EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical (IHC) staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia induicible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

A prognostic marker LTBP1 is associated with epithelial mesenchymal transition and can promote the progression of gastric cancer.

LTBP1 is closely related to TGF-ß1 function as an essential component, which was unclear in gastric cancer (GC). Harbin Medical University (HMU)-GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined to form a training cohort to calculate the connection between LTBP1 mRNA expression, prognosis and clinicopathological features. The training cohort was also used to verify the biological function of LTBP1 and its relationship with immune microenvironment and chemosensitivity. In the tissue microarrays (TMAs), immunohistochemical (IHC) staining was performed to observe LTBP1 protein expression. The correlation between LTBP1 protein expression level and prognosis was also analyzed, and a nomogram model was constructed. Western blotting (WB) was used in cell lines to assess LTBP1 expression. Transwell assays and CCK-8 were employed to assess LTBP1's biological roles. In compared to normal gastric tissues, LTBP1 expression was upregulated in GC tissues, and high expression was linked to a bad prognosis for GC patients. Based on a gene enrichment analysis, LTBP1 was primarily enriched in the TGF-ß and EMT signaling pathways. Furthermore, high expression of LTBP1 in the tumor microenvironment was positively correlated with an immunosuppressive response. We also found that LTBP1 expression (p = 0.006) and metastatic lymph node ratio (p = 0.044) were independent prognostic risk factors for GC patients. The prognostic model combining LTBP1 expression and lymph node metastasis ratio reliably predicted the prognosis of GC patients. In vitro proliferation and invasion of MKN-45 GC cells were inhibited and their viability was decreased by LTBP1 knockout. LTBP1 plays an essential role in the development and progression of GC, and is a potential prognostic biomarker and therapeutic target for GC.

Development and Validation of Tumor Marker Indices in Advanced Gastric Cancer Patients.

BACKGROUND: Tumor markers (TMs) are important for the prognosis of gastric cancer (GC). However, the prognostic importance of the tumor marker index (TMI) based on GC-specific TMs for advanced gastric cancer (AGC) still needs to be further explored. METHODS: We retrospectively examined patients who underwent radical gastric cancer surgery between February 2014 and June 2016 at the Department of Gastroenterological Surgery, Affiliated Cancer Hospital, Harbin Medical University. The patients were divided into training and validation groups. TMI was determined as the geometric mean of the standard cancer antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels. Patient overall survival was assessed using the Kaplan-Meier method. Independent prognosis-associated risk factors were identified using Cox hazard regression models. A nomogram model incorporating TMI and clinicopathological factors was developed, and its performance was evaluated using a decision curve analysis, concordance index, and calibration plots. RESULTS: In the TMI training cohort, the cutoff value was set at .439, categorizing patients into TMI-High and TMI-Low groups. The 5-year survival rate in the TMI-Low group significantly surpassed that in the TMI-High group (78.2% vs 58.1% and 49.7 vs 41.6, P < .001). TMI emerged as an independent prognostic factor. The nomogram accurately predicted patient prognosis by using TMI and clinicopathological characteristics. Validation of the TMI in the independent cohort yielded satisfactory results. CONCLUSION: The TMI constructed based on specific TMs associated with gastric cancer can offer a precise prognostic prediction for patients.

Impact of AADAC gene expression on prognosis in patients with Borrmann type III advanced gastric cancer.

BACKGROUND: The prognosis of Borrmann type III advanced gastric cancer (AGC) is known to vary significantly among patients. This study aimed to determine which differentially expressed genes (DEGs) are directly related to the survival time of Borrmann type III AGC patients and to construct a prognostic model. METHODS: We selected 25 patients with Borrmann type III AGC who underwent radical gastrectomy. According to the difference in overall survival (OS), the patients were divided into group A (OS<1 year, n=11) and group B (OS>3 years, n=14). DEGs related to survival time in patients with Borrmann type III AGC were determined by mRNA sequencing. The prognosis and functional differences of DEGs in different populations were determined by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The expression of mRNA and protein in cell lines was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). Immunohistochemical (IHC) staining was used to detect protein expression in the paraffin-embedded tissues of 152 patients with Borrmann type III AGC who underwent radical gastrectomy. After survival analysis, nomograms were constructed to predict the prognosis of patients with Borrmann type III AGC. RESULTS: Arylacetamide deacetylase (AADAC) is a survival-related DEG in patients with Borrmann type III AGC. The higher the expression level of its mRNA and protein is, the better the prognosis of patients. Bioinformatics analysis found that AADAC showed significant differences in prognosis and function in European and American populations and Asian populations. In addition, the mRNA and protein expression levels of AADAC were high in differentiated gastric cancer (GC) cells. We also found that AADAC was an independent prognostic factor for patients with Borrmann type III AGC, and its high expression was significantly correlated with better OS and disease-free survival (DFS). Nomogram models of AADAC expression level combined with clinicopathological features can be used to predict the OS and DFS of Borrmann type III AGC. CONCLUSION: AADAC can be used as a biomarker to predict the prognosis of Borrmann type III AGC and has the potential to become a new therapeutic target for GC.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

ELF3-AS1 contributes to gastric cancer progression by binding to hnRNPK and induces thrombocytosis in peripheral blood.

Numerous studies have reported that a variety of long noncoding RNAs (lncRNAs) can promote the proliferation, invasion, and migration of different tumor cells. However, different lncRNAs regulate cell functions in various forms, and the exact mechanisms are not clear. Here, we investigated the effect of the lncRNA ELF3-AS1 on gastric cancer (GC) cell function and explored the exact mechanism. Quantitative real-time polymerase chain reaction was used to detect the expression of ELF3-AS1 in GC tissues and adjacent nontumor tissues. Knockdown and overexpression of ELF3-AS1 was used to detect the effect of ELF3-AS1 on cell function. Potential downstream target genes were identified using RNA transcriptome sequencing, while RNA immunoprecipitation, chromatin immunoprecipitation, and Western blotting were performed to explore the tumor promotion mechanisms of ELF3-AS1. We observed that ELF3-AS1 was highly expressed in GC tissues, and high ELF3-AS1 expression predicted poor prognosis. The knockdown of ELF3-AS1 significantly inhibited cell proliferation, migration, and epithelial-mesenchymal transition and promoted apoptosis. Mechanistic investigations revealed that ELF3-AS1 may regulate the downstream target gene, C-C motif chemokine 20, by binding with the RNA-binding protein hnRNPK. Additionally, we found that high ELF3-AS1 expression was associated with thrombocytosis. Interleukin-6 and thrombopoietin may be involved in ELF3-AS1-induced paraneoplastic thrombocytosis. Together, our results demonstrate that aberrantly expressed ELF3-AS1 in GC may play important roles in oncogenesis and progression and is expected to become a new target for the diagnosis and treatment of GC.

Association of ZNF331 and WIF1 methylation in peripheral blood leukocytes with the risk and prognosis of gastric cancer.

BACKGROUND: Peripheral blood leukocyte (PBL) DNA methylation may serve as a surrogate marker to evaluate the susceptibility to and prognosis of gastric cancer (GC). In this study, blood-derived DNA methylation levels of two tumour-related genes, namely, ZNF331 and WIF1, and their impacts on the risk and prognosis of GC were evaluated. METHODS: In total, 398 GC cases and 397 controls were recruited for the study. Then, all cases were followed up for 5 years. ZNF331 and WIF1 promoter methylation status in PBLs was measured using a methylation-sensitive high-resolution melting method. Logistic and Cox regression models were used to analyse the correlation between gene methylation and the risk and prognosis of GC. Confounders were balanced through propensity score (PS) matching. RESULTS: High ZNF331 methylation significantly decreased GC risk after PS adjustment (OR = 0.580, 95% CI: 0.375-0.898, P = 0.015), which also presented in males (OR = 0.577, 95% CI: 0.343-0.970, P = 0.038). However, WIF1 methylation was not associated with GC risk. Additionally, significant combined effects between ZNF331 methylation and the intake of green vegetables and garlic were observed (OR = 0.073, 95% CI: 0.027-0.196, P < 0.001 and OR = 0.138, 95% CI: 0.080-0.238, P < 0.001, respectively). Furthermore, ZNF331 and WIF1 methylation had no impact on the prognosis of GC. CONCLUSION: ZNF331 methylation in PBLs may affect GC risk in combination with the consumption of green vegetables and garlic and may act as a potential biomarker of GC.

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BACKGROUND: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer. METHODS: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety. DISCUSSION: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer. TRIAL REGISTRATION: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.

Proximal gastrectomy with gastric tube reconstruction or jejunal interposition reconstruction in upper-third gastric cancer: which offers better short-term surgical outcomes?

OBJECTIVE: Proximal gastrectomy acts as a function-preserving operation for upper-third gastric cancer. The aim of this study was to compare the short-term surgical outcomes between proximal gastrectomy with gastric tube reconstruction and proximal gastrectomy with jejunal interposition reconstruction in upper-third gastric cancer. METHODS: A retrospective review of 301 patients who underwent proximal gastrectomy with jejunal interposition (JI) or gastric tube (GT) at Harbin Medical University Cancer Hospital between June 2007 and December 2016 was performed. The Gastrointestinal Symptom Rating Scale (GSRS) and Visick grade were used to evaluate postgastrectomy syndromes. Gastrointestinal fiberoscopy was used to evaluate the prevalence and severity of reflux esophagitis based on the Los Angeles (LA) classification system. RESULTS: The JI group had a longer operation time than the GT group (220 ± 52 vs 182 ± 50 min), but no significant difference in blood loss was noted. Compared to the GT group, the Visick grade and GSRS score were significantly higher. Reflux esophagitis was significantly increased in the GT group compared with the JI group. CONCLUSION: Proximal gastrectomy is well tolerated with excellent short-term outcomes in patients with upper-third gastric cancer. Compared with GT construction, JI construction has clear functional advantages and may provide better quality of life for patients with upper-third gastric cancer.

CircPIP5K1A facilitates gastric cancer progression via miR-376c-3p/ZNF146 axis.

BACKGROUND: Recently, many emerging circular RNAs (circRNAs) have been studied in human malignancies, including gastric cancer (GC). Researches concerning cancers have revealed that aberrant expression of circRNAs play a big part in tumorigenesis and development of diverse malignant tumors. Although hsa_circ_0014130 (circPIP5K1A) has been confirmed to be closely related to non-small cell lung cancer (NSCLC) progression, the knowledge of its function on GC progression remains unclear. Therefore, it is of great interest to uncover the underlying role of circPIP5K1A in GC. METHODS: The expression and characteristic of circPIP5K1A were separately analyzed by RT-qPCR, nucleic acid electrophoresis, RNase R and Actinomycin D treatment. CCK-8, colony formation, EdU, transwell, TUNEL, flow cytometry, luciferase reporter, RIP and RNA pull-down assays were employed to testify the regulatory role of circPIP5K1A in GC. RESULTS: In current study, circPIP5K1A, featured with closed-loop structure, was proved to be highly expressed in tissues and cells of GC. Loss-of-function assays depicted that silencing circPIP5K1A suppressed GC development. Follow-up mechanism tests unveiled that circPIP5K1A bound with miR-376c-3p and inhibition of miR-376c-3p reversed circPIP5K1A downregulation-mediated effect on GC progression. Additionally, ZNF146 was verified to be the downstream molecule of circPIP5K1A/miR-376c-3p axis in modulating GC progression. CONCLUSIONS: circPIP5K1A stimulates GC progression by sponging miR-376c-3p to upregulate ZNF146 expression.

Comprehensive Analysis of the Relationship Between RAS and RAF Mutations and MSI Status of Colorectal Cancer in Northeastern China.

BACKGROUND/AIMS: Colorectal cancer (CRC) is mainly caused by chromosomal instability (CIN) and microsatellite instability (MSI). The RAS and RAF genes are essential components of the CIN pathway, and several studies have found that RAS and RAF mutations are associated with MSI status in CRC. Here, we examined these three factors in CRC in Northeast China and aimed to reveal new details of the relationship between these mutations and MSI status. METHODS: This study involved 290 patients with CRC who had RAS or RAF gene mutation detected using fluorescence-based allele-specific polymerase chain reaction or Sanger sequencing. The majority of the identified patients were found to harbor MSI (MSI status). Accurate molecular detection was carried out using formalin-fixed paraffin-embedded tissue or blood samples. RESULTS: The rates of RAS and RAF mutations were 58.5% and 4.1%, respectively. The prevalence of RAS mutation in CRC was clearly higher and that of RAF mutation was lower in Northeast China compared with previously reported cohorts in other locations. High MSI level (MSI-H status) was more complex, at around 10%. This was consistent with previous data from China. However, compared with data reported from other continents, MSI-H was higher than that of Japan or South Korea in Asia, and lower than that of Europe or the United States. CONCLUSION: RAS/RAF mutations and MSI status in CRC are closely associated with tumor location and ethnicity. Further studies investigating the relationship between these three factors can help in the development of treatment strategies for patients with CRC.

Evaluation of a multi-slice spiral computed tomography perfusion for the prediction of the recurrence of gastric cancer.

AIM: The study aimed to elucidate the value of multislice spiral computed tomography (MSCT) perfusion for the early prediction of gastric cancer (GC) recurrence. METHODS: MSCT perfusion scans were performed to obtain values pertaining to blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface (PS). Logistic regression analysis was employed to evaluate the risk factors of postoperative recurrence in GC. RESULTS: The maximum diameter of GC has a positive relationship with PS. The maximum enhancement of GC was positively correlated with BF, blood volume and PS. PS, BF, vascular thrombus and Tumor, Node, Metastasis staging were found to be significant risk factors in relation to the recurrence of GC (p = 0.006, p = 0.002, p < 0.001). CONCLUSION: MSCT perfusion is strongly correlated with postoperative recurrence of GC, and PS and BF values, vascular thrombus and Tumor, Node, Metastasis staging were discovered as being prominent factors influencing the recurrence of GC.

Relationships of MMP-9, E-cadherin, and VEGF expression with clinicopathological features and response to chemosensitivity in gastric cancer.

The matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor play an important role in behavior of tumor cell growth, invasion, and metastasis. In this study, we investigated the relationships of matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor expression with clinicopathological features and results of chemosensitivity tested by collagen gel droplet-embedded culture-drug sensitivity test in gastric cancer. Fresh specimens were used for collagen gel droplet-embedded culture-drug sensitivity test and paired fixed specimens were used for immunohistochemistry. Positive expression of matrix metalloproteinase-9 was associated with poorly differentiated carcinoma (p = 0.032), lymph node metastasis (p = 0.022), and tumor stage (p = 0.023). Negative expression of E-cadherin was associated with poorly differentiated carcinoma (p = 0.007), lymph node metastasis (p = 0.012), and tumor stage (p = 0.007). Positive expression of vascular endothelial growth factor was associated with tumor size (p = 0.040) and stage (p = 0.007). Collagen gel droplet-embedded culture-drug sensitivity test was successfully evaluated in 56 patients. Among them, 29 (51.7%) patients were resistant to TS-1 and 31 (55.3%) patients were resistant to L-OHP. The L-OHP resistance rate in vascular endothelial growth factor positive patients was significantly higher than that in negative patients (p = 0.031). The L-OHP resistance rate in E-cadherin negative patients was significantly higher than that in positive patients (p = 0.014). In conclusion, matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor were involved in tumor invasion and metastasis. Positive expression of matrix metalloproteinase-9 and vascular endothelial growth factor and negative expression of E-cadherin were malignant markers for gastric cancer. Positive expression of vascular endothelial growth factor and negative expression of E-cadherin were associated with L-OHP resistance.

Addition of peritonectomy to gastrectomy can predict good prognosis of gastric adenocarcinoma patients with intraoperatively proven single P1/P2 carcinomatosis.

This study was to evaluate the prognosis of peritonectomy following gastrectomy for gastric adenocarcinoma patients with intraoperatively proven single P1/P2 carcinomatosis and to define the best therapeutic strategy of the patient cohort. The patients with intraoperatively proven single P1/P2 carcinomatosis from a prospectively maintained database were divided into resection group and non-resection group based on complete gross resection of peritoneal carcinomatosis. From 2005 to 2012, there were 103 patients in the resection group and 122 patients in the non-resection group. There was no difference in morbidity and mortality between groups. The patients did not have improved median survival in P1 carcinomatosis compared to P2 carcinomatosis (15.53 vs 14.80 months, p = 0.450). The median survival was significantly improved in the resection group compared to the patients in the non-resection group (21.07 vs 13.37 months, p < 0.001). The patients undergoing complete gross peritonectomy plus postoperative chemotherapy had a significantly longer median survival than patients who had complete gross peritonectomy alone, patients receiving postoperative chemotherapy alone, and patients receiving neither peritonectomy nor postoperative chemotherapy (27.33 vs 12.00 vs 16.00 vs 10.33 months, p < 0.001). In the multivariate analysis, poor performance status ( p = 0.036), absence of complete gross peritonectomy ( p < 0.001), and lack of postoperative chemotherapy ( p < 0.001) were identified as independently associated with poor survival. The data indicate complete gross peritonectomy following gastrectomy confers a survival benefit to gastric cancer patients with intraoperatively proven single P1/P2 carcinomatosis. In addition, postoperative chemotherapy improves survival regardless of resection of peritoneal carcinomatosis and should be recommended.

C-C motif chemokine 22 ligand (CCL22) concentrations in sera of gastric cancer patients are related to peritoneal metastasis and predict recurrence within one year after radical gastrectomy.

BACKGROUND: Gastric cancer is a common cancer with a poor prognosis. Chemokines play important roles in the tumor microenvironments to support tumor growth and metastasis. The effects of C-C motif chemokine ligand 22 (CCL22) in gastric cancer remain unclear. MATERIALS AND METHODS: Between January 1, 2014 and April 31, 2014, a total of 298 gastric cancer patients were recruited to this study. Circulating concentrations of CCL22 were measured in gastric cancer patients before surgery, at discharged and during follow-up visits. The expression of CCL22 in gastric cancer tumor beds was measured by immunohistochemistry. The proportion of CD3+CD4+CD25+Foxp3+ regulatory T cells in tumor sites was assessed by flow cytometry. RESULTS: Gastric cancer patients had higher serum CCL22 levels compared to healthy controls (P < 0.001). Immunohistochemistry indicated that the gastric cancer tumor beds were the source of serum CCL22, as gastric cancer patients had an increased proportion of strong expression of CCL22 (P < 0.01), and immunohistochemistry scores were positively correlated with levels of circulating CCL22 (P < 0.001). Gastric cancer tissue harbored a higher percentage of regulatory T cells compared to normal tumor-free stomach margins (P < 0.001), and this abundance of regulatory T cells was positively correlated with circulating levels of CCL22 (P < 0.001). Gastric cancer patients with peritoneal metastasis showed increased levels of circulating CCL22 before surgery compared to metastasis-free patients (P < 0.001). Gastric cancer patients with the recurrence within the first year after surgery had elevated serum CCL22 concentrations at different time points compared to those of recurrence-free patients (P < 0.001). Logistic regression analysis indicated that high CCL22 circulating levels before surgery is a risk factor for peritoneal metastasis and an independent risk factor for an early recurrence after surgery. CONCLUSIONS: CCL22 plays an important role in supporting gastric cancer development presumably by increasing the percentage of regulatory T cells in the tumor microenvironments. CCL22 levels in sera have a predictive value for gastric cancer peritoneal metastasis and the early recurrence. Therefore, CCL22 may be a therapeutic target for gastric cancer.

Serum fibrinogen levels are positively correlated with advanced tumor stage and poor survival in patients with gastric cancer undergoing gastrectomy: a large cohort retrospective study.

BACKGROUND: Platelet and blood coagulation abnormalities frequently occur in cancer patients. Fibrinogen is an important hemostatic factor that regulates the hemostatic pathway. Hyperfibrinogenemia is increasing recognized as an important risk factor influencing cancer development and outcome. However, few reports have investigated the prognostic potential of fibrinogen for predicting the survival of gastric cancer (GC) patients. The primary aim of this study was to evaluate the usefulness of preoperative serum fibrinogen as a biomarker for predicating tumor progression and survival of patients with GC. PATIENTS AND METHODS: This retrospective study was conducted in GC patients who underwent gastrectomy from 2005 to 2007. Patient demographics, clinicopathological characteristics, preoperative plasma fibrinogen levels and median survival time (MST) were analyzed. Univariate and multivariate proportional hazard analysis of risk factors were used. RESULTS: This study included 1196 patients (885 males and 311 females) with GC, more than half of whom had advanced GCs. Radical lymph node dissection was performed in 71.6 % of these patients. MST was 41.9 ± 32.4 months. Patient survival was significantly affected by family GC history (p <0.05), lymph node dissection mode (p <0.001), tumor size (≥5 cm; p <0.001), tumor location (p < 0.001), poor tumor differentiation (p <0.001), tumor histologic classification (p <0.001), extent of tumor invasion (p <0.001), number of metastatic lymph nodes (p <0.001), advanced stage of disease (p <0.001), extended operation duration (>150 min; p <0.001), higher operative bleeding volume (>200 ml; p <0.001), postoperative transfusion, preoperative serum fibrinogen levels, CEA levels and CA 19-9 levels (p <0.001). Multivariate analysis indicated that the independent prognostic factors significantly associated with poor survival included non-radical lymph node dissection, palliative lymph node dissection, multi-organ involvement, advanced TNM stages, poor tumor differentiation, higher preoperative serum fibrinogen levelsand higher CA19-9 levels. CONCLUSIONS: Serum fibrinogen levels are positively correlated with advanced tumor stages and poor survival in GC patients undergoing gastrectomy. Preoperative plasma fibrinogen levels are an independent risk factor for survival in these patients. Serum fibrinogen is a useful biomarker for patients with clinically advanced GC.

Clinicopathological features of gastric adenocarcinoma patients with metachronous distant metastasis.

Metachronous distant metastasis influences the postoperative survival of gastric adenocarcinoma patients with radical gastrectomy. We retrospectively reviewed 108 gastric adenocarcinoma patients with metachronous distant metastasis admitted to our hospital between January 2006 and December 2011. First, these patients were divided into two groups according to the time of metastasis: the early metastasis group (EMG) and late metastasis group (LMG). Second, according to the survival time after metastasis, these patients were divided into the longer survival group (LSG) and shorter survival group (SSG). Chi-square and Fisher exact tests were used to analyze associations between categorical variables. Survival data were estimated using the Kaplan-Meier method. Multivariate analyses of the prognostic factors related to overall survival were conducted using the Cox stepwise proportional hazards test. Results shows that the EMG was significantly associated with depth of invasion (p = 0.005), Union for International Cancer Control (UICC) stage (p = 0.003), degree of differentiation (p = 0.002), and vascular invasion (p = 0.001). The SSG was significantly associated with depth of invasion (p = 0.026) and normal carcinoembryonic antigen (CEA) level of after metastasis (p = 0.003). Survival analysis showed that depth of invasion (p < 0.001), degree of differentiation (p = 0.001), and vascular invasion (p = 0.011) were independent prognostic factors for gastric adenocarcinoma patients with metachronous distant metastasis. Gastric adenocarcinoma patients with metachronous distant metastasis exhibit characteristics that can be used to effectively estimate the possibility of early distant metastasis and the prognosis of these patients.

Clinico-pathological features and prognostic analysis of gastric cancer patients in different age groups.

BACKGROUND/AIMS: The prognostic value of age on patients with gastric cancer is not well defined. The aim of this retrospective study is to analyze the impact of age on survival in patients with gastric cancer. METHODOLOGY: A total of 1800 patients with gastric carcinoma, who had undergone gastrectomy between 1997-2007 years were included. They were divided into six different age groups (21-30, 31-40, 41-50, 51- 60, 61-70 and 71-80 years). We reviewed patient's clinico-pathological characteristics and the prognosis with special reference to their ages. RESULTS: Among the six age groups, the younger patients have more female-dominated patients and poorly differentiated carcinoma, whereas the older patients have a higher incidence of large tumors (≥5 cm) and more patients with stage T3. Moreover, there were more liver metastases in the older age groups. Univariate analysis showed that there were significant differences in 5-year survival rates among the six age groups. Multivariate analysis confirmed age, tumor size, pT stage, pN stage and curability were independent prognostic factors. CONCLUSION: There are several distinctive properties related to age of patients with gastric cancer, the older patients have more aggressive features and poorer prognosis than the younger patients.

Clinical investigation of combined Billroth II with Braun anastomosis for patients with gastric cancer.

BACKGROUND/AIMS: This study gives insight into the effect of combined Billroth II with Braun anastomosis for patients with gastric cancer. METHODOLOGY: The clinical data of 720 patients with gastric cancer who underwent surgical treatment in our hospital from 1997 to 2011 were reviewed retrospectively. The results of different operative approaches were analyzed. RESULTS: Combined Billroth II with Braun anastomosis was performed in 378 cases, and Billroth II in 342 cases. The Gastrointestinal Quality of Life Index (GIQLI) was used to evaluate postoperative quality of life. CONCLUSIONS: If the indications for combined Billroth II with Braun anastomosis are strictly controlled, and more attention is paid to perioperatively support, combined Billroth II with Braun anastomosis can prolong the life span of the patients with gastric cancer rather than increase the surgical complications and the mortality.

Clinicopathologic characteristics and prognosis of gastric cancer patients underwent gastrectomy combined with splenectomy.

BACKGROUND/AIMS: This study gives insight into the effect of splenectomy in radical surgery for gastric cancer. METHODOLOGY: The study included 631 patients who underwent radical resection for gastric cancer. Of these 631 patients, 105 underwent splenectomy and 526 had splenic preservation. The clinicopathologic features of 105 patients underwent gastrectomy combined with resection of the spleen (splenectomy group) and 526 patients underwent gastrectomy (spleen-preservation group) were compared. RESULTS: Gastric cancer with splenectomy was characterized by tumor located in gastric cardia (33.3%), positive lymph node metastasis (91.4%), and serosal invasion (94.3%). For age, gender, and tumor size, there was no significant difference between the patients with splenectomy and spleen-preservation. The 5-year survival of splenectomy group was 21.3% as compared with 38.6% for spleen-preservation group (P<0.001). With respect to patients with splenectomy, multivariate analysis showed that lymph node metastasis was significant factors affecting survival. CONCLUSIONS: Compared with spleen-preservation group, patients who underwent gastrectomy combined with splenectomy have a greater chance of tumor located in gastric cardia, positive lymph node metastasis, and serosal invasion and a significantly poor prognosis.