Staging laparoscopy improves treatment decision-makingfor advanced gastric cancer

AIM To evaluate the clinical value of staging laparoscopyin treatment decision-making for advancedgastric cancer （GC）.METHODS： Clinical data of 582 patients with advancedGC were retrospectively analyzed. All patientsunderwent staging laparoscopy. The strength ofagreement between computed tomography （CT） stage,endoscopic ultrasound （EUS） stage, laparoscopic stage,and final stage were determined by weighted Kappastatistic （Kw）. The number of patients with treatmentdecision-changes was counted. A χ 2 test was used toanalyze the correlation between peritoneal metastasisor positive cytology and clinical characteristics.RESULTS： Among the 582 patients, the distributions ofpathological T classifications were T2/3 （153, 26.3%）,T4a （262, 45.0%）, and T4b （167, 28.7%）. Treatmentplans for 211 （36.3%） patients were changed after staging laparoscopy was performed. Two （10.5%） of19 patients in M1 regained the opportunity for potentialradical resection by staging laparoscopy. Unnecessarylaparotomy was avoided in 71 （12.2%） patients. Thestrength of agreement between preoperative T stageand final T stage was in almost perfect agreement （Kw= 0.838; 95% confidence interval （CI）： 0.803-0.872;P 〈 0.05） for staging laparoscopy; compared with CTand EUS, which was in fair agreement. The strengthof agreement between preoperative M stage andfinal M stage was in almost perfect agreement （Kw= 0.990; 95% CI： 0.977-1.000; P 〈 0.05） for staginglaparoscopy; compared with CT, which was in slightagreement. Multivariate analysis revealed that tumorsize （≥ 40 mm）, depth of tumor invasion （T4b）, andBorrmann type （Ⅲ or Ⅳ） were significantly correlatedwith either peritoneal metastasis or positive cytology.The best performance in diagnosing P-positive wasobtained when two or three risk factors existed.CONCLUSION： Staging laparoscopy can improvetreatment decision-making for advanced GC anddecrease unnecessary exploratory laparotomy.

Laparoscopic gastric cancer surgery:Current evidence andfuture perspectives

Laparoscopic gastrectomy has been widely accepted as a standard alternative for the treatment of early-stage gastric adenocarcinoma because of its favorable shortterm outcomes. Although controversies exist, such as establishing clear indications, proper preoperative staging, and oncologic safety, experienced surgeons and institutions have applied this approach, along with various types of function-preserving surgery, for the treatment of advanced gastric cancer. With technical advancement and the advent of state-of-the-art instruments, indications for laparoscopic gastrectomy are expected to expand as far as locally advanced gastric cancer. Laparoscopic gastrectomy appears to be promising; however, scientific evidence necessary to generalize this approach to a standard treatment for all relevant patients and care providers remains to be gathered. Several multicenter, prospective randomized trials in high-incidence countries are ongoing, and results from these trials will highlight the short- and long-term outcomes of the approach. In this review, we describe up-to-date findings and critical issues regarding laparoscopic gastrectomy for gastric cancer.

Multimodal treatment of gastric cancer in the west: Where are we going?

The incidence of gastric cancer(GC) is decreasing worldwide,especially for intestinal histotype of the distal third of the stomach.On the contrary,proximal location and diffuse Lauren histotype have been reported to be generally stable over time.In the west,no clear improvement in long-term results was observed in clinical and population-based studies.Results of treatment in these neoplasms are strictly dependent on tumor stage.Adequate surgery and extended lymphadenectomy are associated with good long-term outcome in early-stage cancer; however,results are still unsatisfactory for advanced stages(Ⅲ and Ⅳ),for which additional treatments could provide a survival benefit.This implies a tailored approach to GC.The aim of this review was to summarize the main multimodal treatment options in advanced resectable GC.Perioperative or postoperative treatments,including chemotherapy,chemoradiotherapy,targeted therapies,and hyperthermic intraperitoneal chemotherapy have been reviewed,and the main ongoing and completed trials have been analyzed.An original tailored multimodal approach to non-cardia GC has been also proposed.

Small gastrointestinal stromal tumor concomitant with early gastric cancer:A case report

The term gastrointestinal stromal tumors （GISTs） is defined diagnostically as the main group of mesenchymal tumors with spindle or epithelioid cells arising from the wall of the gastrointestinal tract with immunohistochemical reactivity for CD117 antibody. Previous studies revealed that cells in GISTs express a growth factor receptor with tyrosine kinase activity （termed c-kit）, which is the product of the c-kit protooncogene. The most specific and practical diagnostic criteria for GISTs are： immunohistochemically determined c-kit （CD117） expression; mitotic score; and tumor size. A small GIST concomitant with early gastric cancer is rarely encountered clinically. Herein we have reported a case of a 1.1-cm GIST detected by esophagogastroduo denoscopy concomitant with a IIc type of early gastric cancer （signet ring cell type）. It was detected during a routine physical health examination. To our knowledge, this is the first report of a small GIST concomitant with a signet ring cell type of early gastric cancer.

Targeted therapies in gastric cancer and future perspectives

Advanced gastric cancer(AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after firstline platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase Ⅰ-Ⅱ trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER(2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

Epidermal growth factor receptor antibody plus recombinant human endostatin in treatment of hepatic metastases after remnant gastric cancer resection

We report a 55-year-old male who developed advanced hepatic metastasis and peritoneal carcinomatosis after resection of remnant gastric cancer resection 3 mo ago. The patient only received epidermal growth factor (EGF) receptor antibody (Cetuximab) plus recombinant human endostatin (Endostar). Anti-tumor activity was assessed by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computer tomography (PET/CT) at baseline and then every 4 wk. The case illustrates that 18FDG-PET/CT could make an early prediction of the response to Cetuximab plus Endostar in such clinical situations. 18FDG-PET/CT is a useful molecular imaging modality to evaluate the biological response advanced hepatic metastasis and peritoneal carcinomatosis to Cetuximab plus Endostar in patients after remnant gastric cancer resection.

Sentinel node navigation surgery for gastric cancer: Overview and perspective

The sentinel node(SN) technique has been established for the treatment of some types of solid cancers to avoid unnecessary lymphadenectomy. If node disease were diagnosed before surgery, minimal surgery with omission of lymph node dissection would be an option for patients with early gastric cancer. Although SN biopsy has been well ascertained in the treatment of breast cancer and melanoma, SN navigation surgery(SNNS) in gastric cancer has not been yet universal due to the complicated lymphatic flow from the stomach. Satisfactory establishment of SNNS will result in the possible indication of minimally invasive surgery of gastric cancer. However, the results reported in the literature on SN biopsy in gastric cancer are widely divergent and many issues are still to be resolved, such as the collection method of SN, detection of micrometastasis in SN, and clinical benefit. The difference in the procedural technique and learning phase of surgeons is also varied the accuracy of SN mapping. In this review, we outline the current status of application for SNNS in gastric cancer.

Clinical significance of CT-defined minimal ascites in patients with gastric cancer

AIM： To study the clinical significance of minimal ascites, which was only defined by the CT and whose nature was not determined preoperatively, in the relationship with the peritoneal carcinomatosis. METHODS： The medical records and the dynamic CT films of 118 patients with gastric cancer were reviewed. Factors associated with peritoneal carcinomatosis were analyzed in 40 patients who had CT-defined ascites of which the nature was surgically confirmed, RESULTS： Only 12.5-25% of the CT-defined minimal ascites, whose volume was estimated to be less than 50 mL, were associated with peritoneal carcinomatosis. When the estimated CT-defined ascitic volume was 50 mL or more, peritoneal carclnomatosis was identified in 75-100%. When CT-defined lymph node enlargements were not found beyond the regional gastric area, perigastric invasions were not suspected, and the size of tumor was less than 3 cm, peritoneal carcinomatosis seemed significantly less accompanied at the univariate analysis. However, except for the minimal volume of CT- defined ascites in comparison with the mild or more, other factors were not confirmed multivariately. CONCLUSION： In the patients with gastric cancer, CT- defined minimal ascites alone is rarely associated with peritoneal carcinomatosis, if it does not accompany other signs suggestive of malignant seeding. Therefore, consideration of active curative resection should not be hesitated, if CT-defined minimal ascites is the only delusive sign.

Emerging roles of non-coding RNAs in gastric cancer:Pathogenesis and clinical implications

Gastric cancer is a leading cause of cancer-related deaths. However, the mechanisms underlying gastric carcinogenesis remain largely unclear. The association of non-coding RNAs(nc RNAs) with cancer has been widely studied during the past decade. In general, nc RNAs have been classified as small nc RNAs, including micro RNAs(mi RNAs), and long non-coding RNAs(lnc RNAs). Emerging evidence shows that mi RNAs and lnc RNAs play key roles in the formation and progression of many cancers. In this review, we focus on the regulation of mi RNAs and lnc RNAs in gastric cancer. mi RNAs and lnc RNAs appear to be involved in gastric tumor growth, invasion, and metastasis and in establishment of the gastric tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing mi RNAs and lnc RNAs as potential biomarkers and therapeutic targets for gastric cancer. Taken together, we summarize the emerging roles of nc RNAs in gastric cancer development and their possible clinical significance.

Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer

AIM： To investigate the prognostic significance of phosphatase regenerating liver 3 （PRL-3） protein expression in gastric cancer.METHODS： PRL-3 expression in paraffin-embedded tumor specimens from 293 patients with gastric cancer was studied retrospectively by immunohistochemistry. Nonoclonal antibody specifically against PRL-3, 3B6, was obtained with hybridoma technique.RESULTS： Positive PRL-3 expression was detected in 43.3% （227 of 293） of gastric cancer cases. High expression of PRL-3 was positively correlated with tumor size, depth of invasion, vascular/lymphatic invasion, lymph node metastasis, high TNM stage and tumor recurrence. Patients with positive PRL-3 expression had a significantly lower 5-year survival rate than those with negative expression （28.3% vs 52.9%, P 〈 0.0001）. Patients who received curative surgery, and with positive PRL-3 expression had a significant shorter overall survival and disease-free disadvantage over patients with negative expression （hazard ratio of 16.7 and 16.6, respectively; P 〈 0.0001 for both）. Multivariate analysis revealed that PRL-3 expression was an independent prognostic indicator for overall and disease-free survival of gastric cancer patients, particularly for survival in TNM stage Ⅲ patients. CONCLUSION： PRL-3 expression is a new independent prognostic indicator to predict the potential of recurrence and survival in patients with gastric cancer at the time of tumor resection,

Diagnostic model of saliva protein finger print analysis of patients with gastric cancer

AIM:To explore the method for early diagnosis of gastric cancer by screening the expression spectrum of saliva protein in gastric cancer patients using mass spectrometry for proteomics.METHODS:Proportional peptide mass fingerprints were obtained by analysis based on proteomics matrix-assisted laser desorption ionization time-of-flight/mass spectrometry.A diagnosis model was established using weak cation exchange magnetic beads to test saliva specimens from gastric cancer patients and healthy subjects.RESULTS:Significant differences were observed in the mass to charge ratio(m/z) peaks of four proteins(1472.78 Da,2936.49 Da,6556.81 Da and 7081.17 Da) between gastric cancer patients and healthy subjects.CONCLUSION:The finger print mass spectrum of saliva protein in patients with gastric cancer can be established using gastric cancer proteomics.A diagnostic model for distinguishing protein expression mass spectra of gastric cancer from non-gastric-cancer saliva can be established according to the different expression of proteins 1472.78 Da,2936.49 Da,6556.81 Da and 7081.17 Da.The method for early diagnosis of gastric cancer is of certain value for screening special biological markers.

Autoantibodies against MMP-7 as a novel diagnostic biomarker in esophageal squamous cell carcinoma

AIM： To evaluate the diagnostic values of serum autoan tibodies against matrix metalloproteinase-7 （MMP-7） in patients with esophageal squamous cell carcinoma （ESCC）. METHODS： The MMP-7 cDNA was cloned from ESCC tissues, and MMP-7 was expressed and purified from a prokaryotic system. MMP-7 autoanUbodies were then measured in sera from 50 patients with primary ESCC and 58 risk-matched controls, using a reverse capture enzyme-linked immunosorbent assay （ELISA） in which autoantibodies to MMP-7 bound to the purified MMP-7 proteins. In addition, MMP-7 autoantibody levels in sera from 38 gastric cancer patients and from control serum samples were also tested. RESULTS： The optimum conditions for recombinant MMP-7 protein expression were determined as 0.04 mmol/L Isopropyl-13-D-Thiogalactopyranoside （IPTG）induction at 37℃ for four hours. The levels of serum autoantibodies against MMP-7 were significantly higher in patients with ESCC than in the matched-control samples （OD450 = 1.69 ±0.08 vs OD450 = 1.55 ± 0.10, P 〈 0.001）. The area under the receiver operating character- istic （ROC） curve was 0.87. The sensitivity and specificity for detection of ESCC were 78.0% and 81.0%, respectively, when the OD450 value was greater than 1.65. Although the levels of autoantibodies against MMP-7 were also significantly higher in patients with gastric cancer compared to control samples （OD450 = 1.62± 0.06 vs OD450 = 1.55±0.10, P 〈 0.001）, the diagnostic accuracy was less significant than in ESCC patients. The area of ROC curve was 0.75, whereas the sensitivity and specificity were 60.5% and 71.7%, respectively, when the cut-off value of OD450 was set at 1.60. CONCLUSION： Serum autoantibody levels of MMP-7 may be a good diagnostic biomarker for esophageal squamous cell carcinoma,

Predictive factors for lymph node metastasis in poorly differentiated early gastric cancer and their impact on the surgical strategy

AIM:To identify the predictive clinicopathological factors for lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC) and to further expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of poorly differentiated EGC. METHODS: Data were collected from 85 poorly- differentiated EGC patients who were surgically treated. Association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. RESULTS: Univariate analysis showed that tumor size (OR = 5.814, 95% CI = 1.050 - 32.172, P = 0.044), depth of invasion (OR = 10.763, 95% CI = 1.259 - 92.026, P = 0.030) and lymphatic vessel involvement (OR = 61.697, 95% CI = 2.144 - 175.485, P = 0.007) were the significant and independent risk factors for LNM. The LNM rate was 5.4%, 42.9% and 50%, respectively, in poorly differentiated EGC patients with one, two and three of the risk factors, respectively. No LNM was found in 25 patients without the three risk factors. Forty-four lymph nodes were found tohave metastasis, 29 (65.9%) and 15 (34.1%) of the lymph nodes involved were within N1 and beyond N1, respectively, in 12 patients with LNM. CONCLUSION: Endoscopic mucosal resection alone may be sufficient to treat poorly differentiated intramucosal EGC (≤ 2.0 cm in diameter) with no histologically-confirmed lymphatic vessel involvement. When lymphatic vessels are involved, lymph node dissection beyond limited (D1) dissection or D1+ lymph node dissection should be performed depending on the tumor location.

Inducible nitric oxide synthetase genotype and Helicobacter pylori infection affect gastric cancer risk

AIM： To investigate the association of the inducible ni- tric oxide synthetase （iNOS） C150T polymorphism with Helicobacter pylori （H. pylor/） infection and gastric can- cer （GC） risk in Iran. METHODS： In order to determine whether there was a correlation between iNOS genotype and GC in Iran, we conducted a case-control study using samples from 329 individuals. For each sample, the C150T ilVOS poly- morphism was genotyped by polymerase chain reaction （PCR） and restriction digestion. Patients were grouped by cancer presence, demographic and behavior charac- teristics, and/-/, pylori infection status. Statistical tests were conducted to determine whether any behavioral factors or a particular iNOS genotype was associated with GC in the study population. RESULTS： In this population, we found that smok- ing, hot beverage consumption, a familial history of GC and H. pylori infection status were significantly associated with GC development （P = 0.015, P 〈 0.001, P = 0.0034, and P 〈 0.015, respectively）. The distribution of the C150T ilVOS genotypes among the two study groups was not statistically significant alone, but was impacted by H. pylori infection status. When compared to the non-/-/, pylori infected group, cancer patients who had a heterozygous CT genotype and were also infected with H. pylori were 2.1 times more at risk of developing GC [odds ratio （OR） = 2.1, P = 0.03] while those with a homozygous TT genotype and infected with H. pylori were 5.0 times more at risk of developing GC （OR = 5.0, P = 0.029）. In contrast, this association was not seen in patients in the control group.CONCLUSION： ACT or TT polymorphism at position 150 in the iNO$ gene significantly increases the risk of GC and may be a marker for GC susceptibility.

Endoscopic submucosal dissection in early gastric cancer in elderly patients and comorbid conditions

The prognosis of early gastric cancer(EGC) is good if there is no concomitant lymph node metastasis. Therefore, the early detection of EGC is important to improve the prognosis of patients with gastric cancer. In Japan, 40% to 50% of all gastric cancers are EGC, and endoscopic submucosal dissection(ESD) is widely accepted as a local treatment for these lesions, particularly for large lesions that at one time were an indication for gastrectomy because of the difficulty of en-bloc resection. Consequently, this procedure can preserve the entire stomach and the patient's postoperative quality of life. ESD has become a general technique with improved procedures and devices, and has become the preferred treatment for EGC rather than gastrectomy. Therefore, ESD may demonstrate many advantages in patients who have several comorbidities, particularly elderly population, patients taking antithrombotic agents, or patients with chronic kidney disease, or liver cirrhosis. However, it is not yet clear whether patients with both EGC and comorbidities are feasible candidates for ESD and whether they would consequently be able to achieve a survival benefit after ESD. In this review, we discuss the clinical problems of ESD in patients with EGC and those comorbid conditions.

Association of Helicobacter pylori IgA antibodies with the risk of peptic ulcer disease and gastric cancer

AIM: To compare the prevalence of Helicobacter pylori (Hpylori) IgG and IgA antibodies between adult subjects,with defined gastric diseases, nondefined gastric disorders and those representing the population.METHODS: Data on H pylori IgG and IgA antibodies,determined by enzyme immunoassay, were analyzed in 3 252 subjects with DGD including 482 patients with gastric ulcer, 882 patients with duodenal ulcer, 1 525patients with chronic gastritis only and 363 subjects with subsequent gastric cancer, 19 145 patients with NoDg and4 854 POPUL subjects. The age-adjusted prevalences were calculated for 1- and 20-year age cohorts.RESULTS: The prevalences of IgG antibodies were equally high (89-96%) in all 20-year age cohorts of the DGD groups, whereas the prevalences of IgG antibodies were lower and increased by age in the POPUL and NoDg groups. The prevalences of IgA antibodies were also higher in the DGD groups; among them CA (84-89%) and GU groups (78-91%) showed significantly higher prevalences than DU (68-77%) and CG patients (59-74%) (OR 2.49, 95%CI 1.86-3.34 between the GU and DU groups). In the CA, GU, and DU groups, the IgA prevalences showed only minor variation according to age, while they increased by age in the CG, POPUL, and NoDg groups (P≤0.0001). The IgA response, but not the IgG response, was associated with an increased risk of CA (OR 2.41, 95%CI 1.79-3.53) and GU (OR 2.57,95%CI 1.95-3.39) in comparison with CG patients.CONCLUSION: An IgA antibody response during H pylori infection is significantly more common in CA and GU patients as compared with CG patients.

Implications of anti-parietal cell antibodies and anti-Helicobacter pylori antibodies in histological gastritis and patient outcome

AIM： To develop a serum or histological marker for early discovery of gastric atrophy or intestinal metaplasia. METHODS： This study enrolled 44 patients with gastric adenocarcinoma, 52 patients with duodenal ulcer, 14 patients with gastric ulcer and 42 consecutive healthy adults as controls. Each patient received an endoscopy and five biopsy samples were obtained. The degrees of histological parameters of gastritis were categorized following the Updated Sydney System. Anti-parietal cell antibodies （APCA） and anti- Helicobacter pylori （ H pylori） antibodies （AHPA） were analyzed by immunoassays. Hpyloriinfection was diagnosed by rapid unease test and histological examination. RESULTS： Patients with gastric cancer and gastric ulcer are significantly older than healthy subjects, while also displaying higher frequency of APCA than healthy controls. Patients with positive APCA showed higher scores in gastric atrophy and intestinal metaplasia of corpus than patients with negative APCA. Patients with positive AHPA had higher scores in gastric atrophy, intestinal metaplasia, and gastric inflammation of antrum than those patients with negative AHPA. Elderly patients had greater prevalence rates of APCA. Following multivariant logistic regression analysis, the only significant risk factor for antral atrophy is positive AHPA, while that for corpus atrophy is positive APCA. CONCLUSION： The existence of positive APCA correlates with glandular atrophy in corpus and the presence of positive AHPA correlates with glandular atrophy in antrum. The existence of serum APCA and AHPA betokens glandular atrophy and requires further examination for gastric cancer.

The Relationship between a Cohort Endoscopic Screening of 15,000 Subjects and the Death of Patients with Esophageal and Gastric Cancers in High-Risk Areas

OBJECTIVE Ci-xian County is located in the north of Chinaand is a high-risk area for esophageal cancer(EC).In 2004,theincidence rate of EC in the county was 127/100,000 and 93/100,000in the male and female population,respectively,and that ofgastric cancer(GC)was 72/100,000 and 36/100,000.Since 2001 acohort screening,supported by a special national fund,utilizingendoscopic examination with iodine staining for the targetpopulation at the age ranging from 40 to 69 years was carried out,so as to reduce the incidence and mortality rates in the high-riskareas of EC.METHODS In October 2001,4 townships in the Ci-xian County,Hebei,China were selected,with 22,016 cases in the interventiongroup(IVG)and 33,410 in the control group(CG).The totalpopulation coverage reached 55,000.There were 3257 males and3339 females in the IVG with the age ranging from 40 to 69 years,and 4299 males and 4430 females in the CG with the same rangeof the age.Endoscopic screening with iodine staining was used inthe IVG,with a screening rate of 53.2%.During the screening byendoscopic examination,97 cases were found to have esophagealsquamous epithelium,carcinoma-in-situ at the cardiac glandularepithelium or intra-mucosal carcinoma.Additionally,102cases were identified to have severe atypical hyperplasia in theesophagus and gastric cardia.The natural incidence rate of cancerand the mortality were observed in the CG.The ICD-0 version wasused in the tumor incidence and death registration coding.Duringa period from June to September 2008,based on the information ofthe tumor registration database of the incidence and mortality inthe Ci-xian County,the cohort groups were studied and followed.RESULTS There were 133 patients with untreatable EC and48 with GC in the IVG,while there were 259 and 37 patients inthe CG who died of esophageal and gastric cancer,respectively.The relative risk(RR)of death was 0.76 in the male patients withEC,95%CI(0.59-0.98),P=0.038,and in the female patients theRR was 0.51,95%CI(0.35-0.75),P=0.000.The RR of death in theGC patients was 2.45,(1.40-4.29)in the male,P=0.01,and 0.99,(0.47-1.99),in the female cases,P=0.906.CONCLUSION Six years after a cohort screening of a largepopulation by endoscopic examination with iodine staining inareas at high risk for EC,the death risk in the male and femalepatients with EC has decreased compared with that in the controlgroup.The difference between the 2 groups was statisticallysignificant.However,no protective method used to decrease thedeath risk in GC patients has been found during this period ofendoscopic screening.

Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo

Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.

A YAP/TAZ-CD54 axis is required for CXCR2-CD44-tumor-specific neutrophils to suppress gastric cancer

As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer cells.Importantly,knockout of YAP/TAz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC progression.Moreover,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient survival.Interestingly,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+tsNeus.Furthermore,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side effects.Thus,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.