95% CI, 1.08-5.26; P = .03; DFS: HR, 2.28; 95% CI, 1.12-4.63; P = .02). Moreover, patients with LN-10 metastasis were more likely to have recurrence (42.1% vs 20.7%, P = .03), especially when multiple site metastasis was present (21.1% vs 4.4%, P = .01). However, patients with LN-10 metastasis who received adjuvant chemotherapy had significantly better OS and DFS than those without adjuvant chemotherapy and achieved the same oncologic effect as those without LN-10 metastasis. This results of this study suggest that LSTG for AUTGC has feasible long-term outcomes. In addition, patients with LN-10 metastasis may have worse survival and may be more prone to recurrence.

In vitro and in vivo Evaluation of a Novel Estrogen-Targeted PEGylated Oxaliplatin Liposome for Gastric Cancer.

BackgroundChemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin.MethodsFour kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice.ResultsThe ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin.ConclusionIn this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.

Promotion of gastric tumor initiating cells in a 3D collagen gel culture model via YBX1/SPP1/NF-\u03baB signaling

BackgroundThe high potential for tumor recurrence and chemoresistance is a major challenge of clinical gastric cancer treatment. Increasing evidence suggests that the presence of tumor initiating cells (TICs) is the principal cause of tumor recurrence and chemoresistance. However, the underlying mechanism of TIC development remains controversial.MethodsTo identify novel molecular pathways in gastric cancer, we screened the genomic expression profile of 155 gastric cancer patients from the TCGA database. We then described an improved 3D collagen I gels and tested the effects of collagen on the TIC phenotype of gastric cells using colony formation assay, transwell assay, and nude mouse models. Additionally, cell apoptosis assay was performed to examine the cytotoxicity of 5-fluorine and paclitaxel on gastric cancer cells cultured in 3D collagen I gels.ResultsElevated expression of type I collagen was observed in tumor tissues from high stage patients (stage T3–T4) when compared to the low stage group (n=10, stage T1–T2). Furthermore, tumor cells seeded in a low concentration of collagen gels acquired TIC-like phenotypes and revealed enhanced resistance to chemotherapeutic agents, which was dependent on an integrin β1 (ITGB1)/Y-box Binding Protein 1 (YBX1)/Secreted Phosphoprotein 1 (SPP1)/NF-κB signaling pathway. Importantly, inhibition of ITGB1/NF-κB signaling efficiently reversed the chemoresistance induced by collagen and promoted anticancer effects in vivo.ConclusionsOur findings demonstrated that type I collagen promoted TIC-like phenotypes and chemoresistance through ITGB1/YBX1/SPP1/NF-κB pathway, which may provide novel insights into gastric cancer therapy.

An Operation-First Approach Improves Overall Survival for Clinical T1-Stage Gastric Cancer

Siegel, Julie B. MD; Mukherjee, Rupak PhD; DeChamplain, Bryce A. BS; Mahvi, David M. MD, FACS; Lancaster, William MD, FACS Author Information

Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer

It is not clear whether laparoscopic and open distal gastrectomy produce similar outcomes among patients with locally advanced gastric cancer. Data from a multicenter, randomized clinical trial (Chinese Laparoscopic Gastrointestinal Surgical Study [CLASS]-01) showed that laparoscopic distal gastrectomy did not result in inferior disease-free survival at 3 years compared with open distal gastrectomy. To report 5-year overall survival data from the CLASS-01 trial of laparoscopic vs open distal gastrectomy among patients with locally advanced gastric cancer. This was a noninferiority, open-label, randomized clinical trial conducted at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 12, 2012, to December 3, 2014. Final follow-up was on December 31, 2019. Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histologic features to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. The 5-year overall survival rates were updated to compare laparoscopic distal gastrectomy with open distal gastrectomy. All analyses were performed on an intention-to-treat basis. In addition, per-protocol and as-treated analyses were performed for overall survival. Data from 1039 patients (726 men [69.9%]; mean [SD] age, 56.2 [10.7] years) who received curative therapy were analyzed. At 5 years, the overall survival rates were 72.6% in the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group (log-rank P = .19; hazard ratio, 1.17; 95% CI, 0.93-1.48; P = .19). After comparison for competing risk events, gastric cancer-related deaths (hazard ratio, 1.14; 95% CI, 0.87-1.49; P = .34) and deaths from other causes (hazard ratio, 1.23; 95% CI, 0.74-2.05; P = .42) did not differ significantly between groups. Overall rates of survival did not differ significantly between groups with each tumor stage. This study found that laparoscopic distal gastrectomy with D2 lymphadenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar 5-year overall survival compared with open distal gastrectomy among patients with locally advanced gastric cancer. ClinicalTrials.gov Identifier: NCT01609309.

High L-Type Amino Acid Transporter 1 Levels Are Associated with Chemotherapeutic Resistance in Gastric Cancer Patients

Introduction: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. Methods: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. Results: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). Conclusion: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment.

Type I collagen promotes tumor progression of integrin β1 positive gastric cancer through a BCL9L/β-catenin signaling pathway

The mechanism of extracellular matrix induced tumor progression is poorly understood. Based on the TCGA database and clinical tumor tissues analysis, we observed abundant type I collagen expression in tumor tissues and poor overall survival in gastric patients with high integrin β1 (ITGB1) expression. In vitro, our study found that 3D collagen culture promoted the capability of colony formation and growth in ITGB1 positive gastric cancer, whereas limited colony growth was observed in ITGB1 negative gastric cancer, suggesting the role of ITGB1 in type I collagen associated tumor progression. Mechanistically, we demonstrated that type I collagen was capable of promoting the activation of BCL9L/β-catenin signaling pathway through ITGB1, thereby contributing to the gastric cancer development. Subsequently, β-catenin signals further up-regulated the expression anti-apoptosis protein BCL2, leading to the chemo-resistance in gastric cancer cells. Blockade of β-catenin signals efficiently improved the anticancer effects of chemotherapy, providing an innovative sight for clinical gastric cancer therapy.

EPLIN Expression in Gastric Cancer and Impact on Prognosis and Chemoresistance.

Epithelial protein lost in neoplasm (EPLIN) has been implicated as a suppressor of cancer progression. The current study explored EPLIN expression in clinical gastric cancer and its association with chemotherapy resistance. EPLIN transcript expression, in conjunction with patient clinicopathological information and responsiveness to neoadjuvant chemotherapy (NAC), was explored in two gastric cancer cohorts collected from the Beijing Cancer Hospital. Kaplan-Meier survival analysis was undertaken to explore EPLIN association with patient survival. Reduced EPLIN expression was associated with significant or near significant reductions of overall, disease-free, first progression or post-progression survival in the larger host cohort and Kaplan Meier plotter datasets. In the larger cohort EPLIN expression was significantly higher in the combined T1 + T2 gastric cancer group compared to the T3 + T4 group and identified to be an independent prognostic factor of disease-free survival and overall survival by multivariate analysis. In the smaller, NAC cohort, EPLIN expression was found to be significantly lower in tumour tissues than in paratumour tissues. EPLIN expression was significantly associated with responsiveness to chemotherapy which contributes to overall survival. Together, EPLIN appears to be a prognostic factor and may be associated with patient sensitivity to NAC.

Surgically treated gastric cancer in Japan: 2011 annual report of the national clinical database gastric cancer registry.

The National Clinical Database (NCD) nationwide registry program of gastric cancer started in 2018. The purpose of this study was to report the treatment results of the NCD registry in the form of treatment results of the real world in Japan. Patients' characteristics, tumor features, treatments, and outcomes were collected using a web-based data entry system. We analyzed the initial NCD database for data on surgically treated gastric cancer patients in 2011. A total of 30,257 patients with malignant gastric tumors were enrolled by the NCD registry program from 501 hospitals in all 47 prefectures. Of these, the status of data entry was not approved in 8.8% of the registered data, and follow-up information was missing in 1.2% of the approved cases. Excluding 1777 cases, which were not resected for primary gastric cancer, 25,306 resected cases included 44.4% of stomach surgeries recorded in the NCD. The 5year survival rate of the resected cases was 71.3% and the operative mortality rate was 0.41%. The stage-specific 5year survival rates were as follows: 89.6% for stage IA, 83.8% for stage IB, 77.3% for stage IIA, 69.1% for stage IIB, 58.7% for stage IIIA, 44.1% for stage IIIB, 30.1% for stage IIIC, and 13.4% for stage IV. The NCD gastric cancer registry program demonstrated validity for database construction. The gastric cancer registry is expected to become a nationwide registry with the dissemination of data entry system and method in the NCD.

MET transcriptional regulator/serine peptidase inhibitor kunitz type 1 panel operating through HGF/c-MET axis as a prognostic signature in pan-cancer.

Dysregulations in transcription factors (TFs) and their genetic products play important roles in tumorigenesis, tumor progression and metastasis. However, prognostic value of the transcriptional regulatory networks in different cancers has not been investigated in depth. The purpose of our study was to identify and validate a potential predictive signature that combines TFs and their regulatory products in eight solid tumors. We used bioinformatics analysis to identify MET Transcriptional Regulator (MACC1) and Serine Peptidase Inhibitor Kunitz Type 1 (SPINT1) as candidate TFs with the respective downstream regulatory proteins for patient prognosis in pan‐cancer. Subsequent molecular analysis of clinical gastric cancer tissue samples further verified the negative correlation between MACC1 and SPINT1. Further, we showed that mechanistically, MACC1/SPINT1 mediated the pro‐HGF proteolysis and c‐Met phosphorylation in HGF/c‐MET signaling pathway. Kaplan‐Meier plots and receiver operating characteristics analysis revealed that the two‐gene signature combining MACC1 with SPINT1 was effective in predicting survival in all eight cancer cohorts tested. In conclusion, our study clarified the regulatory relationship between MACC1 and SPINT1 in the context of the HGF/c‐MET signaling pathway and determined MACC1/SPINT1 panel as a valuable signature for the prediction of prognosis in patients for multiple solid cancer types.

Clinical feasibility and oncologic safety of primary endoscopic submucosal dissection for clinical submucosal invasive early gastric cancer.

This study aimed to evaluate the clinical feasibility and oncologic safety of primary endoscopic submucosal dissection for cT1bN0M0 gastric cancer by identifying patients who had undergone curative resection after endoscopic submucosal dissection and patients who had undergone primary surgery but could be treated with endoscopic submucosal dissection. A single-center retrospective cohort study was conducted on patients with cT1bN0M0 gastric cancer (size: ≤ 30mm) and differentiated histology from January 2007 to May 2017. Submucosal invasion was evaluated using conventional endoscopy and endoscopic ultrasonography. Patients were divided into the primary endoscopic submucosal dissection and primary surgery groups according to initial treatment. Curative resection rate was 65.0% (91/140) in the primary endoscopic submucosal dissection group. Of patients in the primary surgery group, 49.1% (82/167) were considered eligible for endoscopic submucosal dissection. No differences in en bloc resection rate were observed between pT1a and pT1b gastric cancers after endoscopic submucosal dissection (97.8 vs. 97.9%). However, the negative horizontal margin rate was higher in pT1a gastric cancer than pT1b gastric cancer (98.9 vs. 91.3%). There was no difference in overall survival among the curative treatment groups (log rank P = 0.310). In this study, 173 (56.4%) out of 307 patients with cT1bN0M0 gastric cancer could avoid unnecessary surgery if primary endoscopic submucosal dissection was used. Based on these findings, it is necessary to add an appropriate indication for endoscopic submucosal dissection in patients with cT1b gastric cancer. Further management could be determined based on pathologic findings after primary endoscopic submucosal dissection.

Risk factors of postoperative complication after total gastrectomy in advanced gastric cancer patients receiving neoadjuvant chemotherapy

Objective: At present, there are few studies focusing on the factors short-term complications after total gastrectomy in patients with advanced gastric cancer receiving neoadjuvant chemotherapy (NACT). The purpose of this study is to provide a reference for clinical prevention of complications in these patients. Methods: A retrospective case-control study was conducted. Case inclusion criteria: (1) clinical stage II-III gastric cancer diagnosed by preoperative gastroscopy, pathology, abdominal CT, EUS or PET-CT; (2) evaluated suitable for NACT by MDT discussion; (3) no previous history of other malignant tumors and no concurrent tumor; (4) undergoing total gastrectomy+ D2 lymphadenectomy after NACT. Exclusion criteria: (1) age <18 or >80 years old; (2) severe concurrent diseases, and ASA classification>grade III; (3) stump gastric cancer or history of gastric surgery; (4) incomplete clinicopathological data. According to the above criteria, clinicopathological data of 140 advanced gastric cancer patients who underwent total gastrectomy after NACT in Chinese PLA General Hospital between June 2012 and June 2019 were collected, including 109 males and 31 females with mean age of (56.9±11.4) years and body mass indey (BMI) of (23.3±3.1) kg/m(2). Logistic analysis was used to analyze the relationship between postoperative complication and clinicopathological data. Factors in univariate analysis with P<0.05 were included in the multivariate analysis. Results: Postoperative complications (Clavien-Dindo classification ≥ II) occurred in 35 cases (25.0%) and severe complications (Clavien-Dindo classification ≥ IIIa) occurred in 4 cases (2.9%), including 1 case of esophago-jejunal anastomotic leakage, 1 case of vena cava thrombosis, 1 case of pleural effusion, 1 case of septic shock during perioperative days resulting in death. Univariate analysis showed that BMI (P=0.011), cycle of NACT (P=0.027), tumor diameter (P=0.021), and vascular invasion (P=0.033) were associated with postoperative complication within 30 days, while open/laparoscopic total gastrectomy were not associated with postoperative complication (P=0.926). Multivariate analysis revealed that BMI ≥ 25 kg/m(2) (OR=3.294, 95% CI: 1.343-8.079, P=0.009) and < 4 cycles of NACT (OR=2.922, 95% CI: 1.217-7.016, P=0.016) were independent risk factors for postoperative complication. The 3-year overall survival rates of patients with or without complication were 54.4% and 64.0%, respectively (P=0.395), and 3-year disease-free survival rates were 47.4% and 52.9%, respectively (P=0.587). Conclusions: Higher BMI and fewer cycles of NACT are independent risk factors of postoperative complication in advanced gastric cancer patients undergoing total gastrectomy after NACT. No obvious association is found between postoperative complication and surgical approaches.

Discrepancy between endoscopic and pathological ulcerative findings in clinical intramucosal early gastric cancer.

Ulcerative finding (UL) is one of the factors that define the indication and curability of endoscopic resection (ER) in early gastric cancer (EGC). Discrepancies between endoscopic UL (cUL) and pathological UL (pUL) sometimes occur in clinical practice. The aim of this study was to investigate the discrepancy rate in UL diagnosis and the risk factors associated with such discrepancies. Patients with clinical intramucosal (cT1a) EGC who underwent ER or surgery between September 2002 and December 2017 were analyzed. The proportion of cUL-negative (cUL0) lesions that were identified as pUL-positive (pUL1) and that of cUL-positive (cUL1) lesions that were identified as pUL-negative (pUL0) were calculated. Logistic regression analysis was performed to estimate the associations between discrepancy in UL diagnosis and clinical variables of the lesion, such as the size, histology, location, and macroscopic type. In total, 5382 lesions were evaluated; 5.5% of cUL0 lesions (256/4619) were identified as pUL1, while 38.7% of cUL1 lesions (295/763) were pUL0. Multivariate analysis indicated that in cUL1 lesions, tumor location in the lower third of the stomach (odds ratio 3.11, 95% confidence interval 1.90-5.08) was identified as an independent risk factor for overestimation. Endoscopic diagnosis of UL in cT1a EGC was overestimated in 38.7% of lesions, especially for lesions located in the lower third of the stomach. This discrepancy should be considered in the management of cT1a EGC with UL.

Acute and chronic infection of H. pylori caused the difference in apoptosis of gastric epithelial cells

Helicobacter pylori (H. pylori) is one of the most important pathogenic bacteria associated with various gastrointestinal diseases. At present, its apoptotic or antiapoptotic mechanism on gastric epithelial cells remains unknown and needs further illustrated. In this study, acute infection model (H. pylori and GES-1 cells were co-cultured for 24 h at a multiplicity of infection MOI of 100:1) and chronic infection model (GES-1 cells were infected repeatedly every 24 h at a multiplicity of infection MOI of 100:1 for approximately 8 weeks) were established, respectively. the chronic H. pylori infected GES-1 cells underwent a typically morphological change and Western Blot results showed that there was slight decrease in expression of E-cadherin, and obvious increase in expression of Vimentin. Apoptosis of these two models were analyzed by flow cytometry compared with the control cells, meanwhile, apoptosis associated markers (Bcl-xL, Bcl-2, Bax, etc) were detected by Western blot, additional in clinical H. pylori-positive gastric cancer tissues. Results showed that compared with the control cells, acute infection of H. pylori significantly accelerated the apoptosis of GES-1, increased the expression of Bax and Cleaved caspase-3, down-regulated expression of Bcl-xL and Bcl-2. Moreover, an opposite result was found in chronic infection of model and clinical gastric cancer tissues, and enhanced expression of NF–κB p65. Taken together, these findings suggest that H. pylori infection plays differential effects on apoptosis of gastric epithelial cells.

B7-H3 inhibits apoptosis of gastric cancer cell by interacting with Fibronectin.

Anti-apoptosis has been widely accepted as a hallmark of malignancy. B7-H3, a type I transmembrane protein, plays a key role in anti-apoptosis and immune escape, but its regulation during cancer development remains unclear. To investigate how the effect of anti-apoptosis is regulated by B7-H3 in gastric cancer, we stably knocked down B7-H3 gene by shRNA in MGC-803 and MKN-45 cells. The correlation between B7-H3 and Fibronectin (FN) expression were investigated by bioinformatics in public data from TCGA (The Cancer Genome Atlas). Here, we reported that B7-H3 expression is positively correlated with FN in clinical gastric cancer samples, and B7-H3 promoted adhesion and inhibited apoptosis of gastric cancer cell through an FN-dependent pathway. Mechanistically, B7-H3 interacted with FN and subsequently activated PI3K/AKT signaling pathway, a critical mediator of oncogenic signaling. In addition, exogenous FN could inhibit the expression of pro-apoptosis-related proteins such as Caspase 3, Caspase 8, Caspase 9, Bax , p53, Apaf-1 and Cleaved PARP, and upregulated the levels of signal molecule p-PI3K, p-AKT and anti-apoptotic proteins Bcl-2 in B7-H3high group, as compared with those in B7-H3low group. In conclusion, we here for the first time revealed that B7-H3 inhibits apoptosis of gastric cancer cell through regulation of FN-mediated PI3K/AKT signaling pathways.

Electrochemical detection of miRNA-100 in the sera of gastric cancer patients based on DSN-assisted amplification

Gastric cancer (GC) is a common malignant digestive tract tumor that leads to high mortality worldwide. Early diagnosis of GC is very important for adequate treatment. However, a rapid, specific and sensitive method for the detection of GC is currently not available. Here, a biosensor CPs/AuNP-AuE, the gold nanoparticle (AuNP)-modified Au electrode (AuE) which was coupled with DNA capture probes (CPs), was developed to detect the content of miR-100 in the sera of GC patients. The results showed that AuNPs were uniformly deposited on the surface of AuE. AuNPs enhanced the electrical conductivity and improved the effective area of AuE. CPs were successfully assembled on AuNP-AuE that could be digested by duplex-specific nuclease (DSN) from the miR-100/CPs complex on the electrode, improving the sensitivity of the biosensor by recycling miR-100. The data revealed that the biosensor was highly specific for the detection of miR-100, which had the ability to distinguish one base-pair mistake in miR-100. The detection of the biosensor for miR-100 ranged from 100 aM to 10 pM and the limit of detection (LOD) was estimated to be 100 aM. The detection results of 100 human sera samples using this biosensor indicated that the cutoff for the detection of gastric cancer was 5 fM. Therefore the biosensor developed in our study served as a rapid, specific and sensitive strategy for the detection of gastric cancer in clinic.

Laparoscopic Versus Open Distal Gastrectomy for Locally Advanced Gastric Cancer: Five-Year Update from the Class-01 Randomized Controlled Trial

BACKGROUND: It is not clear whether laparoscopic and open distal gastrectomy produce similar outcomes in patients with locally advanced gastric cancer. Data from a multicenter, randomized, controlled trial (CLASS-01) showed that laparoscopic distal gastrectomy did not result in inferior disease-free survival at 3 years compared with open distal gastrectomy. Here, we present 5-year overall survival data from this trial. METHODS: From September 2012 through December 2014, we randomly assigned 1056 patients with clinical stage T2, T3, or T4a gastric cancer (without bulky nodes or distant metastases) to undergo either laparoscopic distal gastrectomy or open distal gastrectomy with D2 lymphadenectomy in a 1:1 ratio. We compared 5-year overall survival between groups in the intent to treat population. RESULTS: We analyzed data from 1039 patients who received curative therapy. At 5 years, the overall survival rates were 72.6% in the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group (log-rank P =0.19; hazard ratio [HR], 1.17; 95% CI, 0.93–1.48; P =0.187). After we compared for competing risk events, gastric cancer-related deaths (HR, 1.14; 95% CI, 0.87–1.49; P =0.34) and deaths from other causes (HR, 1.23; 95% CI, 0.74–2.05; P =0.42) did not differ significantly between groups. Overall rates of survival did not differ significantly between groups with each tumor stage. CONCLUSIONS: Laparoscopic distal gastrectomy with D2 lymphadenectomy results in similar 5-year overall survival compared to open distal gastrectomy in patients with locally advanced gastric cancer by experienced surgeons in high-volume specialized institutions. TRIAL REGISTRATION: ClinicalTrials.gov. number, NCT01609309 FUNDING STATEMENT: This work was supported by the National Natural Science of China, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, the Key Clinical Specialty Discipline Construction Program from the National Health and Family Planning Commission of China, and the Program of Global Medical Affairs Department of Johnson & Johnson Medical Ltd. DECLARATION OF INTERESTS: None. ETHICS APPROVAL STATEMENT: Each participating center obtained institutional review board approval, according to local regulations. Patients provided written informed consent.

Crocin reverses 1-methyl-3-nitroso-1-nitroguanidine (MNNG)-induced malignant transformation in GES-1 cells through the Nrf2/Hippo signaling pathway.

Crocin, an active constituent of saffron, has anticancer activity. In this study, we investigated the relationship of Crocin with human gastric epithelial cells induced by 1-methyl-3-nitroso-1-nitroguanidine (MNNG), and explored the underlying mechanism. In vivo, the animal growth and atypical hyperplasia were observed in Sprague-Dawley rats. A cell model was established by treating the human gastric mucosa epithelial cell line GES-1 with MNNG. The effects of Crocin on proliferation, cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT) in GES-1 cells were analyzed using Cell Counting Kit-8, colony formation, flow cytometry, and Transwell assay, respectively. Western blot was used to explore the potential mechanism.. The gastric mucosa of animal model deteriorated obviously, the weight growth rate slowed down, and the atypical hyperplasia of gastric mucosa increased. The GES-1 cells had characteristics of malignant cells such as proliferation, apoptosis, and metastasis ability. It was found that Crocin suppressed the cell proliferation, increased apoptosis, and blocked the cycle arrest in G0/G1 phase simultaneously. Furthermore, Crocin negatively regulated the invasion ability of MNNG-treated GES-1 cells and EMT process. Crocin also increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), decreased TAZ in MNNG-treated GES-1 cells. Interestingly, Crocin regulated the expression of TAZ and yes-associated protein (YAP) by increasing Nrf2 level, as well as their upstream targets, mercaptopyruvate sulfurtransferase (MST) and large tumor suppressor (LATS). Crocin protected against MNNG-induced malignant transformation through the Nrf2/Hippo signaling pathway, which might be a drug candidate for clinical gastric cancer management.

Focal adhesion ribonucleoprotein complex proteins are major humoral cancer antigens and targets in autoimmune diseases

Despite the accumulating evidences of the significance of humoral cancer immunity, its molecular mechanisms have largely remained elusive. Here we show that B-cell repertoire sequencing of 102 clinical gastric cancers and molecular biological analyses unexpectedly reveal that the major humoral cancer antigens are not case-specific neo-antigens but are rather commonly identified as ribonucleoproteins (RNPs) in the focal adhesion complex. These common antigens are shared as autoantigens with multiple autoimmune diseases, suggesting a direct molecular link between cancer- and auto-immunity on the focal adhesion RNP complex. This complex is partially exposed to the outside of cancer cell surfaces, which directly evokes humoral immunity and enables functional bindings of antibodies to cancer cell surfaces in physiological conditions. These findings shed light on humoral cancer immunity in that it commonly targets cellular components fundamental for cytoskeletal integrity and cell movement, pointing to a novel modality of immunotherapy using humoral immunological reactions to cancers.