Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. METHODS: Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. RESULTS: There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P = .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P = .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P = .038). CONCLUSIONS: A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.

Military training-related abdominal injuries and diseases: Common types, prevention and treatment.

Military training is intense, difficult and often dangerous, so all kinds of injuries or diseases frequently occur during training. Most of the previous studies and reviews on military training-related injuries focused on musculoskeletal system, whereas there are no reviews of abdominal injuries and diseases. Although the incidence of military training-related abdominal injuries and diseases is relatively low, the patients' condition is often critical especially in the presence of abdominal organ injury, leading to multi-organ dysfunction syndrome and even death. This paper elaborates on common types of military training-related abdominal injuries and diseases as well as the prevention and treatment measures, which provides some basis for scientific and reasonable training and improvement of medical security.

Recent Advances in the Diagnosis, Staging, Treatment, and Prognosis of Advanced Gastric Cancer: A Literature Review.

Gastric cancer is one of the most common cause of cancer related deaths worldwide which results in malignant tumors in the digestive tract. The only radical treatment option available is surgical resection. Recently, the implementation of neoadjuvant chemotherapy resulted in 5-year survival rates of 95% for early gastric cancer. The main reason of treatment failure is that early diagnosis is minimal, with many patients presenting advanced stages. Hence, the greatest benefit of radical resection is missed. Consequently, the main therapeutic approach for advanced gastric cancer is combined surgery with neoadjuvant chemotherapy, targeted therapy, or immunotherapy. In this review, we will discuss the various treatment options for advanced gastric cancer. Clinical practice and clinical research is the most practical way of reaching new advents in terms of patients' characteristics, optimum drug choice, and better prognosis. With the recent advances in gastric cancer diagnosis, staging, treatment, and prognosis, we are evident that the improvement of survival in this patient population is just a matter of time.

AKT inhibits the phosphorylation level of H2A at Tyr57 via CK2α to promote the progression of gastric cancer.

BACKGROUND: Histone H2A and its variants have an important effect on DNA damage repair and cancer development. Protein kinase B (AKT) can regulate various cellular functions and play critical roles in the progression of different cancers. However, the interaction mechanism of H2A with AKT in gastric cancer (GC) has not been reported. A series of experiments were carried out in the present study to investigate this issue. METHODS: Firstly, we used western blot and immunoprecipitation assays to determine the correlation between AKT and H2A, then detected the relationship between AKT and protein kinase CK2α that can phosphorylate H2A at Tyr57 site (H2AY57), and next examined the interaction among AKT, CK2α, and H2A in SNU-16 cells. Subsequently, the effect of these molecules on the cellular proliferation, migration, and invasion was measured by Cell Counting Kit-8 (CCK-8), wound healing, and transwell invasion assays. RESULTS: Our study preliminarily found that AKT was negatively correlated with H2A phosphorylation at the Tyr 57 site (H2AY57p). It was revealed that AKT mediated the phosphorylation of CK2α at the T13 site, which decreased the affinity of CK2α with its substrate histone H2A and inhibited the level of H2AY57p in GC cells. Furthermore, AKT-mediated CK2α phosphorylation promoted the proliferation, migration, and invasion of SNU-16 cells possibly through downregulating H2AY57p level. CONCLUSIONS: These findings contribute to understanding the interactions among AKT, CK2α, and H2A in GC, and provide the potential biomarkers for the diagnosis and treatment of GC.

Establishment and validation of a nomogram to predict the risk of ovarian metastasis in gastric cancer: Based on a large cohort.

BACKGROUND: Ovarian metastasis is a special type of distant metastasis unique to female patients with gastric cancer. The pathogenesis of ovarian metastasis is incompletely understood, and the treatment options are controversial. Few studies have predicted the risk of ovarian metastasis. It is not clear which type of gastric cancer is more likely to metastasize to the ovary. A prediction model based on risk factors is needed to improve the rate of detection and diagnosis. AIM: To analyze risk factors of ovarian metastasis in female patients with gastric cancer and establish a nomogram to predict the probability of occurrence based on different clinicopathological features. METHODS: A retrospective cohort of 1696 female patients with gastric cancer between January 2006 and December 2017 were included in a single center, and patients with distant metastasis other than ovary and peritoneum metastasis were excluded. Potential risk factors for ovarian metastasis were analyzed using univariate and multivariable logistic regression. Independent risk factors were chosen to construct a nomogram which received internal validation. RESULTS: Ovarian metastasis occurred in 83 of 1696 female patients. Univariate analysis showed that age, Lauren type, whether the primary lesion contained signet-ring cells, vascular tumor emboli, T stage, N stage, the expression of estrogen receptor, the expression of progesterone receptor, serum carbohydrate antigen 125 and the neutrophil-to-lymphocyte ratio were risk factors for ovarian metastasis of gastric cancer (all P < 0.05). Multivariate analysis showed that age ≤ 50 years, Lauren typing of non-intestinal, gastric cancer lesions containing signet-ring cell components, N stage > N2, positive expression of estrogen receptor, serum carbohydrate antigen 125 > 35 U/mL, and a neutrophil-to-lymphocyte ratio > 2.16 were independent risk factors (all P < 0.05). The independent risk factors were constructed into a nomogram model using R language software. The consistency index after continuous correction was 0.840 [95% confidence interval: (0.774-0.906)]. After the internal self-sampling (Bootstrap) test, the calibration curve of the model was obtained with an average absolute error of 0.007. The receiver operating characteristic curve of the obtained model was drawn. The area under the curve was 0.867, the maximal Youden index was 0.613, the corresponding sensitivity was 0.794, and the specificity was 0.819. CONCLUSION: The nomogram model performed well in the prediction of ovarian metastasis. Attention should be paid to the possibility of ovarian metastasis in high-risk populations during re-examination, to ensure early detection and treatment.

Preoperative albumin levels predict prolonged postoperative ileus in gastrointestinal surgery.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a prolonged state of "pathological" gastrointestinal (GI) tract dysmotility. There are relatively few studies examining the influence of preoperative nutritional status on the development of PPOI in patients who underwent GI surgery. The association between preoperative albumin and PPOI has not been fully studied. We hypothesized that preoperative albumin may be an independent indicator of PPOI. AIM: To analyze the role of preoperative albumin in predicting PPOI and to establish a nomogram for clinical risk evaluation. METHODS: Patients were drawn from a prospective hospital registry database of GI surgery. A total of 311 patients diagnosed with gastric or colorectal cancer between June 2016 and March 2017 were included. Potential predictors of PPOI were analyzed by univariate and multivariable logistic regression analyses, and a nomogram for quantifying the presence of PPOI was developed and internally validated. RESULTS: The overall PPOI rate was 21.54%. Advanced tumor stage and postoperative opioid analgesic administration were associated with PPOI. Preoperative albumin was an independent predictor of PPOI, and an optimal cutoff value of 39.15 was statistically calculated. After adjusting multiple variables, per unit or per SD increase in albumin resulted in a significant decrease in the incidence of PPOI of 8% (OR = 0.92, 95%CI: 0.85-1.00, P = 0.046) or 27% (OR = 0.73, 95%CI: 0.54-0.99, P = 0.046), respectively. Patients with a high level of preoperative albumin (≥ 39.15) tended to experience PPOI compared to those with low levels (< 39.15) (OR = 0.43, 95%CI: 0.24-0.78, P = 0.006). A nomogram for predicting PPOI was developed [area under the curve (AUC) = 0.741] and internally validated by bootstrap resampling (AUC = 0.725, 95%CI: 0.663-0.799). CONCLUSION: Preoperative albumin is an independent predictive factor of PPOI in patients who underwent GI surgery. The nomogram provided a model to screen for early indications in the clinical setting.

Nomogram to predict prolonged postoperative ileus after gastrectomy in gastric cancer.

BACKGROUND: Prolonged postoperative ileus (PPOI) is one of the common complications in gastric cancer patients who underwent gastrectomy. Evidence on the predictors of PPOI after gastrectomy is limited and few prediction models of nomogram are used to estimate the risk of PPOI. We hypothesized that a predictive nomogram can be used for clinical risk estimation of PPOI in gastric cancer patients. AIM: To investigate the risk factors for PPOI and establish a nomogram for clinical risk estimation. METHODS: Between June 2016 and March 2017, the data of 162 patients with gastrectomy were obtained from a prospective and observational registry database. Clinical data of patients who fulfilled the criteria were obtained. Univariate and multivariable logistic regression models were performed to detect the relationship between variables and PPOI. A nomogram for PPOI was developed and verified by bootstrap resampling. The calibration curve was employed to detect the concentricity between the model probability curve and ideal curve. The clinical usefulness of our model was evaluated using the net benefit curve. RESULTS: This study analyzed 14 potential variables of PPOI in 162 gastric cancer patients who underwent gastrectomy. The incidence of PPOI was 19.75% in patients with gastrectomy. Age older than 60 years, open surgery, advanced stage (III-IV), and postoperative use of opioid analgesic were independent risk factors for PPOI. We developed a simple and easy-to-use prediction nomogram of PPOI after gastrectomy. This nomogram had an excellent diagnostic performance [area under the curve (AUC) = 0.836, sensitivity = 84.4%, and specificity = 75.4%]. This nomogram was further validated by bootstrapping for 500 repetitions. The AUC of the bootstrap model was 0.832 (95%CI: 0.741-0.924). This model showed a good fitting and calibration and positive net benefits in decision curve analysis. CONCLUSION: We have developed a prediction nomogram of PPOI for gastric cancer. This novel nomogram might serve as an essential early warning sign of PPOI in gastric cancer patients.

[Corrigendum] Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer.

An interested reader drew to the attention of the Journal that the western blot featured in Fig. 3B of the above paper also appeared as Fig. 3D in the following publication, featuring many of the same authors: Xi HQ, Cai AZ, Wu XS et al: Leucine­rich repeat­containing G­protein­coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer. Br J Cancer 110: 2011­2020, 2014. After having consulted the authors about this matter, they conceded that there was a data sharing violation here, and that the image should not have been reproduced in the above article without having received the prior permission of the British Journal of Cancer. This permission has now been sought after and obtained, and Fig. 3 is reproduced opposite, now including the appropriate credit for the original source of Fig. 3B. The authors apologize to the Editors of the British Journal of Cancer and Oncology Reports, and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 32: 181­188, 2014; DOI: 10.3892/or.2014.3204].

Comparing PET/MRI with PET/CT for Pretreatment Staging of Gastric Cancer.

18F-FDG PET/MRI has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MRI in gastric cancer are rare because of motion artifacts. We investigated the value of PET/MRI for preoperative staging compared with PET/CT in gastric cancer (GC). Thirty patients with confirmed GC underwent PET/CT and PET/MRI. TNM staging for each patient was determined from the PET/MRI and PET/CT images. The diagnostic performance of PET/MRI and PET/CT was calculated compared with the pathologic TNM stage. The two methods were compared using statistical analyses. The accuracy for T staging between PET/MRI and PET/CT was 76.9% vs. 57.7%, respectively. In T1 and T4a staging, the sensitivity and specificity for PET/MRI vs. PET/CT was 1.0 vs. 0.6 and 1.0 vs. 0.8, respectively. The area under the curve (AUC) for PET/MRI vs. PET/CT was 1.00 vs. 0.78 in the T1 stage, 0.73 vs. 0.66 in the T2 stage, 0.72 vs. 0.57 in the T3 stage, and 0.86 vs. 0.83 in the T4 stage. The accuracy for N staging of PET/MRI vs. PET/CT was 53.9% vs. 34.0%, and that for N0 vs. N+ was 85.0% vs. 77.0%. The sensitivity for PET/MRI in N3 staging was 0.67 and 0 for PET/CT. There was a statistically significant difference in the AUC for N1 staging (PET/MRI vs. PET/CT, 0.63 vs. 0.53, p = 0.03). SUVmax/ADC positively correlated with tumor volume and Ki-67. PET/MRI performs more accurately in TNM staging compared with PET/CT and is optimal for accurate N staging. SUVmax/ADC has positive correlations with tumor volume and Ki-67.

Timing of surgery after neoadjuvant chemotherapy for gastric cancer: Impact on outcomes.

AIM: To evaluate whether the neoadjuvant chemotherapy (NACT)-surgery interval time significantly impacts the pathological complete response (pCR) rate and long-term survival. METHODS: One hundred and seventy-six patients with gastric cancer undergoing NACT and a planned gastrectomy at the Chinese PLA General Hospital were selected from January 2011 to January 2017. Univariate and multivariable analyses were used to investigate the impact of NACT-surgery interval time (< 4 wk, 4-6 wk, and > 6 wk) on pCR rate and overall survival (OS). RESULTS: The NACT-surgery interval time and clinician T stage were independent predictors of pCR. The interval time > 6 wk was associated with a 74% higher odds of pCR as compared with an interval time of 4-6 wk (P = 0.044), while the odds ratio (OR) of clinical T3vs clinical T4 stage for pCR was 2.90 (95%CI: 1.04-8.01, P = 0.041). In Cox regression analysis of long-term survival, post-neoadjuvant therapy pathological N (ypN) stage significantly impacted OS (N0vs N3: HR = 0.16, 95%CI: 0.37-0.70, P = 0.015; N1vs N3: HR = 0.14, 95%CI: 0.02-0.81, P = 0.029) and disease-free survival (DFS) (N0vs N3: HR = 0.11, 95%CI: 0.24-0.52, P = 0.005; N1vs N3: HR = 0.17, 95%CI: 0.02-0.71, P = 0.020). The surgical procedure also had a positive impact on OS and DFS. The hazard ratio of distal gastrectomy vs total gastrectomy was 0.12 (95%CI: 0.33-0.42, P = 0.001) for OS, and 0.13 (95%CI: 0.36-0.44, P = 0.001) for DFS. CONCLUSION: The NACT-surgery interval time is associated with pCR but has no impact on survival, and an interval time > 6 wk has a relatively high odds of pCR.

Comparison between laparoscopic and open surgery for large gastrointestinal stromal tumors: A meta-analysis.

AIM: To investigate whether laparoscopic surgery is as safe and feasible as open resection for patients with larger gastrointestinal stromal tumors (GISTs) (≥ 5 cm). METHODS: A systematic search of PubMed, EMBASE, Web of Science and the Cochrane Library database was performed. Relevant studies of laparoscopic and open surgery for GISTs of > 5 cm published before December 2016 were identified from these databases. The quality of the studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The tumor size, operation time, blood loss, postoperative hospital stay, complication rate, and disease-free survival rate were assessed. The software Stata (version 12.0) was used for the meta-analysis. RESULTS: Five clinical trials comprising 209 patients with GISTs of similar larger sizes were evaluated. The pooled analysis of 100 patients in the laparoscopic resection group and 109 patients in the open resection group demonstrated that laparoscopic surgery was significantly associated with a shorter postoperative hospital stay (P < 0.001) and less blood loss (P = 0.002). Moreover, there were no statistically significant differences in the operation time (P = 0.38), postoperative complication rate (P = 0.88), or disease-free survival rate (P = 0.20) between two groups. CONCLUSION: Our findings revealed that for patients with large GISTs of comparable sizes, laparoscopic surgery did not significantly influence the operation factors or clinical outcomes compared with open surgery. This suggests that laparoscopic resection is as acceptable as open surgery for treatment of large gastric GISTs.

Expression and clinicopathologic significance of TUFM and p53 for the normal-adenoma-carcinoma sequence in colorectal epithelia.

BACKGROUND: Evidence indicates that most cases of colorectal carcinoma (CRC) develop from adenoma. A previous study demonstrated that mitochondrial Tu translation elongation factor (TUFM) might serve as an independent prognostic factor for colorectal cancer. However, the expression and function of TUFM in the normal-adenoma-cancer sequence have not been reported. In this study, we investigated the clinicopathologic significance of TUFM and p53 expression for the normal-adenoma-carcinoma sequence in colorectal epithelia and evaluated the roles of TUFM during the progression of colorectal tumors. METHODS: Paraffin-embedded specimens from 261 colorectal normal mucosa samples, 157 adenomas, and 104 early carcinomas were analyzed for TUFM and p53 expression by immunohistochemistry. RESULTS: Expression of TUFM and p53 was significantly increased during the colorectal normal-adenoma-carcinoma sequence (all P < 0.05). The expression of TUFM and p53 was associated with histologic type of adenomas (P = 0.028; P = 0.001) and grade of dysplasia (all P = 0.001). Expression of TUFM was positively correlated with that of p53 (r = 0.319, P = 0.001). CONCLUSIONS: Upregulated TUFM expression may play an important role in the transformation from colorectal normal mucosa to carcinoma through adenoma. Combined immunohistochemical detection of TUFM and p53 may be useful for evaluating the biological behavior of colorectal adenoma.

RNAi-mediated inhibition of Lgr5 leads to decreased angiogenesis in gastric cancer.

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a novel gastric cancer marker. However, it is unclear whether it can play roles in tumor angiogenesis. In this study, we aim to investigate the role of Lgr5 on gastric cancer angiogenesis. Lgr5, VEGF expression levels and microvessel density (MVD) were detected in tumor tissue. Then, Lgr5 mRNA was downregulated by small interference RNA technique. Western blotting and real-time quantitative PCR (qRT-PCR) were performed to detect the expression of Lgr5 and VEGF protein and mRNA in Lgr5 siRNA-transfected gastric cancer cells. The effect of silencing Lgr5 on angiogenesis was examined by assessing human umbilical vein endothelia cell (HUVEC) capillary tube formation. The results indicated that Lgr5 expression was upregulated in gastric cancer and positively correlated with VEGF (r=0.305, P=0.001) and MVD (r=0.312, P=0.001). Silencing of Lgr5 expression resulted in suppression of VEGF mRNA and protein (all P=0.001). Moreover, when HUVECs were stimulated with conditioned medium from Lgr5 siRNA-transfected gastric cancer cells, tube formation was significantly decreased (2.51 ± 0.19 mm/mm2) compared with the treatment with regular cell culture medium (DMEM) (7.34 ± 0.30 mm/mm2) or medium from control siRNA-transfected cells (7.18 ± 0.33 mm/mm2) (all P=0.001). In conclusion, Lgr5 plays important roles in angiogenesis. Lgr5-specific siRNA could be designed into an effective therapeutic agent to inhibit gastric cancer angiogenesis.

Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer.

AIM: To investigate the association between serum human epidermal growth factor receptor 2 (HER2) extracellular domain (ECD) and tissue HER2 status, and the prognostic value of serum HER2 ECD in patients with gastric cancer. METHODS: A total of 239 patients with gastric cancer were enrolled from December 2012 to June 2013. Serum HER2 ECD was determined by chemiluminescent assay, and tissue HER2 status was evaluated by immunohistochemistry and fluorescence in situ hybridization assay. A receiver operating characteristic (ROC) curve was plotted to identify the optimal cut-off value for serum HER2 ECD assay for predicting survival in gastric cancer patients. RESULTS: Serum HER2 ECD was significantly correlated with tissue HER2 status (P < 0.001), tumor size (P < 0.001), and intestinal type of gastric cancer (P = 0.021). Serum HER2 ECD levels differed significantly between patients with HER2-positive tissue expression and those with HER2-negative tissue expression. ROC analysis yielded an area under the curve value of 0.79 (95%CI: 0.71-0.87, P < 0.001), with a sensitivity and specificity of 0.54 (95%CI: 0.37-0.70) and 0.93 (95%CI: 0.88-0.96), respectively. With a cut-off value of 24.75 ng/mL, high serum HER2 ECD had a negative impact on overall survival of the patients (HR: 1.93, 95%CI: 1.32-4.38, P = 0.006). CONCLUSION: Serum HER2 ECD could be a highly specific surrogate biomarker for tissue HER2 status in gastric cancer. Optimal cut-off criteria for predicting survival should be established.

Palliative Therapy for Gastric Outlet Obstruction Caused by Unresectable Gastric Cancer: A Meta-analysis Comparison of Gastrojejunostomy with Endoscopic Stenting.

BACKGROUND: Gastrojejunostomy (GJJ) and endoscopic stenting (ES) are palliative treatments for gastric outlet obstruction (GOO) caused by gastric cancer. We compared the outcomes of GJJ with ES by performing a meta-analysis. METHODS: Clinical trials that compared GJJ with ES for the treatment of GOO in gastric cancer were included in the meta-analysis. Procedure time, time to resumption of oral intake, duration of hospital stay, patency duration, and overall survival days were compared using weighted mean differences (WMDs). Technical success, clinical success, procedure-related mortality, complications, the rate of re-obstruction, postoperative chemotherapy, and reintervention were compared using odds ratios (OR s). RESULTS: Nine studies were included in the analysis. Technical success and clinical success were not significantly different between the ES and GJJ groups. The ES group had a shorter procedure time (WMD = -80.89 min, 95% confidence interval [CI] = -93.99 to -67.78,P < 0.001), faster resumption of oral intake (WMD = -3.45 days, 95% CI = -5.25 to -1.65,P < 0.001), and shorter duration of hospital stay (WMD = -7.67 days, 95% CI = -11.02 to -4.33,P < 0.001). The rate of minor complications was significantly higher in the GJJ group (OR = 0.13, 95% CI = 0.04-0.40,P < 0.001). However, the rates of major complications (OR = 6.91, 95% CI = 3.90-12.25,P < 0.001), re-obstruction (OR= 7.75, 95% CI = 4.06-14.78,P < 0.001), and reintervention (OR= 6.27, 95% CI = 3.36-11.68,P < 0.001) were significantly lower in the GJJ group than that in the ES group. Moreover, GJJ was significantly associated with a longer patency duration (WMD = -167.16 days, 95% CI = -254.01 to -89.31,P < 0.001) and overall survival (WMD = -103.20 days, 95% CI = -161.49 to -44.91, P= 0.001). CONCLUSIONS: Both GJJ and ES are effective procedures for the treatment of GOO caused by gastric cancer. ES is associated with better short-term outcomes. GJJ is preferable to ES in terms of its lower rate of stent-related complications, re-obstruction, and reintervention. GJJ should be considered a treatment option for patients with a long life expectancy and good performance status.

LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and ß-catenin.

Liver kinase B1 (LKB1) is known to suppress the proliferation, energy metabolism and mesenchymal transition of various cancer cells, and is involved in the regulation of Hippo-Yes-associated protein (Yap) and the Wnt/ß-catenin signaling pathways. However, the role of LKB1 in gastric cancer (GC) was not fully understood. Thus, in the present study, we studied LKB1 and found that protein expression (0.37±0.061 vs. 0.59±0.108, P=0.006) and the protein ratio of p-Yap/Yap (0.179±0.085 vs. 0.8±0.126, P=0.001) were reduced in 54 gastric adenocarcinoma (GAC) tissues compared with the matched adjacent non-cancerous tissues, using western blotting and RT-qPCR assays. LKB1 expression was also observed decreased in 109 GAC tissues compared with 54 adjacent non-cancerous tissues (χ2=4.678, P=0.0306), and negatively correlated with the nuclear expression of Yap (r=-0.6997) and ß-catenin (r=-0.3510), using immunohistochemical analysis. In GC patients, LKB1 expression was negatively associated with tumor size, tumor infiltration, lymph node metastasis and the TNM stage. LKB1 expression was determined to be positively correlated with longer overall survival of GC patients using Kaplan-Meier analysis (P=0.001). Subsequently, LKB1 expression in human GAC AGS cells was enhanced with a full­length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and ß-catenin expression were assessed by western blotting and RT-qPCR, and were found to be increased in the cytoplasm but decreased in the nucleus in LKB1-overexpressing GC cells compared with the control cells. The increase in cytoplasmic ß-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and ß-catenin mRNA were barely altered by LKB1 overexpression. Thus, we concluded that LKB1 expression was reduced in GAC tissues but that it correlated positively with better prognosis for GC patients. LKB1 inhibits the proliferation of GC cells by suppressing the nuclear translocation of Yap and ß-catenin.

Isoprenaline Induces Periostin Expression in Gastric Cancer.

PURPOSE: Periostin mediates critical steps in gastric cancer and is involved in various signaling pathways. However, the roles of periostin in promoting gastric cancer metastasis are not clear. The aim of this study was to investigate the relevance between periostin expression and gastric cancer progression and the role of stress-related hormones in the regulation of cancer development and progression. MATERIALS AND METHODS: Normal, cancerous and metastatic gastric tissues were collected from patients diagnosed with advanced gastric cancer. The in vivo expression of periostin was evaluated by in situ hybridization and immunofluorescent staining. Meanwhile, human gastric adenocarcinoma cell lines MKN-45 and BGC-803 were used to detect the in vitro expression of periostin by using quantitative real-time polymerase chain reaction (PCR) and western blotting. RESULTS: Periostin is expressed in the stroma of the primary gastric tumors and metastases, but not in normal gastric tissue. In addition, we observed that periostin is located mainly in pericryptal fibroblasts, but not in the tumor cells, and strongly correlated to the expression of α-smooth muscle actin (SMA). Furthermore, the distribution patterns of periostin were broader as the clinical staging of tumors progressed. We also identified a role of stress-related signaling in promoting cancer development and progression, and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells. CONCLUSION: These findings suggest that the distribution pattern of periostin was broader as the clinical staging of the tumor progressed and found that isoprenaline upregulated expression levels of periostin in gastric cancer cells.

Comparison of Therapeutic Efficacy between Gastrectomy with Transarterial Chemoembolization Plus Systemic Chemotherapy and Systemic Chemotherapy Alone in Gastric Cancer with Synchronous Liver Metastasis.

BACKGROUND: Systemic chemotherapy (SC) is the recommended treatment for gastric cancer with liver metastasis. However, the improvement in survival has been disappointing. The aim of this study was to compare the therapeutic efficacy of gastrectomy with transarterial chemoembolization plus SC (GTC) and SC alone for gastric cancer with synchronous liver metastasis. METHODS: From January 2008 to December 2013, 107 gastric cancer patients with synchronous liver metastasis attending the four participating centers were enrolled in this multicenter, ambispective, controlled cohort study. Patients who underwent GTC (n = 32) were compared with controls who were received SC alone (n = 75). The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). The secondary endpoints were response rate to treatment and treatment-related adverse effects. RESULTS: The median OS was 14.0 months (95% confidence interval [CI ]: 13.1-14.9 months) in the GTC treatment group and 8.0 months (95% CI : 6.6-9.4 months) in SC group, this difference being statistically significant (P < 0.001). The median PFS was significantly longer in the GTC than in the SC group (5 months, 95% CI : 2.2-7.8 months vs. 3 months, 95% CI : 2.3-3.4 months, respectively) (P < 0.001). The rate of response to treatment was significantly better in the GTC than the SC group (59.4% vs. 37.4%, respectively) (P = 0.035). According to multivariate analysis, OS in patients receiving combination treatment was significantly correlated with the size (P = 0.037) and extent of liver metastases (P < 0.001). PFS was also correlated with the extent of liver metastases (P = 0.003). CONCLUSIONS: GTC is more effective than SC alone in patients with gastric cancer with synchronous liver metastasis. GTC therapy prolongs the survival of selected gastric cancer patients with synchronous liver metastasis.

RNF43 Inhibits Cancer Cell Proliferation and Could be a Potential Prognostic Factor for Human Gastric Carcinoma.

BACKGROUND/AIMS: RNF43 is a member of transmembrane E3 ubiquitin ligases and plays important roles in tumor formation progression. In current study, we aimed to explore RNF43 expression and analyze its role in gastric carcinoma. METHODS AND RESULTS: The level of RNF43 was detected in 77 cases of gastric carcinoma and matched normal tissues by real-time PCR, western blotting and immunohistochemistry. We found that the expression of RNF43 was significantly down-regulated in the gastric carcinoma tissues compared to the normal mucosae (all P<0.001). In addition, RNF43 was significantly correlated with histological differentiation (P = 0.001), T-stage cancer (P<0.001), depth of invasion (P<0.001), metastasis of regional lymph nodes (P<0.001), pTNM stage (P<0.001) and survival (P = 0.021). We further explored the biological functions of RNF43 in gastric carcinoma cell lines. Both gain- and loss-function assays show that RNF43 could suppress cell proliferation while promotes cell apoptosis. Further, we found that RNF43 was positively correlated with p53 and cleaved-caspase3 and negatively correlated with Ki67 and Lgr5. CONCOLUSION: In conclusion, RNF43 might act as a tumor suppressor in gastric carcinoma and might be a potential indicator for the clinical assessment of gastric cancer prognosis.

Prognostic role of miR-200c in various malignancies: a systematic review and meta-analysis.

MiR-200c expression is dysregulated in various malignancies and may predict the survival of patients with cancer, although the results of different studies conflict. Therefore, we conducted a meta-analysis to resolve this discrepancy. We queried the PubMed and Embase using multiple search strategies. Data were extracted from studies comparing overall survival and progression-free survival in patients with cancer with high and low levels of miR-200c expression. Fixed and random models were used where appropriate. A combined hazards ratio (HR) was calculated to estimate the association of high levels of miR-200c with survival. We selected 16 studies of 1485 participants for our final meta-analysis. Upregulated expression of miR-200c predicted significantly worse overall survival in patients with cancer (HR 1.51; 95% confidence interval [CI] 1.06-2.16, P = 0.023). Subgroup analysis indicated that high levels of miR-200c was associated with decreased survival of Caucasians and patients with gynecological tumors with pooled HR values of 1.82 (95% CI 1.27-2.26, P = 0.01) and 3.23 (95% CI 1.11-9.38, P = 0.032), respectively. Because of the absence of apparent heterogeneity, the combined HRs were 1.69 (95% CI 1.24-2.30, P = 0.001) for squamous cell carcinoma and 1.91 (95% CI 1.40-2.59, P < 0.001) for samples from peripheral blood. Increased expression of miR-200c significantly associated with shorter progression-free survival of patients with cancer (HR 2.37; 95% CI 1.47-3.81, P < 0.001). Our meta-analysis indicates that the level of miR-200c expression predicted survival of patients with cancer, particularly for Caucasians and patients with gynecological cancer. Increased expression of miR-200c predicted shorter survival of patients with squamous cell carcinomas. Our findings indicate that monitoring the levels of miR-200c in blood may be useful for following tumor progression as well as patients' prognosis.