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Intraperitoneal chemotherapy combined with systemic chemotherapy is one of the therapeutic modalities currently used for the treatment of gastric cancer patients with peritoneal metastasis. This study was designed to evaluate the efficacy and safety of sintilimab plus S-1 combined intraperitoneal and intravenous paclitaxel. This is an open-label, single-center, phase II study including 36 gastric adenocarcinoma patients with peritoneal metastases diagnosed by laparoscopy. All enrolled patients received sintilimab, intraperitoneal and intravenous paclitaxel plus oral S-1 every three weeks. Conversion operation should be considered when a patient responds to the regimen and the peritoneal metastasis disappears. After gastrectomy, the protocol treatment is repeated until disease progression, unacceptable toxicity, investigator decision or patient withdrawal. The primary end point is the one-year survival rate. Clinical Trial Registration: NCT05204173 ( ClinicalTrials.gov )

Background: Different types of neoadjuvant chemotherapy regimens have been compared for gastric cancer, mostly in terms of radiological downgrading or pathological tumor regression; however, no large-scale multicenter RCT study has conducted a head-to-head comparison of the overall survival rate between perioperative or neoadjuvant chemotherapy(NAC) and postoperative or adjuvant chemotherapy(AC). We explored whether the five-year overall survival rate was greater in patients who received perioperative chemotherapy plus surgery than in those who underwent surgery first and then had postoperative chemotherapy. Methods: Altogether, 77 patients with a clinical diagnosis of cTNM stage III were included. Five-year overall survival rates (OS) were compared between patients who underwent neoadjuvant chemotherapy plus surgery (NAC) and patients who underwent surgery first plus adjuvant chemotherapy (AC). Propensity score matching was applied to adjust for the disparity between the two groups. A Kaplan‒Meier plot was created for survival analysis, and the log rank method was used to compare the difference in OS. Results: A total of 34 patients were in the NAC group, and 43 patients were in the AC group. There was no significant difference in age (median 64 vs. 66 years), cTNM staging, or extent of gastrectomy between the two groups (p0.05). There was no significant difference in the severity grading of postoperative complications between the two groups (p>0.05). Conclusions: There was no significant difference in the five-year overall survival rate between the patients who underwent perioperative chemotherapy plus surgery and those who underwent surgery first plus postoperative chemotherapy. A well-controlled prospective study is necessary to reconfirm whether perioperative chemotherapy is superior to postoperative chemotherapy for gastric cancer patients.

Background. This paper investigates whether or not there are some preoperative predictors identifying lymph node metastasis (LNM) in patients with T1b gastric cancer and discusses the possibility of replacement by segmental gastrectomy (SG) or local gastrectomy (LG). Methods. This study included patients with gastric cancer who underwent radical gastrectomy between January 2012 and December 2018, as well as those diagnosed with pT1b. Independent risk factors of lymph node metastasis were determined using univariate and multivariable logistics regression among clinicopathological characteristics. ROC curve was established to predict lymph node metastasis based on external data for validation. Results. Among the 636 patients with pT1b gastric cancer as the internal training set, 168 (26.4%) had no lymph node metastasis. In addition, 3 cm or less in size (odds ratio [OR] 0.56, PConclusions. Based on this retrospective study, T1b gastric cancer of the middle part of the stomach which is 3 cm or less in size, differentiated-type, negative HER2 status, and without lymphatic-vascular invasion might indicate pylorus-preserving gastrectomy due to lack of lymph node involvement. Trial registration. The study is retrospectively registered.

BackgroundDespite the lack of decisive research advocating neoadjuvant chemotherapy there is a broad consensus that it is beneficial for gastric cancer in terms of survival. However, there is no comparative research on whether it is similarly helpful in senile patients with the age above 75 years old. Here we compared the survival rate between neoadjuvant plus surgery with Direct Surgery.MethodsWe analyzed 79 patients with locally advanced gastric cancer who were preoperatively suspicious of serosa positive or beyond (cT4a or cT4b); or extensive lymph node involvement (cN3). Postoperative complications and overall survival rate were compared between the patients who underwent neoadjuvant chemotherapy (NAC) plus surgery and the patients who had direct surgery.ResultsA total of 15 (19%) patients underwent neoadjuvant chemotherapy and 64 (81%) patients had direct surgery. The median follow-up time was 34 months (range of 24-60 months). While the median survival time was not reached in the direct surgery group, the median survival time for the NAC plus Surgery Group was 37 months. Two years of overall survival (OS) for the patients in the NAC plus Surgery group and direct surgery group were 53.3% and 70.3% respectively. There was no statistical difference between the two groups (p>0.05) in overall postoperative complication and length of postoperative stay.ConclusionsReduced does of neoadjuvant chemotherapy was feasible in senile patients. There was no difference in survival rate between the patients who had neoadjuvant plus surgery compared to those who had direct surgery. While this result contradicts the previous assumption that neoadjuvant chemotherapy is beneficial for late-stage gastric cancer patients, a well-controlled prospective study is mandatory for a better understanding of whether neoadjuvant chemotherapy is beneficial to senile patients too.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1–T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1–T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1–T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov)

Objective: To quantify the potential benefit of adjuvant chemotherapy (ACT) with respect to survival, and to identify factors for predicting prognoses in early gastric cancer patients. Methods: Patients with pT1 gastric cancer (GC) who underwent radical resection with D2 lymphadenectomy were retrospectively analyzed. Based on lymph node metastasis (LNM) status and treatment regimens, patients were classified into groups, and clinicopathological variables, overall survival (OS), and disease-specific survival (DSS) were compared. Results: Of 1,050 enrolled patients, 151 patients (14.4%) had a positive LNM status. Submucosal invasion, undifferentiated state, tumor size > 2 cm, ulceration, and lymphovascular invasion were independent risk factors for LNM using multivariate analyses. The 5-year OS of all patients was 96.4%. HER2 positive, perineural invasion, and LNM were independent factors for worse survival. Patients with pT1N3 GC had a worse 5-year OS and DSS than pT1N0, pT1N1, and pT1N2 patients (P < 0.001). The 5-year OS and DSS for pT1N1 patients showed no significant difference between ACT and surgery only patients. For pT1N2 patients, the 5-year OS and DSS showed no significant difference between S-1 and Xelox treatments. For pT1N3 patients, 7 (36.8%) received S-1, while 12 (63.2%) received Xelox treatment. Patients receiving Xelox treatment showed a better 5-year OS (75.0% vs. 14.3%) and DSS (81.8% vs. 20.0%) than patients receiving S-1 (P < 0.05). Conclusions: Curative surgery only was adequate for patients with pT1N0 and pT1N1. Xelox showed no survival benefits for pT1N2 patients. Therefore, S-1 is the optimal choice for pT1N2 patients, when considering adverse effects. Xelox is recommended for pT1N3 patients.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with median survival of less than one year and overall 5-year survival less than 5%. Gemcitabine has been the cornerstone in PDA treatment, yet its efficacy remains limited. Over the past decades, extensive investigations suggested a role of tumor microenvironment (TME) in rendering PDA resistance to gemcitabine, however, its underlying mechanism remained largely unknown. Cellular profiling has revealed the macrophages as a major immune cell component of PDA-TME. Our recent study showed that the expression of the homeobox protein VentX, a master regulator of macrophage plasticity, is significantly down-regulated in tumor associated macrophages (TAMs) of PDA. We demonstrated that restoration of VentX expression in PDA-TAMs polarizes the TAMs from a pro-tumor M2-like phenotype to an anti-tumor M1-like phenotype. We showed further that VentX-regulated-TAMs (VentX-TAMs) revert immune suppression of PDA-TME by inhibiting CD4 Treg differentiation and by promoting CD8 proliferation and activation. Using a newly developed tumor immune microenvironment-enabling model system (TIME-EMS), we showed that VentX-TAMs drastically promote efficacy of gemcitabine against PDA for about 4-fold but not cytotoxicity on normal pancreatic tissue. As such, our data suggested a function of VentX-TAMs to promote chemosensitivity of gemcitabine and to improve PDA prognosis. Citation Format: Joanna Le, Hong Gao, Yi Le, William Richards, Scott Radig, Ronald Bleday, Thomas Clancy, Zhenglun Zhu. VentX-modulated tumor associated macrophages revert immune suppression in tumor microenvironment and promote efficacy of gemcitabine against pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5111.

Introduction Gastric cancer (GC) is a common malignant tumor with a high mortality rate. Aim To determine the accuracy of preoperative imaging information obtained from the combined use of general gastroscopy (GS), endoscopic ultrasonography (EUS), and multi-detector computed tomography (MDCT) regarding absolute indication of endoscopic submucosal dissection (ESD) in early gastric cancer (EGC). Material and methods The relationship between clinical features of 794 EGC patients and lymph node metastasis (LNM) was analyzed. Multivariate logistic regression analysis was used to investigate the risk factors for LNM. Additionally, the accuracy of diagnosis of imaging techniques for ESD indications was determined by receiver operating characteristic (ROC) analysis. Results Data showed that tumor size > 2 cm (p = 0.0071), T1b stage (p < 0.0001), undifferentiated histology (p < 0.0001), and vascular invasion (p = 0.0007) were independent risk factors for LNM in patients with EGC. Indications for ESD have a specificity of 100% for the diagnosis of patients with LNM. Additionally, the diagnostic efficacy of the use of GS, EUS, and MDCT in identifying node positive status, T1a disease, tumor size ≤ 2 cm, and ulceration was found to be moderate with area under the curve (AUC) of receiver operating characteristic curve (ROC) of 0.71, 0.64, 0.72, and 0.68, respectively. Furthermore, the use of imaging techniques for overall indication criteria for ESD had a moderate utility value with an AUC of 0.71. Conclusions Our data suggested that, based on the combined use of GS, EUS, and MDCT, a high specificity of patient selection for ESD treatment can be achieved.

Gastric cancer (GC) is one of the most common and lethal malignancies worldwide, and its poor prognosis is mainly due to the rapid tumor progression including tumor invasion, distant metastasis, etc. Understanding the molecular mechanisms regulating GC progression lays the basis for the development of targeted therapeutic agents. Increasing evidence suggests that guanine nucleotide-binding protein subunit beta-4 (GNB4), a key subunit of heterotrimeric G protein, plays a crucial role in the initiation and progression of multiple malignancies. However, whether and how GNB4 promotes GC progression are still unknown. In this study, we found that GNB4 was highly expressed in GC tissues compared to that in non-tumor tissues and was significantly associated with tumor invasion depth, pathological stage and poor survival rate of GC patients. Both gain-of-function and loss-of-function studies revealed that GNB4 significantly enhanced GC cell growth and motility both in vitro and in vivo. Further studies revealed that GNB4 overexpression induced G1-S transition and promoted the process of epithelial-mesenchymal transformation. These tumor promoting effects were mediated by GNB4 which activates the Erk1/2 pathway through upregulating Erk1/2 phosphorylation, as U0126, an Erk1/2 phosphorylation inhibitor, could significantly inhibit GNB4-mediated cell proliferation, migration and invasion. In summary, GNB4 contributes to the proliferation and metastasis of GC cells by activating the Erk1/2 signaling pathway, and it may serve as a potential therapeutic target of GC.

The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/mOf 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

Summary: Background: Endoscopic submucosal dissection (ESD) has gained more popularity in the treatment of early gastric cancer (EGC). Although there is a lack of confirmed evidence for the feasibility of ESD for undifferentiated EGC. The aim of the study was to investigate the feasibility of ESD with expanded indications for undifferentiated EGC patients. Methods: Data from patients with undifferentiated EGC (including signet-ring cell carcinoma, mucinous adenocarcinoma, mixed adenocarcinoma, and poorly differentiated adenocarcinoma) who underwent radical surgical resection were retrospectively reviewed. The relationship between the clinical parameters and the incidence of lymph node metastasis (LNM) was investigated. Results: A total of 517 patients were included in this study. The results showed that LNM was significantly associated with ulceration, tumor size, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate stepwise logistic regression analysis revealed that tumor size (OR = 1.61, 95% CI = 1.03–2.52, P = 0.0367), depth of tumor invasion (OR = 2.77, 95% CI = 1.66–4.63, P = 0.0001), and lymphatic invasion (OR = 14.74, 95% CI = 1.58–137.36, P = 0.0182) were independent risk factors for LNM. In the patients who would be included under the new proposed guidelines for ESD, including men with mucosal tumors ≤2 cm and without ulceration or lymphatic or venous infiltration, LNM was present in 11.9% (14/118). Conclusion: Caution to be exercised in expanding application of ESD should be carefully weighed in undifferentiated EGC. Keywords: Early gastric cancer, Endoscopic submucosal dissection, Expanded indication, Lymph node metastasis

Objective Intraperitoneal (IP) chemotherapy through subcutaneous port is an effective treatment for gastric cancer (GC) patients with peritoneal metastasis (PM). The objective of this study is to assess the port complications and risk factors for complications in GC patients with PM. Methods In retrospective screening of 301 patients with subcutaneous ports implantation, 249 GC patients with PM who received IP chemotherapy were screened out for analysis. Port complications and risk factors for complications were analyzed. Results Of the 249 analyzed patients, 57 (22.9%) experienced port complications. Subcutaneous liquid accumulation (42.1%) and infection (28.1%) were the main complications, and other complications included port rotation (14.1%), wound dehiscence (12.3%), inflow obstruction (1.7%) and subcutaneous metastasis (1.7%). The median interval between port implantation and occurrence of complications was 3.0 months. Eastern Cooperative Oncology Group (ECOG) performance status [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.12−2.69], albumin (OR, 3.67; 95% CI, 1.96−6.86), implantation procedure optimization (OR, 0.33; 95% CI, 0.18−0.61) and implantation groups (OR, 0.37; 95% CI, 0.20−0.69) were independent risk factors for port complications (P

Background: There is no global consensus on adjuvant chemotherapy (ACT) for pT2N0M0 gastric cancer. We conducted a retrospective study to reveal the role of ACT in such patients.Methods: Patients with pT2N0M0 gastric cancer who underwent radical resection with D2 lymphadenectomy for primary gastric cancer between January 2012 and May 2016 were included. Kaplan–Meier and Cox regression were used to evaluate overall survival (OS), disease-specific survival (DSS) and predictors of prognosis. Stratified analysis based on high-risk factors was conducted.Results: Of enrolled 307 patients, 111 patients underwent surgery alone and 196 patients received ACT. Surgery alone (HR = 2.913, 95% CI: 1.494-5.682, p = 0.002) and total gastrectomy (HR = 2.445, 95% CI: 1.279-4.675, p = 0.007) were independently associated with decreased OS. With the median follow-up of 73.1 months, the 5-year OS rate was 87.9% and 5-year DSS rate was 91.8%. Patients receiving ACT showed a better 5-year OS rate (92.9 vs. 79.3%, p < 0.001) and DSS rate (96.8 vs. 83.0%, p < 0.001) than patients underwent surgery alone. Patients receiving monotherapy (n = 130) had a relatively poor prognosis compared to patients receiving dual-drug (n = 66) without a significant difference (92.3 vs. 93.9%, p = 0.637). In patients without high-risk factors based on the Chinese Society of Clinical Oncology (CSCO) Guidelines, ACT also provided survival benefit (96.0 vs 82.9%, p = 0.038).Conclusions: ACT was accompanied with higher 5-year OS and DSS rates of patients with pT2N0M0 gastric cancer. Patients with pT2N0M0 gastric cancer, regardless of high-risk factors based on the CSCO guidelines, might be considered candidates for ACT. In regard to the therapy regimen, monotherapy might be the optimal choice, considering the adverse events.

The prognosis of stage III gastric cancer (GC) is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and efficacy of sintilimab in GC. A combination of Nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. The aim of this article is to describe the design of this prospective Dragon-VII trial, conducted to evaluate the safety and efficacy of the combination of Nab-PTX, S-1 and sintilimab.Lay abstract The prognosis of stage IIIC gastric cancer is poor and the treatment for it is not satisfying. This is a clinical trial that aims to explore a more effective therapy in gastric cancer patients of stage IIIC. Patients with stage IIIC gastric cancer must meet all of the inclusion criteria and none of the exclusion criteria to be eligible for this trial. The eligible patients will be given eight cycles of combinatory therapy of albumin-bound paclitaxel, a chemotherapy (day 1 and day 8), and S-1, another chemotherapy (days 1 to 14), plus sintilimab, a type of immunotherapy called an immune checkpoint inhibitor (day 1) every 3 weeks and then sintilimab maintenance for up to 12 months.

BackgroundFor gastric cancer (GC) with extensive lymph node metastasis (bulky N2 and/or para-aortic lymph node metastases), there is no standard therapy worldwide. In Japan, preoperative chemotherapy (PCT) followed by D2 gastrectomy plus para-aortic lymph node dissection (PAND) is considered the standard treatment for these patients. However, in China, the standard operation for GC patients with only bulky N2 metastases was D2 gastrectomy. Besides, after PCT, whether doing PAND improves survival or not is debatable for GC patients with para-aortic lymph node (PAN) metastases. Therefore, we conducted this study to investigate whether D2 lymphadenectomy alone is suitable for these patients after PCT.MethodsWe retrospectively collected data on patients from our electronic medical record system. GC patients with bulky N2 and/or PAN metastases who underwent D2 lymphadenectomy alone after PCT were enrolled. The survival outcomes and chemotherapy responses were analyzed and compared with the results of the JCOG0405 study.ResultsFrom May 2009 to December 2017, a total of 83 patients met all eligibility criteria and were enrolled. The median survival duration for all patients was 40.0 months. The 3-year and 5-year OS rates for all patients were 50.3% and 45.6%, respectively. For patients with only bulky N2 metastasis, the 3-year and 5-year OS rates were 77.1% and 71.6%, respectively, which were similar to the results of the JCOG0405 study (82.7% and 73.4%). For patients with only PAN metastases, the 3-year and 5-year OS rates were 50.0% and 50.0%, respectively, which seemed to be lower than those of the JCOG0405 study (64.3% and 57.1%). For patients with bulky N2 and PAN metastases, the 3-year and 5-year OS rates were 7.4% and 0.0%, respectively, which were lower than those of the JCOG0405 study (20.0% and 20.0%).ConclusionThe results of our study suggest that D2 lymphadenectomy alone is suitable for GC patients with only bulky N2 metastasis after PCT. However, D2 lymphadenectomy alone perhaps is not suitable for patients with bulky N2 and PAN metastases after PCT.

BackgroundFor locally advanced gastric cancer (LAGC) with serosal invasion (cT4NxM0), adjuvant chemotherapy (AC) after D2 gastrectomy is the standard therapy in Asia. However, perioperative chemotherapy (PCT) combined with D2 gastrectomy is mostly suggested in Europe and America. As a part of PCT, the value of neoadjuvant chemotherapy (NAC) is unclear. We investigated whether NAC could further improve survival and other outcomes for these patients.MethodsPatients with cT4NxM0 gastric cancer who underwent D2 gastrectomy were analyzed. The patients were divided into two groups based on whether they received NAC: the neoadjuvant chemotherapy (NAC) and direct surgery (S) groups. After propensity score matching (1:1 ratio), survival and perioperative outcomes were analyzed between the two groups.ResultsA total of 902 patients met all the eligibility criteria and were enrolled. After propensity score matching, 221 matched pairs of patients were identified. The median overall survival (OS) and disease-free survival (DFS) of all patients were 75.10 and 43.67 months, respectively. The median OS of patients in the NAC and S groups were undefined and 29.80 months, respectively (PConclusionThis study suggested NAC can further improve prognosis and prevent recurrence in LAGC (cT4NxM0) patients. NAC is feasible and safe for LAGC (cT4NxM0) patients, and does not increase the risk of perioperative surgery.

BackgroundPreoperative chemotherapy (PCT) has been considered an important treatment for advanced gastric cancer (AGC). The tumor regression grade (TRG) system is an effective tool for the assessment of patient responses to PCT. Pathological complete response (TRG = 0) of the primary tumor is an excellent predictor of better prognosis. However, which patients could achieve pathological complete response (TRG = 0) after chemotherapy is still unknown. The study aimed to find predictors of TRG = 0 in AGC.MethodsA total of 304 patients with advanced gastric cancer from July 2009 to November 2018 were enrolled retrospectively. All patients were randomly assigned (2:1) to training and internal validation groups. In addition, 124 AGC patients receiving PCT from December 2018 to June 2020 were included prospectively in the external validation cohort. A prediction model for TRG = 0 was established based on four predictors in the training group and was validated in the internal and external validation groups.ResultsThrough univariate and multivariate analyses, we found that CA199, CA724, tumor differentiation and short axis of the largest regional lymph node (LNmax) were independent predictors of TRG = 0. Based on the four predictors, we established a prediction model for TRG = 0. The AUC values of the prediction model in the training, internal and external validation groups were 0.84, 0.73 and 0.82, respectively.ConclusionsWe found that CA199, CA724, tumor differentiation and LNmax were associated with pathological response in advanced gastric cancer. The prediction model could provide guidance for clinical work.

Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer., Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.

Background: Neoadjuvant chemotherapy (NAC) plays an important role in the therapeutic strategy of locally advanced gastric cancer (LAGC). However, the response of LAGC after NAC varies among different patients. The objective response after NAC has proven to be an excellent indicator for benefiting from NAC, yet effective predictors of objective response are still lacking. The present study aimed to identify potential predictors of objective response in LAGC patients treated with NAC. Methods: Clinicopathological data from 267 patients with LAGC who received NAC and met the inclusion criteria between July 2009 and December 2018 were retrospectively reviewed. Patients were randomly divided into the training and test sets at a 2:1 ratio. Univariate analysis was used to investigate whether any factors were correlated with objective response in the training set. Multivariate logistic regression analysis was applied to find independent predictors. A risk score model was then constructed based on the independent predictors, and its performance in predicting objective response was validated in the test set. Results: Univariate analysis found that gender, age, short axis diameter of the largest regional lymph node (LN(max)), serum total protein content, CEA detection value, tumor location, tumor differentiation, signet ring cell carcinoma component and Borrmann type were potential predictors for objective response. In multivariate logistic regression analysis, gender, LN(max) and signet ring cell carcinoma component were independent predictors for objective response. Based on independent predictors, we developed a prediction model for objective response. Conclusions: We found gender, LN(max) and signet ring cell carcinoma component were independent predictors for objective response. The prediction model is a good tool to predict the objective response for LAGC patients treated with NAC, which can be applied to guide clinical practice.

Background: Despite of growing trends there is no consensus on types of drug for neoadjuvant chemotherapy in gastric cancer, especially between East and West. Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil and Leucovorin (FLOT) regimen has showed promising results in terms of pathological response and survival rate. However, S1 or TGO plus oxaliplatin (SOX) is more favorable chemotherapy regimen in eastern countries. We conducted this study to evaluate the safety and efficacy of both regimens. Methods: This is a prospective, open label, randomized controlled trial. Patients with locally advanced gastric cancer were 1：1 randomized to FLOT or SOX group. Patients in FLOT group received 4 cycles of FLOT chemotherapy and the patients in SOX group received 3 cycles of TGO plus oxaliplatin prior to curative gastrectomy. The primary endpoint was the comparison of complete or sub-total tumor regression grading (TRG1a+ TRG1b) in the primary tumour. Results: Altogether 74 cases enrolled between August 2018 and March 2020, all 74 randomly assigned cases were considered as intention-to-treat (ITT) population and the 55 patients who completed the planned chemotherapy and surgery were considered as per protocol (PP) population. There was no significant difference in pre-treatment clinical parameters between two groups (p>0.05). There was no significant difference of adverse effects or postoperative morbidity and mortality between two groups (p>0.05). Similarly, there was no significant difference in proportion of tumor regression grading between two groups (p>0.05). In ITT population, complete or sub-total TRG was 20.0 percent in FLOT versus 32.4 percent in SOX group (p>0.05). Conclusions: Our study demonstrates that FLOT and SOX regimens were safe in terms of toxicity and postoperative morbidity. Both regimens were similarly effective for gastric cancer patients in terms of pathological response. A large scale phase 3 randomized controlled trial is necessary for the validation of this result.

Background Helicobacter pylori (H. pylori) is recognized as the most evident etiologic factor of infection-related gastric cancer (GC) and its involvement in GC initiation and progression has been well investigated. However, only a limited number of studies were performed to identify prognostic biomarkers and evaluate their clinical significance in GC patients infected with H. pylori. This study was conducted to investigate the clinical significance as well as its potential prognostic value of GNB4 in H. pylori-positive GC patients receiving standard treatment. Methods Retrospective statistical analysis was performed on 448 H. pylori-positive GC patients, with 137 early gastric cancer (EGC) patients undergoing radical gastrectomy alone and 311 advanced gastric cancer (AGC) patients receiving the same surgical procedure followed by fluorouracil-based chemotherapy. GNB4 expression was detected by immunohistochemistry staining on patient samples. H. pylori infection was routinely examined on endoscopic biopsy and/or surgical specimen of GC patients. Results High expression of GNB4 was 65.7% (90/137) in EGC and 62.7% (195/311) in AGC patients infected with H. pylori, respectively. In EGC patients, GNB4 expression was not associated with either clinicopathological parameters or 5-year overall survival (OS). In AGC patients however, high expression of GNB4 was significantly associated with patient’s pathological stage (P=0.047). Univariate analysis showed that tumor invasion depth (P=0.001), lymph node metastasis (P

Immune suppression in the tumor microenvironment (TME) is a central obstacle to effective immunotherapy. Tumor-associated macrophages (TAMs) are key components of the TME. Although TAMs have been viewed as an ideal target of intervention to steer immunity in cancer treatment, the approach has been hampered by the lack of knowledge of how TAM plasticity is controlled by cell intrinsic factors. VentX is a homeobox protein implicated in proliferation and differentiation of human hematopoietic and immune cells. Using clinical samples obtained from cancer patients, we find that VentX expression is drastically reduced in TAMs. We show here that VentX promotes M1 differentiation of TAMs, and that VentX-regulated TAMs, in turn, revert immune suppression at the TME. Using a NSG mouse model of human colon cancers, we demonstrate that VentX regulates TAM function in tumorigenesis in vivo. Our findings suggest a mechanism underlying immune suppression at TME and potential applications of VentX-regulated TAMs in cancer immunotherapy., Tumour associated macrophages (TAMs) polarize into either pro-tumor or anti-tumor phenotypes. Here the authors show that the homeobox protein VentX is downregulated in clinical samples of colorectal cancer and regulates TAMs plasticity with its forced re-expression converting TAMs into an anti-tumor phenotype.

BACKGROUND: Ovarian metastasis following radical gastrectomy, also known as metachronous ovarian metastasis (MOM), pose a significant threat to the long-term survival of female gastric cancer (GC) patients. However, a mechanism to identify and characterize operated patients at high risk of developing MOM remains unknown. This retrospective study aimed to identify risk factors for the occurrence of MOM based on the profiling of clinicopathological parameters and expression of sex hormone receptors (SHR) of operated GC patients with and without ovarian relapse. METHODS: The clinicopathological data of 1,055 female GC patients from two medical centers who underwent surgery between January 2011 and December 2015 were reviewed. A total of 378 patients with and without the occurrence of MOM met the eligibility criteria, including the availability of medical records, adequacy of lymph node dissection, completeness of clinicopathological data, sufficient follow-up time, and no administration of neoadjuvant chemotherapy were selected for further analysis. Expressions of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and progesterone receptor (PR) were detected by immunohistochemical staining on the surgical specimens of patients, and retrospective statistical analyses identified independent risk factors for the occurrence of MOM. A risk prediction model in the format of a polygenic hazard score (PHS) for the occurrence of MOM was established by introducing and modifying the previously validated polygenic risk score (PRS)/PHS. RESULTS: A Cox regression-based multivariate analysis identified premenopausal with an HR of 3.15 (95% CI, 1.66–5.98), more advanced pathological T stage with an HR of 3.79 (95% CI, 2.14–6.69), more advanced pathological N stage with an HR of 1.85 (95% CI, 1.35–2.54), and negative expression of ERβ with an HR of 0.33 (95% CI, 0.15–0.7) as independent risk factors for the occurrence of MOM (P

Background To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study. Method Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored. Results Faster recovery of bowel function (43 ± 5 h vs 68 ± 7, P P P > 0.05). The 3 year DFS rate analysis showed that the prophylactic HIPEC group had a higher DFS rate (93% vs 65%, P = 0.0054). The peritoneal recurrence rate was lower in the HIPEC group (3% vs 23%, P Conclusion Prophylactic HIPEC with radical D2 Gastrectomy improves survival and peritoneal recurrence rates for AGC with favorable post-operative recovery at low and acceptable morbidity.

// Hong Gao 1, 2, * , Bin Wu 1, 3, * , Yi Le 1 , Zhenglun Zhu 1 1 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA 2 Current address: Department of Medicine, Tufts Medical Center, Boston, 02115, Massachusetts, USA 3 Current address: Department of Gastroenterology, Third Hospital, Sun Yat-Sen University, Guangzhou, 510630, China * These authors contributed equally to this work Correspondence to: Zhenglun Zhu, e-mail: zzhu@partners.org Keywords: ventX, apoptosis, p53, caspase-3, PARP Received: December 18, 2015 Accepted: April 24, 2016 Published: May 09, 2016 ABSTRACT Identifying novel tumor suppressors holds promise for improving cancer treatment. Our recent studies identified VentX, a homeobox transcriptional factor, as a putative tumor suppressor. Here we demonstrate that VentX exerts strong inhibitory effects on the proliferation and survival of cancer cells, but not primary transformed cells, such as 293T cells. Mechanistically, both in vitro and in vivo data showed that VentX induces apoptosis of cancer cells in a p53-independent manner. We found that VentX expression can be induced by chemotherapeutic agents. Taken together, our findings suggest that VentX may function as a novel therapeutic target in cancer treatment.

BACKGROUND: Endoscopic submucosal dissection (ESD) has increasingly gained broad application in the treatment of early gastric cancer (EGC). This study aimed at evaluating the clinical significance of lymph node metastasis (LNM) in patients with ulcer positive [UL (+)] EGC and assessing the feasibility of expanded indications of ESD for such cases. METHODS: Patients with UL (+) EGC undergoing radical surgical resection between January 2012 and December 2018 were retrospectively reviewed. Associations between clinicopathological factors and the incidence of LNM were investigated by univariate and multivariate linear regression analysis. RESULTS: Retrospective statistical analysis was performed on 653 EGC patients. The multivariate linear regression analysis showed that the presence of LNM was significantly associated with depth of invasion (P

Background/aims Aberrant expression of miR-106b is a specific symptom of many solid carcinomas. Overexpression of miR-106b has been observed in gastric cancer. The effect of miR-106b on gastric cancer has been investigated in different cell culture models. However, the effect of miR-106b on metastasis of early gastric cancer (EGC) remains unknown. Methods In the study, qRT-PCR, FISH, western blot, luciferase reporter assay, migration and invasion assays, flow cytometry and TUNEL staining were used to investigate the effect of miR-106b on metastasis of EGC. Results To explore the function of miR-106b in EGC, we investigated the downstream signaling of miR-106b and found that ALEX1 was a direct target of miR-106 in gastric cancer cells. Up-regulation of ALEX1 effectively rescued the cell apoptosis induced by miR-106b inhibitor and promoted the expression levels of phosphorylation of JAK1 and STAT3. Moreover, overexpression of JAK1 reduced the cell apoptosis induced by miR-106b inhibitor and decreased the expression levels of the apoptotic proteins in gastric cancer cells. Furthermore, down-regulation of miR-106b promoted apoptosis of gastric cancer cells via inhibiting JAK1/STAT3 signaling pathway in vitro and in vivo. In addition, GLPG0643, a JAK1 inhibitor, enhanced the inhibitory effect of miR-106b inhibitor on gastric cancer growth in vivo. Conclusion These findings provided a potential therapeutic manner for the treatment of metastasis of EGC in clinic.

The dorsal cell fate determination factor β-catenin and its antagonist, the ventral cell fate determination factor Xom, are expressed and distributed in a polarized fashion during early vertebrate embryogenesis. Ubiquitin-mediated proteolysis has been shown to control the abundance of both β-catenin and Xom. However, the mechanism of ubiquitin-mediated proteolysis in regulating dorsoventral patterning remains largely unclear. Our current study shows that Xom induces proteolysis of β-catenin through GSK3-mediated phosphorylation of Ser33/37 of β-catenin. Our findings reveal a novel pathway that regulates β-catenin stability, and suggest, for the first time, a critical function of ubiquitin-mediated proteolysis in balancing the integration of dorsal-ventral signals and the polarized distribution of β-catenin and Xom during dorsoventral axis formation.

Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression.

Dendritic cells (DCs) are specialized antigen presentation cells that play critical roles in the initiation and regulation of immune responses. The molecular determinants of DC differentiation and maturation are target of extensive investigation. VentX is a human homeobox transcriptional factor that regulates proliferation and differentiation of hematopoietic cells. In the current study, we report that ablation of VentX expression in monocytes significantly impaired their differentiation into DCs. Conversely, overexpression of VentX in monocytic THP1 cells accelerated their differentiation toward DCs. We showed that VentX regulates DC differentiation, in part, through modulating IL6 expression. Clinically, we found that VentX expression was elevated in intestinal lamina propria DCs (LPDCs) of inflamed mucosa from inflammatory bowel disease patients. Knockdown experiments suggested that VentX is essential for the maturation of LPDCs. In addition, corticosteroid treatment markedly decreased VentX expression in LPDCs and enforced expression of VentX counteracted the effects of corticosteroid on DCs maturation. Our data suggest that VentX is a critical transcriptional regulator of DC differentiation and maturation, and a potential target of immune regulation and therapy.

e15503 Background: Locally advanced gastric cancer (LAGC) has a poor prognosis. Neoadjuvant chemotherapy can reduce tumor loading, degrade staging and increase possibility of complete resection, thus prolonging the survival of LAGC patients (pts). We conducted a phase II trial to assess the feasibility of SOX regimen in combination with apatinib (an anti-angiogenic agent) as neoadjuvant therapy in LAGC. Methods: This study recruited untreated LAGC pts with pathologically and/or cytologically confirmed adenocarcinoma. Treatment included three 21-day cycles of apatinib (oral, 500 mg qd; discontinued in the last cycle), S-1 (oral, 40-60 mg, bid, day 1-day 14) and oxaliplatin (iv, 130 mg/m2, day 1), followed by radical surgery after 4 weeks. The primary outcome was neoadjuvant therapy related toxicity, and the secondary outcomes included tumor response, R0 resection rate, postoperative pathological evaluation and surgical morbidity. Results: Between December 2, 2016 and August 1, 2018, 31 patients were enrolled. Total 29 patients were eligible for safety and efficacy analyses of SOXA as NAC. During NAC treatment, the incidence of adverse events (AEs, any grade) was 100%, and the incidence of grade 3/4 AEs was 34.48%. No treatment-related death. The ORR of 79.31% (95%CI, 60.28-92.01%) and DCR of 96.55% (95%CI, 82.24-99.91%) were achieved. One patient was evaluated as PD with hepatic metastasis after 3 cycles of preoperative chemotherapy, and this case was inoperable. Resection with curative intent was undertaken in 28 patients with R0 resection rate of 100%. Operative morbidity was observed in 12 of 28 patients including fever (9, 32.14%), anastomotic leakage (1, 3.57%), fat liquefaction of post-surgical incision (1, 3.57%), and gastroparesis (1, 3.57%). Additionally, after surgery 1 patient had pulmonary infection and 1 patient had pleural effusion. The median tumor regression was 90% on pathological findings after surgery. Conclusions: Neoadjuvant therapy with apatinib plus SOX for LAGC showed acceptable toxicity and promising efficacy.

To investigate the clinicopathological features and postoperative short-term complications in the elderly gastric cancer patients.Clinical data of 270 elderly patients with gastric cancer who underwent gastrectomy in Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine between July 2012 and June 2014 were analyzed retrospectively. Among 270 patients, 220 were 70 to 79 years old( old group) and 50 were ≥80 years old(oldest group). The clinicopathological features were compared between the two groups. Perioperative factors were analyzed to determine if they are associated with postoperative complications. Multivariate logistic regression model was performed.Before operation, most elderly patients (n=161, 59.6%) had 2 or more than 2 comorbidities, including hypertension (n=154, 57.0%), anaemia (n=126, 46.7%), diabetes (n=53, 19.6%), arhythmia (n=52, 19.3%), cardiovascular disease(n=33, 12.2%), and chronic pulmonary disease(n=28, 10.4%). Elderly gastric cancers were more likely to locate at the lower third of the stomach (n=116, 43.0%). The pathological type was mainly the poorly differentiated carcinoma (n=152, 56.3%), and stage III was more common in TNM staging(n=138, 51.1%). As compared to the old group, the oldest group had more preoperative comorbid diseases(P=0.048), more previous surgery(P=0.029), more preoperative transfusion (P=0.019), more combined cholecystectomy (P=0.007) and feeding jejunostomy (P=0.037), but less tumor invasion of nerves(P=0.045). No significant differences in other clinicopathological parameters were found between the two groups (all P0.05). A total of 121 (44.8%) patients presented postoperative complications, including severe complication in 30 cases(11.1%) and death in 4 cases(1.5%). Forty-seven patients(17.4%) presented operation-associated complications, including infection in 28 cases(10.4%) and leakage in 21 cases(7.8%). One hundred and seven(39.6%) patients presented non-operation-associated complications, including pneumonia in 48 cases(17.8%), hypertension in 23 cases(8.5%), and arhythmia in 17 cases(6.3%). Postoperative morbidities of Clavien-Dindo class II complication and non-operation-associated complication were higher in the oldest group compared with old group(P0.05), while other postoperative complications were compared between the two groups, only urinary tract infection was significantly different(P0.05). Univariate analysis showed that postoperative complications were significantly associated with age(χ(2)=7.308, P=0.007), number of comorbid diseases (χ(2)=10.872, P=0.001), cardiovascular disease (χ(2)=9.412, P=0.002), hypertension (χ(2)=4.934, P=0.026) and preoperative transfusion (χ(2)=3.911, P=0.048). Multivariate analysis showed that only the number of comorbid diseases was an independent risk factor for postoperative complications(OR=2.810, 95% CI: 1.710 to 4.616, P=0.000).Non-operation-associated postoperative complications are more likely to occur in the elderly patients due to more comorbid diseases. Perioperative intensive care should be carried out for the elderly gastric cancer patients with comorbid diseases in order to improve surgical safety and efficacy.