Ketohexokinase-A deficiency attenuates the proliferation via reducing ß-catenin in gastric cancer cells.

Overconsumption of fructose is closely related to cancer. Ketohexokinase (KHK) catalyzes the conversion from fructose to fructose-1-phosphate (F1P), which is the first and committed step of fructose metabolism. Recently, aberrant KHK activation has been identified in multiple malignancies. However, the roles of KHK in gastric cancer (GC) cells are largely unclear. Herein, we reveal that the expression of ketohexokinase-A (KHK-A), one alternatively spliced KHK isoform that possesses low affinity for fructose, was markedly increased in GC cells. Depletion of endogenous KHK-A expression using lentiviruses encoding short hairpin RNAs (shRNAs) or pharmaceutical disruption of KHK-A activity using KHK-IN-1 hydrochloride in GC NCI-N87 and HGC-27 cells inhibited the proliferation in vitro and in vivo. Additionally, the mitochondrial respiration in the GC cells with KHK-A deficiency compared with the control cells was significantly impaired. One commercially-available antibody array was used to explore the effects of KHK-A knockdown on signaling pathways, showing that ß-catenin was remarkably reduced in the KHK-A deficient GC cells compared with the control ones. Pharmaceutical reduction in ß-catenin levels slowed down the proliferation of GC cells. These data uncover that KHK-A promotes the proliferation in GC cells, indicating that this enzyme might be a promising therapeutical target for GC treatment.

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity.

BACKGROUND: The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. METHODS: This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. RESULTS: EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. CONCLUSIONS: EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.

The Key Role of Tumor Budding in Predicting the Status of Lymph Node Involvement in Early Gastric Cancer Patients: A Clinical Multicenter Validation in China.

BACKGROUND: Accurate preoperative prediction of lymph node (LN) involvement is essential for the management of early gastric cancer (EGC). Our objective was to formulate a potent nomogram for predicting LN involvement in EGC by leveraging an innovative predictor of tumor budding. METHODS: We assembled a cohort of EGC patients who underwent radical surgery at two tertiary cancer centers. Tumor budding was stratified by using an optimal cutoff value and integrated with other clinicopathological variables to ascertain the risk factors associated with LN involvement. A nomogram was developed and its predictive performance was assessed by using receiver operating characteristic (ROC) curves and calibration plots. In addition, we conducted decision curve analysis to evaluate its clinical utility. Finally, an external validation was conducted by using an independent cohort. RESULTS: Finally, 307 eligible patients (215 in the primary cohort and 92 in the validation cohort) were included. Tumor budding, categorized by a count of two, exhibited a robust association with LN involvement (OR 14.12, p = 0.012). Other significant risk factors include lymphovascular invasion, depth of tumor invasion, ulceration, and tumor differentiation. Notably, the nomogram demonstrated exceptional discriminative power (area under the ROC curve, 0.872 in the primary cohort and 0.885 in the validation cohort) and precise predictive capabilities. Furthermore, the nomogram showed notable clinical applicability through decision curve analysis, particularly in endoscopic curability C-2, by mitigating the risk of overtreatment. CONCLUSIONS: Tumor budding is a robust predictor of LN involvement in EGC. The incorporation of tumor budding into a nomogram is an effective strategy, thereby informing and enhancing clinical decision-making.

Establishment and validation of a risk score model based on EUS: assessment of lymph node metastasis in early gastric cancer.

BACKGROUND AND AIMS: Lymph node metastasis significantly affects the prognosis of early gastric cancer patients. EUS plays a crucial role in the preoperative assessment of early gastric cancer. This study evaluated the efficacy of EUS in identifying lymph node metastasis in early gastric cancer patients and developed a risk score model to aid in choosing the best treatment options. METHODS: We retrospectively analyzed the effectiveness of EUS for detecting lymph node metastasis in early gastric cancer patients. A risk score model for predicting lymph node metastasis preoperatively was created using independent risk factors identified through binary logistic regression analysis and subsequently validated. Receiver operating characteristic curves were generated for both the development and validation cohorts. RESULTS: The overall accuracy of EUS in identifying lymph node metastasis was 85.3%, although its sensitivity (29.2%) and positive predictive value (38.7%) were relatively low. Patients were categorized based on preoperative risk factors for lymph node metastasis, including tumor size of ≥20 mm, lymph nodes of ≥10 mm, body mass index of ≥24 kg/m2, and lymph node metastasis on CT scans. A 7-point risk score model was developed to assess the likelihood of lymph node metastasis. The areas under the receiver operating characteristic curve for the development and validation sets were 0.842 and 0.837, respectively, with sensitivities of 64% and 79%, respectively. CONCLUSIONS: We developed a practical risk score model based on preoperative factors to help EUS predict lymph node metastasis in early gastric cancer patients, guiding the selection of optimal treatment approaches for these patients.

DEPTOR as a novel prognostic marker inhibits the proliferation via deactivating mTOR signaling pathway in gastric cancer cells.

Aberrantly activated mTOR signaling pathway is commonly found in malignancies including gastric cancer (GC). DEPTOR, as a naturally occurred inhibitor of mTOR, functions in the pro- or anti-tumor manner depending on distinct tumor contexts. However, the roles of DEPTOR in GC remain largely unknown. In this study, DEPTOR expression was identified to be significantly decreased in GC tissues compared with matched normal gastric tissues, and reduced DEPTOR level was indicative of poor prognosis in patients. Restored DEPTOR expression inhibited the propagation in AGS and NCI-N87 cells, whose DEPTOR levels are low, via deactivating mTOR signaling pathway. Likewise, cabergoline (CAB) attenuated the proliferation in AGS and NCI-N87 cells via partially rescuing DEPTOR protein level. Targeted metabolomics analysis showed that several key metabolites, such as l-serine, significantly changed in AGS cells with DEPTOR restoration. These results revealed the anti-proliferation function of DEPTOR in GC cells, suggesting that restored DEPTOR expression using CAB may be a potential therapeutic approach for patients with GC.

Comparison of short­term outcomes and 3-year overall survival between robotic and laparoscopic gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: Despite the increasing use of robotic gastrectomy (RG) as an alternative to laparoscopic gastrectomy (LG) in treating gastric cancer, controversy remains over the advantages of RG compared to LG and there is a paucity of studies comparing the two techniques regarding patient survival. METHODS: In this retrospective cohort study, 675 patients undergoing minimally invasive gastrectomy were recruited from January 2016 to January 2018 (LG: n = 567; RG: n = 108). A one-to-one propensity score matching (PSM) analysis was applied to minimize the selection bias due to confounding factors, yielding 104 patients in each of the RG and LG groups. After matching, the short-term outcomes and 3-year overall survival were compared in the two groups. RESULTS: The PSM cohort analysis showed a similar 3-year overall survival between RG and LG groups (p = .249). Concerning the short-term outcomes, the RG compared to LG resulted in lower blood loss (p = .01), lower postoperative complications (p = .001), lower postoperative pain (p = .016), earlier initiation of soft diet (p = .011), shorter hospital stay |(p = .012), but higher hospitalization expenses (p = .001). CONCLUSION: Our findings suggest that RG may offer advantages in terms of blood loss, surgical complications, recovery time, and pain management compared to LG while maintaining similar overall survival rates. However, RG is associated with higher hospital costs, potentially limiting its wider adoption. Further research, including large, multi-center randomized controlled trials with longer patient follow-up, particularly for advanced gastric cancer, is needed to confirm these findings.

The Relationship Between Body Mass Index and Bone Mineral Density: A Mendelian Randomization Study.

Body mass index (BMI) is closely associated with bone mineral density (BMD) in both men and women. However, the relationship between BMI and BMD varies according to different studies. Using SNPs strongly associated with BMI in 336,107 individuals, we conducted a two-sample Mendelian randomization study to identify whether and to what extent BMD at different skeletal sites was affected by BMI. A power calculation was also performed. We found that BMI may causally increase lumbar BMD (ß 0.087; 95% CI 0.025 to 0.149; P = 0.006) and heel calcaneus BMD (ß 0.120; 95% CI 0.082 to 0.157; P = 1 × 10-7). The associations of BMI with forearm and femoral neck BMD were not statistically significant. Our study suggested that higher BMI plays a causal role in increasing BMD and the effects are similar across the skeleton. BMI was causally and positively associated with lumbar and heel calcaneus BMD. However, no statistically significant effects were observed for BMI on femoral neck or forearm BMD.

Elevated preoperative plasma D-dimer dose not adversely affect survival of gastric cancer after gastrectomy with curative intent: A propensity score analysis.

OBJECTIVE: Elevated plasma D-dimer has been reported to be associated with advanced tumor stage and poor survival in several types of malignancies. The purpose of this study was to assess the potential impact of preoperative plasma D-dimer level (PDL) on overall survival (OS) of gastric cancer (GC) patients undergoing curative surgery by applying propensity score analysis. METHODS: A total of 1,025 curatively resected GC patients in Tianjin Medical University Cancer Institute & Hospital were enrolled. Patients were categorized into two groups based on preoperative PDL: the elevated group (EG) and the normal group (NG). To overcome bias due to the different distribution of covariates for the two groups, a one-to-one match was applied using propensity score analysis, after matching, prognostic factors were analyzed. RESULTS: In analysis for the whole study series, patients in the EG were more likely to have a larger proportion of tumor size ≥5 cm (67.5% vs. 55.8%, P=0.006), elder mean age (64.0±10.8 years vs. 60.5±11.6 years, P<0.001) and advanced tumor (T), node (N), and TNM stage. Patients with elevated PDL demonstrated a significantly lower 5-year OS than those with normal PDL (27.0%vs. 42.6%, P<0.001), however, the PDL was not an independent prognostic factor for OS in multivariate analysis [hazard ratio: 1.13, 95% confidence interval (95% CI): 0.92-1.39, P=0.236]. After matching, 163 patients in the EG and 163 patients in the NG had the same characteristics. The 5-year OS rate for patients in the EG was 27.0% compared with 25.8% for those in the NG (P=0.809, log-rank). CONCLUSIONS: The poor prognosis of GC patients with elevated preoperative PDL was due to the advanced tumor stage and elder age rather than the elevated D-dimer itself.

The effect of antisense inhibitor of miRNA 106b∼25 on the proliferation, invasion, migration, and apoptosis of gastric cancer cell.

Accumulating data has demonstrated that miRNA 106b∼25, which are composed of the highly conserved miRNA 106b, miRNA 93, and miRNA 25, play carcinogenic roles in cancers. We investigated the expression of miRNA 106b∼25 in gastric cancer cells (SGC 7901, MGC 803, BGC 823) and normal gastric epithelial cell then inhibited miRNA 106b∼25 expression via transiently transfecting their antisense inhibitor. After miRNA 106b∼25 cluster was inhibited, MTT, Scratch test, Transwell invasion test, and flow cytometry were applied to investigate the proliferation, invasion, migration, cell cycle, and apoptosis of gastric cancer cell. The expression of miRNA 106b, miRNA 93, and miRNA 25 in gastric cancer cells SGC 7901, MGC 803, and BGC 823 was significantly higher than in gastric epithelial cell GES-1. The most significant suppression of miRNA 106b∼25 expressions can be detected in MGC 803 cell after transiently transfecting their antisense inhibitors. So, MGC 803 cell was selected as our research object. After inhibiting miRNA 106b and miRNA 93 respectively and combined, the proliferation, migration, and invasion of gastric cancer cell MGC 803 were significantly suppressed. The most significant suppression was observed in combined inhibiting group. After miRNA 106b∼25 cluster was inhibited respectively or combined, more gastric cancer cells were arrested in the G0G1 phase. However, there was no statistical difference in comparing with control groups. While the percentages of apoptotic cells increased after miRNA 106b∼25 cluster was inhibited, the statistical difference was detected only in combined inhibiting group. Inhibiting miRNA 106b∼25 cluster via transfecting antisense inhibitor can influence biological behavior of gastric cancer cell.

Blood transfusion does not affect survival of gastric cancer patients.

BACKGROUND: To initially assess the impact of perioperative blood transfusions (PBTs) on overall survival of patients underwent curative resection of Ⅰ-Ⅲ TNM stage gastric cancer (GC) using the propensity scoring method. METHODS: The medical records of 1150 GC patients who underwent curative resection in the Tianjin Cancer Hospital between 2003 and 2008 were retrospectively analyzed. Both transfusion and nontransfusion patients were assessed the prognostic differences after surgery using the propensity score analysis. RESULTS: A total of 299 GC patients (26.0%) were administrated the PBT. With the unadjusted analysis, patients with PBT presented older age, more operative blood loss, lower hemoglobin, lower albumin level, and higher risk of the advanced disease. The 5-y survival rate for patients with PBT was 31.0%, which was significantly lower than that (47.9%) of patients without PBT (P < 0.05). However, we demonstrated that there was not any statistical 5-y survival rate difference of between patients with PBT and patients without PBT with the propensity score analysis (31.0% versus 31.3%, P > 0.05). In addition, we also found that PBT was not significantly associated with the increasing risk of mortality (hazard ratio, 1.054; P = 0.628). CONCLUSIONS: PBT could not give rise to the worse prognoses of GC patients.

Superiority of the ratio between negative and positive lymph nodes for predicting the prognosis for patients with gastric cancer.

BACKGROUND: This study aimed to elucidate the prognostic prediction superiority of the ratio between negative and positive lymph nodes (RNP) in gastric cancer (GC). METHODS: The clinicopathologic data of 1,563 GC patients were analyzed to demonstrate the prognostic significances of the RNP stage. The tumor RNP metastasis (TRNPM) classification system also was evaluated to determine the potential superiorities of the prognostic prediction for GC patients. RESULTS: In the univariate survival analysis, both RNP stage and TRNPM classification were demonstrated to be relative factors in the overall survival (OS) of GC patients. Like the tumor-node-metastasis (TNM) and positive and dissected lymph node (TRPDM) classifications, the TRNPM classification was identified as an independently prognostic predictor of GC patients using multivariate survival analysis. However, TRNPM classification has smaller Akaike information criterion and Bayesian information criterion values than the TNM and TRPDM classifications, and TRNPM classification was demonstrated to be the most intensive indicator for the OS of GC patients using the case-control matched approach, which represented the comparative superiorities of prognostic prediction of TRNPM classification. CONCLUSION: The RNP stage should be considered as the optimal variable for evaluating the prognosis of GC in the clinic.

Tumor size as a recommendable variable for accuracy of the prognostic prediction of gastric cancer: a retrospective analysis of 1,521 patients.

BACKGROUND: It is still controversial whether tumor size (Ts) should be considered an important indicator for evaluation the prognosis of gastric cancer (GC). The purpose of this study was to elucidate the prognostic prediction superiority of Ts in the large-scale cohort of GC patients. METHODS: Data from 1,521 patients who underwent the curative resection were analyzed for demonstration the prognostic value of Ts. In addition, a tumor size-node-metastasis (TsNM) classification system was proposed to evaluate the comparative superiorities of the prognostic prediction of GC patients. RESULTS: With the univariate and multivariate analyses, Ts was identified as an independently prognostic predictor of GC patients, as was T stage. Ts was demonstrated to have smaller Akaike information criterion and Bayesian Information Criterion values within the Cox regression analyses than shown by T stage, which represented the optimum prognostic stratification. TsNM classification was also found to be competent for accurately prognostic evaluation of GC patients. The matched case-control logistic regression showed that TsNM classification could provide very powerful discriminations of patients' overall survival, compared with TNM classification. Additionally, Ts stage was found to enhance the survival discriminations in patients with certain clinicopathological characteristics, including male gender, T4a stage, N0 stage, diffuse type of Lauren classification, or age ≤60 years. CONCLUSIONS: Ts should be recommended as an important clinicopathologic variable to enhance the accuracy of the prognostic prediction of GC clinical patients.

Positive impact of adding No.14v lymph node to D2 dissection on survival for distal gastric cancer patients after surgery with curative intent.

BACKGROUND: D2 lymphadenectomy has been increasingly regarded as standard surgical procedure for advanced gastric cancer (GC), while the necessity of No.14v lymph node (14v) dissection for distal GC is still controversial. METHODS: A total of 920 distal GC patients receiving at least a D2 lymph node dissection in Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital were enrolled in this study, of whom, 243 patients also had the 14v dissected. Other 677 patients without 14v dissection were used for comparison. RESULTS: Forty-five (18.5%) patients had 14v metastasis. There was no significant difference in 3-year overall survival (OS) rate between patients with and without 14v dissection. Following stratified analysis, in TNM stages I, II, IIIa and IV, 14v dissection did not affect 3-year OS; in contrast, patients with 14v dissection had a significant higher 3-year OS than those without in TNM stages IIIb and IIIc. In multivariate analysis, 14v dissection was found to be an independent prognostic factor for GC patients with TNM stage IIIb/IIIc disease [hazard ratio (HR), 1.568; 95% confidence interval (CI): 1.186-2.072; P=0.002]. GC patients with 14v dissection had a significant lower locoregional, especially lymph node, recurrence rate than those without 14v dissection (11.7% vs. 21.1%, P=0.035). CONCLUSIONS: Adding 14v to D2 lymphadenectomy may be associated with improved 3-year OS for distal GC staged TNM IIIb/IIIc.

N stages of the seventh edition of TNM Classification are the most intensive variables for predictions of the overall survival of gastric cancer patients who underwent limited lymphadenectomy.

The objective of this study was to explore the prognostic prediction rationality of the seventh edition N stage for gastric cancer (GC) patients who underwent the limited lymphadenectomy. Clinicopathological data of 769 GC patients who underwent the curative resection between 1997 and 2006 were analyzed for demonstration that the seventh edition N stage had the significant superiorities of prognostic prediction to the patients who underwent the limited lymphadenectomy. Although the extent of lymphadenectomy was associated with the overall survival (OS) of gastric cancer (GC) patients, the N stages of the seventh edition of the TNM Classification were identified as the most intensively independent predictors of GC prognosis. Using stratum analysis, the 5-year survival rate of patients who underwent limited lymphadenectomy was observed to be significantly different from that of patients who underwent extended lymphadenectomy, regardless of the extent of lymph node metastasis. Multinomial logistic regression analysis revealed that combining the extents of lymph node metastasis and lymphadenectomy could improve the prediction accuracy of patient survival status. Case control analysis showed that regardless of the extent of lymphadenectomy, the seventh edition N stages featured significant superiority for OS evaluation of GC patients. The seventh edition N stage had the prediction rationality for the OS of GC patients who underwent the limited lymphadenectomy.

Oncogenic and immunological role of EDIL3 in human tumours: From pan-cancer analysis to validation in gastric cancer.

Background: Epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) is a secreted extracellular matrix protein implicated in diverse physiological and pathological processes including embryonic development, angiogenesis, and anti-inflammatory responses. Recent reports have indicated that EDIL3 play critical roles in carcinogenesis and progression of many cancers. Herein, we performed a pan-cancer investigation to study the potential functions of EDIL3 in various cancers and experimentally validate its function in gastric cancer (GC). Methods: We analysed EDIL3 expression profiles in different tumours using The Cancer Genome Atlas database. The Kaplan-Meier Plotter was used to investigate the prognostic value of EDIL3, while receiver operating characteristic curve was performed to analyze its diagnostic efficacy. Several bioinformatics tools were used to study the association between EDIL3 and promoter methylation, gene enrichment analysis, immune infiltration, immune-related genes, and drug sensitivity. Molecular biology experiments were conducted to validate the tumorigenic effects of EDIL3. Results: EDIL3 is variably expressed in different cancers and is closely associated with clinical outcomes. An inverse correlation between EDIL3 and DNA methylation has been observed in 13 cancers. Enrichment analysis indicated that EDIL3 is correlated with many cellular pathways such as extracellular matrix receptor interactions and focal adhesion. EDIL3 was tightly associated with immune infiltration and immune checkpoints. EDIL3 knockdown can promote GC calls apoptosis while preventing proliferation, migration, and invasion in vitro. Conclusion: EDIL3 is a promising prognostic, diagnostic, and immunological biomarker in various cancers, which could be applied as a new target for cancer therapy.

CLEC4D as a Novel Prognostic Marker Boosts the Proliferation and Migration of Gastric Cancer via the NF-κB/AKT Signaling Pathway.

Purpose: The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods: This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results: In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion: Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.

ACAT2 suppresses the ubiquitination of YAP1 to enhance the proliferation and metastasis ability of gastric cancer via the upregulation of SETD7.

The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.

Association of survival with adjuvant chemotherapy in patients with stage IB gastric cancer: a multicentre, observational, cohort study.

Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious. Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy. Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52-1.00; DFS: HR, 0.91; 95% CI, 0.64-1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08-0.57; P = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17-0.62; P < 0.001 for multiplicative interaction), or positive lymph nodes (HR, 0.17; 95% CI, 0.07-0.38; P < 0.001 for multiplicative interaction). The survival prediction models mainly based on variables associated with chemotherapy benefits in the subgroup analysis demonstrated good calibration and discrimination, with relatively high C-indexes. The C-indexes for OS were 0.74 for patients treated with adjuvant chemotherapy and 0.70 for patients treated with postoperative observation. Two nomograms were built from the models that can calculate individualized estimates of expected net survival gain attributable to adjuvant chemotherapy. Interpretation: In this cohort study, pathologic stage IB alone was not associated with survival benefits from adjuvant chemotherapy compared with postoperative observation in patients with early-stage GC. High-risk clinicopathologic features should be considered simultaneously when evaluating patients with stage IB GC for adjuvant chemotherapy. Funding: National Natural Science Foundation of China; the National Key R&D Program of China.

STAT3 is associated with lymph node metastasis in gastric cancer.

This study aims to explore the detailed signal transduction mechanism of epidermal growth factor receptor (EGFR)/signal transducers and activators of transcription 3 (STAT3) that contributes to the progression of gastric cancer (GC). The STAT3 expression, phosphorylated STAT3 (pSTAT3) expression, and EGFR expression were evaluated by using molecular detection methods of GC tissues, adjacent non-tumor tissues, GC cell lines, and normal gastric cell line. Cetuximab was administered in each cell line to demonstrate the correlations among the above biomarkers. Survival and relationship analyses were adopted to demonstrate the important mechanism of EGFR/STAT3 signaling pathway contributing to the progression of GC. STAT3 expression, pSTAT3 expression, and EGFR expression in GC tissues were significantly higher than those in adjacent non-tumor tissues, respectively. Similarly, we found that STAT3 expression, pSTAT3 expression, and EGFR expression were much higher in GC cell lines than those in GES-1 cell line. With cetuximab administration, both STAT3 expression and pSTAT3 expression in all GC cell lines decreased simultaneously. With Cox proportional hazards model analysis, pSTAT3 expression was identified as the independent predictors of the overall survival of GC patients, as was EGFR expression. Furthermore, we found that there were significant associations between STAT3 expression, pSTAT3 expression, EGFR expression, and lymph node metastasis in GC tissues. The activation of EGFR/STAT3 signaling pathway may contribute to lymph node metastasis, which can promote the progression of GC.

Overexpression of stathmin 1 is associated with poor prognosis of patients with gastric cancer.

Recently, stathmin 1 has been proposed to function as an oncogene based on some relevant studies in multiple types of human cancers. However, the role of stathmin 1 in gastric cancer carcinogenesis has not been elucidated yet. The aim of this study was to investigate the expression of stathmin 1 as well as its association with overall survival of gastric cancer patients. The expression of stathmin 1 was detected by real-time quantitative reverse transcription polymerase chain reaction and Western blotting in gastric cancer and adjacent nontumor tissues. In addition, stathmin 1 expression was analyzed by immunohistochemistry in paraffin samples from 210 primary gastric cancer patients. The expression levels of stathmin 1 mRNA and protein in gastric cancer tissues were both significantly higher than those in adjacent nontumor tissues. In addition, the expression of stathmin 1 is correlated with Lauren's classification, depth of invasion, lymph node metastases, and tumor node metastasis (TNM) stage (all P < 0.05). Univariate analysis showed that high stathmin 1 expression was associated with poor prognosis in gastric cancer patients (P = 0.040). Multivariate analysis demonstrated that only lymph node metastasis and TNM stage were the independent prognostic indicators for gastric cancer. Stathmin 1 expression status is not an independent prognostic factor for patients with gastric cancer. Further subgroup analysis revealed that stathmin 1 expression was significantly correlated with prognosis in diffuse type gastric cancer. This research showed that the stathmin 1 overexpression might play an important role in the pathogenesis and subsequent progression of gastric cancer. Stathmin 1 could also be a potential therapeutic target in gastric cancer, especially for diffuse type gastric cancer.