Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis.

The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan-Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity.

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

Patient stratification based on urea cycle metabolism for exploration of combination immunotherapy in colon cancer.

BACKGROUND: Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy. METHODS: We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation. RESULTS: Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues. CONCLUSION: Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.

Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer.

BACKGROUND: In the face of poor prognosis and immunotherapy failure of gastric cancer (GC), this project tried to find new potential biomarkers for predicting prognosis and precision medication to ameliorate the situation. METHODS: To form synthetic matrices, we retrieved stomach adenocarcinoma transcriptome data from Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Necroptosis-related prognostic lncRNA was identified by coexpression analysis and univariate Cox regression. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the necroptosis-related lncRNA model. Next, the Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), univariate Cox (uni-Cox) regression, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were made to verify and evaluate the model. Gene set enrichment analyses (GSEA), principal component analysis (PCA), immune analysis, and prediction of the half-maximal inhibitory concentration (IC50) in risk groups were also analyzed. For further discussing immunotherapy between the cold and hot tumors, we divided the entire set into two clusters based on necroptosis-related lncRNAs. RESULTS: We constructed a model with 16 necroptosis-related lncRNAs. In the model, we found the calibration plots showed a good concordance with the prognosis prediction. The area's 1-, 2-, and 3-year OS under the ROC curve (AUC) were 0.726, 0.763, and 0.770, respectively. Risk groups could be a guide of systemic treatment because of significantly different IC50 between risk groups. Above all, clusters could help distinguish between the cold and hot tumors effectively and contribute to precise mediation. Cluster 2 was identified as the hot tumor and more susceptible to immunotherapeutic drugs. CONCLUSION: The results of this project supported that necroptosis-related lncRNAs could predict prognosis and help make a distinction between the cold and hot tumors for improving individual therapy in GC.

Ectopic bronchogenic cyst in the retroperitoneal region: a case report and literature review of adult patients.

BACKGROUND: Bronchogenic cyst is congenital aberration of bronchopulmonary malformation, which is rarely encountered in the abdomen and retroperitoneum. We present a case report and literature review of retroperitoneal bronchogenic cyst. CASE PRESENTATION: A 53-year-old female presented to outpatient clinic for a routine checkup of lumbar intervertebral disc herniation. She received a contrast computed tomography scan of the abdomen which revealed a retroperitoneal cystic lesion below the left crura of diaphragm. Afterward, the patient underwent a laparoscopic excision of the cystic lesion and was discharged uneventfully at postoperative day 4. Histopathological findings confirmed the diagnosis of retroperitoneal bronchogenic cyst. Our literature review identified 55 adult cases in recent two decades. The average age at diagnosis was 43.2 (range 17-69) years. 44 (80%) cases had a retroperitoneal cyst on the left side, and 52 (94.5%) cases underwent curative excision through open or laparoscopic surgery. In the available follow up of cases, there was no recurrence after surgery. CONCLUSIONS: Bronchogenic cyst is rare in the retroperitoneal region. It should be considered as one of the differential diagnoses of a retroperitoneal neoplasm.

A Substage Increase in The AJCC Classification System Improves Prognostic Prediction in Stage III Gastric Cancer With Insufficient Lymph Nodes Removed.

BACKGROUND: The impact of lymph nodes (LNs) removed on the survivals of patients with stage III gastric cancer, especially on that of those who undergo the adjuvant chemotherapy as a compensation for a possibly insufficient lymphadenectomy, is still unclear. METHODS: Consecutive patients (n = 488) with stage III gastric cancer under R0 curative resection followed by adjuvant chemotherapy were analyzed. The overall survival (OS) was compared between patients with insufficient LNs removed (ILNr, <16 LNs) and sufficient LNs removed (SLNr, ≥16 LNs). Performance of the prediction systems was evaluated using the Likelihood ratio χ2 test, Akaike information criterion (AIC), Harrell's concordance index (C-index), and area under the receiver operating characteristic curves (AUC). RESULTS: The OS of patients were significantly longer in those with SLNr relative to those with ILNr (for stage IIIA, 68.2 vs. 43.2 months, P = 0.042; for stage IIIB, 43.7 vs. 24.9 months, P < 0.001; for stage IIIC, 23.9 vs. 8.3 months, P < 0.001; and for total stage III, 37.7 vs. 21.7 months, P < 0.001). However, the OS were similar between stage IIIA patients with ILNr and stage IIIB patients with SLNr (P = 0.928), between IIIB patients with ILNr and IIIC patients with SLNr (P = 0.962), and IIIC patients with ILNr and stage IV (P = 0.668), respectively. A substage increase in the AJCC classification system, from IIIA to IIIB, from IIIB to IIIC, and from IIIC to IV in patients with ILNr, enhanced the accuracy of prognostic prediction in patients with stage III gastric cancer compared to the current TNM system (Likelihood ratio χ2, 188.6 vs. 184.8; AIC, 4336.4 vs. 4340.6; C-index, 0.695 vs. 0.679, P = 0.002). The ROC curves revealed that the performance of prognostic prediction was better in the new prediction system (AUC = 0.699) compared with the current TNM system (AUC = 0.676). CONCLUSIONS: ILNr (LNs <16) impairs the long-term outcomes of stage III gastric cancer underwent adjuvant chemotherapy. The status of LNs removal adds values to the current TNM system in prognostic prediction of stage III gastric cancer.

p53-Induced LINC00893 Regulates RBFOX2 Stability to Suppress Gastric Cancer Progression.

Long noncoding RNAs (lncRNAs) have been reported to regulate diverse tumorigenic processes. However, little is known about long intergenic non-protein coding RNA 00893 (LINC00893) and its role in gastric cancer (GC). Herein we investigated its biological functions and molecular mechanism in GC. LINC00893 was decreased in GC tissues but significantly elevated in AGS cells after treatment with Nutlin-3. In GC patients, it was found that low expression of LINC00893 was correlated with tumor growth, metastasis and poor survival. Functionally, overexpression of LINC00893 suppressed the proliferation, migration and invasion of GC cells. Mechanistically, LINC00893 regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins by binding to RNA binding fox-1 homolog 2 (RBFOX2) and promoting its ubiquitin-mediated degradation, thus suppressing the EMT and related functions of GC. In addition, the transcription factor p53 can regulate the expression of LINC00893 in an indirect way. Taken together, these results suggested that LINC00893 regulated by p53 repressed GC proliferation, migration and invasion by functioning as a binding site for RBFOX2 to regulate its stability and the expression of EMT-related proteins. LINC00893 acts as a tumor-inhibiting lncRNA that is induced by p53 in GC and regulates EMT by binding to RBFOX2, thus providing a novel experimental basis for the clinical treatment of GC.

MicroRNA-188-5p targeting Forkhead Box L1 promotes colorectal cancer progression via activating Wnt/ß-catenin signaling.

Objective: MicroRNA-188-5p (miR-188) enhances oncologic progression in various human malignancies. This study aimed to explore its role in colorectal cancer (CRC). Materials and Methods: Human CRC tissues paired with normal tissues, and several CRC cell lines were utilized. Real-time quantitative PCR was applied to measure the expression of miR-188. Overexpression and knockdown were used to access the function of miR-188 and to investigate whether FOXL1/Wnt signaling mediates such function. The proliferation, migration and invasion of cancer cells were evaluated by CCK8, wound-healing and transwell assays, respectively. Whether FOXL1 acted as a direct target of miR-188 was verified by dual-luciferase reporter assays. Results: Levels of miR-188 were upregulated in CRC tissues than in paired-normal tissues, as well as in various CRC cell lines. High expression of miR-188 was strongly associated with advanced tumor stage, accompanied with significant tumor cell proliferation, invasion and migration. It was confirmed that FOXL1 played positive crosstalk between miR-188 regulation and downstream Wnt/ß-catenin signaling activation. Conclusions: All findings indicate that miR-188 promotes CRC cell proliferation and invasion through targeting FOXL1/Wnt signaling and could be served as a potential therapeutic target for human CRC in the future.

MicroRNA-188-5p targeting Forkhead Box L1 promotes colorectal cancer progression via activating Wnt/ß-catenin signaling.

MicroRNA-188-5p (miR-188) enhances oncologic progression in various human malignancies. This study aimed to explore its role in colorectal cancer (CRC). Human CRC tissues paired with normal tissues, and several CRC cell lines were utilized. Real-time quantitative PCR was applied to measure the expression of miR-188. Overexpression and knockdown were used to access the function of miR-188 and to investigate whether FOXL1/Wnt signaling mediates such function. The proliferation, migration and invasion of cancer cells were evaluated by CCK8, wound-healing and transwell assays, respectively. Whether FOXL1 acted as a direct target of miR-188 was verified by dual-luciferase reporter assays. Levels of miR-188 were upregulated in CRC tissues than in paired-normal tissues, as well as in various CRC cell lines. High expression of miR-188 was strongly associated with advanced tumor stage, accompanied with significant tumor cell proliferation, invasion and migration. It was confirmed that FOXL1 played positive crosstalk between miR-188 regulation and downstream Wnt/β-catenin signaling activation. All findings indicate that miR-188 promotes CRC cell proliferation and invasion through targeting FOXL1/Wnt signaling and could be served as a potential therapeutic target for human CRC in the future.

Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

A precise temperature control during hyperthermic intraperitoneal chemotherapy promises an early return of bowel function.

INTRODUCTION: The hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely applied in clinical practice for peritoneal carcinomatosis (PC). The temperature is one of the important elements affecting the efficacy of HIPEC, and it can become fluctuant by several factors. This study is aimed to explore the role of a stable perfusion temperature in promoting bowel recovery of PC patients due to gastrointestinal malignancies. METHODS: Between January 2012 and July 2013, 59 PC patients undergoing cytoreductive surgery and three-cycle HIPEC were included. Patients having stable perfusion temperature for all cycles were assigned into the study group, with the rest having unstable temperature into the control group. Time of flatus and defecation passage and initiation time of enteral nutrition were compared between both groups to detect the significance in bowel function recovery, with visual analogue scale (VAS) pain intensity and overall survival (OS) compared meanwhile. RESULTS: In sum, 33 (55.9%) patients obtained stable temperature during HIPEC, and the rest of 26 (44.1%) developed fluctuant perfusion temperature. Average time of flatus (2.3 ± 1.2 vs 3.9 ± 2.2 days, P =.002), defecation passage (5.2 ± 2.1 vs 7.1 ± 2.9 days, P =.004) and enteral nutrition initiation (4.3 ± 1.5 vs 6.7 ± 2.3 days, P <.001) were much shorter in the study group than the control group. Additionally, the VAS score (4.5 ± 2.3 vs 6.3 ± 1.3, P <.001) and 5-year OS rate (17.8% vs 11.1%, P=.135) were both improved, with significance observed in postoperative pain control. CONCLUSIONS: During HIPEC, a precise temperature control could promise an early recovery of bowel function and reduce postoperative pain, without survival significance found based on the current cohort.

CT-based radiomics scores predict response to neoadjuvant chemotherapy and survival in patients with gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy is a promising treatment option for potential resectable gastric cancer, but patients' responses vary. We aimed to develop and validate a radiomics score (rad_score) to predict treatment response to neoadjuvant chemotherapy and to investigate its efficacy in survival stratification. METHODS: A total of 106 patients with neoadjuvant chemotherapy before gastrectomy were included (training cohort: n = 74; validation cohort: n = 32). Radiomics features were extracted from the pre-treatment portal venous-phase CT. After feature reduction, a rad_score was established by Randomised Tree algorithm. A rad_clinical_score was constructed by integrating the rad_score with clinical variables, so was a clinical score by clinical variables only. The three scores were validated regarding their discrimination and clinical usefulness. The patients were stratified into two groups according to the score thresholds (updated with post-operative clinical variables), and their survivals were compared. RESULTS: In the validation cohort, the rad_score demonstrated a good predicting performance in treatment response to the neoadjuvant chemotherapy (AUC [95% CI] =0.82 [0.67, 0.98]), which was better than the clinical score (based on pre-operative clinical variables) without significant difference (0.62 [0.42, 0.83], P = 0.09). The rad_clinical_score could not further improve the performance of the rad_score (0.70 [0.51, 0.88], P = 0.16). Based on the thresholds of these scores, the high-score groups all achieved better survivals than the low-score groups in the whole cohort (all P < 0.001). CONCLUSION: The rad_score that we developed was effective in predicting treatment response to neoadjuvant chemotherapy and in stratifying patients with gastric cancer into different survival groups. Our proposed strategy is useful for individualised treatment planning.

Complement C3 overexpression activates JAK2/STAT3 pathway and correlates with gastric cancer progression.

BACKGROUND: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. METHODS: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. RESULTS: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. CONCLUSIONS: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.

Aberrant AFP expression characterizes a subset of hepatocellular carcinoma with distinct gene expression patterns and inferior prognosis.

Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored. Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied. Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024). Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue.

Gastric duplication 20 years after a partial distal gastrectomy: a case report and review of literature.

Gastric duplications are the least common gastrointestinal duplications, especially in adults. Duplication cyst with an accessory pancreatic lobe is extremely rare and is even more uncommon in the setting of polysplenia. No gastric duplication after partial gastrectomy has been reported. We present a 41-year-old male diagnosed with gastric duplications with an accessory pancreatic lobe and polysplenia. Another characteristic of this case is partial gastrectomy 20 years ago without the discovery of duplication cysts. The gastric duplications, accessory pancreatic lobe and accessory spleen were successfully resected.

Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation.

Background: As a class of endogenous noncoding RNAs, some circular RNAs (circRNAs) have recently been reported to play a role in the regulation of tumorigenesis and progression in colorectal cancer (CRC). However, the mechanisms by which most these circRNAs function in CRC are still unclear. Purpose: The objective of this study was to identify the role of circRNA-ITGA7 in CRC cell proliferation. Patients and methods: Human genome-wide circRNA microarray v2 analysis was used for expression profile analysis. Target genes were predicted using online bioinformatics database, including TargetScan, miRDB, miRTarbase and miRMap. Gene overexpression and silencing cell models were built using cell transfection. qRT-PCR and Western blot were performed for gene and protein expression assessment. CCK8, colony formation and cell cycle analysis were used for proliferation testing. Annexin V-FITC analysis was performed for apoptosis detection. Results: CircRNA sequencing analysis suggested that compared to that in adjacent normal control tissue, the expression of circ-ITGA7, a novel circRNA, is decreased significantly in CRC. Gain-of-function studies further demonstrated that circ-ITGA7 suppressed proliferation of CRC cells. Based on prediction and verification, we subsequently revealed that miR-3187-3p is a circ-ITGA7-associated miRNA. Furthermore, RNA sequencing and bioinformatics analyses showed that ASXL1-5'UTR, the target of miR-3187-3p, is upregulated in circ-ITGA7-overexpressed cells and mediates the circ-ITGA7-induced suppression of proliferation. Conclusion: Circ-ITGA7 might suppress CRC proliferation by sponging miR-3187-3p and increasing ASXL1 expression. Thus, circ-ITGA7 might be a potential diagnostic biomarker and a therapeutic target for CRC.

Does Lymphadenectomy with at Least 15 Perigastric Lymph Nodes Retrieval Promise an Improved Survival for Gastric Cancer: A Retrospective Cohort Study in Southern China.

Background: Specific guidelines recommend at least 15 or 16 lymph nodes (LNs) be examined to adequately assess nodal category of gastric cancer (GC), but the requirement for minimum number of regional LNs retrieval is not mentioned. This study aims to investigate survival significance from various numbers of perigastric (N1) LNs retrieval and to determine an optimal number harvested in such region. Study design: From April 1994 to March 2012, 1003 resectable GC patients with at least 15 LNs examined were included. Patients with at least 15 N1 nodes retrieval were assigned into study group, with the rest into control group. The 5-year overall survival (OS) rate was compared between two groups, and an optimal number of examined N1 nodes was detected by a survival joinpoint analysis. Results: 635 (63.3%) patients in study group had median 22 (range, 15-75) N1 nodes and 3 (range, 0-74) positive N1 nodes retrieval, with median 10 (range, 0-14) N1 nodes and 1 (range, 0-29) metastatic N1 nodes examined in control group. The number of N1 nodes retrieval was associated with tumor location (P=0.007), tumor stage (P<0.001) and total number of harvested LNs ( r =0.691, P<0.001). Median survival time (79.0 vs. 72.0 months, P=0.462) and actual 5-year OS rate (41.0% vs. 39.2%, P=0.463) were slightly improved in study group compared with control group, with significance obtained via stage-by-stage analysis. The joinpoint analysis indicated that at least seven N1 nodes retrieval achieved survival significance (81.0 vs. 35.0 months, P=0.036), with survival superiority remained until reaching up to 15 N1 nodes. Conclusion: Adequate retrieval of perigastric LNs is essential for radical gastrectomy. A harvest of at least 7-15 perigastric LNs could achieve long-term survival benefit for GC patients.

The prognostic role of Helicobacter pylori in gastric cancer patients: A meta-analysis.

BACKGROUND: The prognostic value of Helicobacter pylori (H. pylori) infection in gastric cancer patients has been investigated over many years; however, the results remain inconclusive. Thus, we performed a comprehensive review of currently available evidence via a systemic meta-analysis to evaluate the effects of H. pylori infection on the prognosis of gastric cancer patients. METHODS: Studies that evaluated the prognostic value of H. pylori infection in gastric cancer were extracted in March 2016 by searching PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. We obtained or calculated hazard ratios (HRs) and the associated 95% confidence intervals (CIs) from the identified studies, and conducted random-effects model analyses of overall survival and progression-free survival. Twenty-four studies with a cumulative sample size of 7191 patients were included in our analysis. RESULTS: Our meta-analysis revealed that H. pylori infection is an indicator of improved overall survival in gastric cancer patients (HR, 0.79; 95% CI, 0.64-0.99); however, this was only true for European patients. The benefits of H. pylori infection were not detected in Asian gastric cancer patients (HR, 1.01; 95% CI, 0.91-1.12) or those in the United States (HR, 0.88; 95% CI, 0.73-1.05). Subgroup analyses revealed that the prognostic significance of H. pylori infection differed with respect to the year of study publication, number of patients, H. pylori detection method, tumor stage, H. pylori-positive rate, and risk of bias. The prognostic value of H. pylori infection on progression-free survival was unclear (HR, 0.84; 95% CI, 0.70-1.01). CONCLUSIONS: These data provide limited, moderate-quality evidence that H. pylori infection is an indicator of good prognosis in European gastric cancer patients. However, this is not necessarily true for other populations.

The mTORC1 signaling modulated by intracellular C3 activation in Paneth cells promotes intestinal epithelial regeneration during acute injury.

Complement activation is associated with regional inflammation during acute gastrointestinal injury (AGI). This study is designed to explore how intracellular C3 activation in Paneth cells (PCs) affects regeneration of intestinal epithelium during AGI. AGI was induced in wildtype C57BL/6 mice, with sham operation employed as control. Exogenous C3 (1 mg, I.P.) was applied at 6 h post-surgery. Intestinal crypts harvested from ileum were cultured with presence or absence of C3 (20 µg/ml), with small interfering RNA against BST1 and complement activation inhibitor selectively applied in vitro. The intestinal integrity, percentage of PCs and intestinal stem cells (ISCs) were evaluated. Importantly, cADPR, C3 fragments, and S6-related proteins were detected in PCs to inspect the mammalian target of rapamycin complex 1 (mTORC1) signaling. AGI caused breakdown of intestinal mucosa integrity and regional inflammation. Exogenous C3 by itself failed to promote the growth of intestinal epithelium, but distinctly enhanced the activity of PCs via intracellular activation, which subsequently supported the expansion of ISCs inside of intestinal crypts. Inhibition of C3 activation was associated with decreased expressions of S6, S6K1 and cADPR, with blocking BST1 found to depress cADPR only. Collectively, these data confirmed intracellular activation of C3 in PCs enhanced expansion of ISCs in response to acute injury. The mTORC1 signaling pathway in PCs contributed to this crosstalk during exogenous C3 treatment.

Intracellular activation of complement C3 in Paneth cells improves repair of intestinal epithelia during acute injury.

AIM: To explore whether Paneth cells (PCs) and complement system collaborate in the repair of enteric epithelia during acute gastrointestinal injury (AGI). METHODS: Wild-type C57BL/6 mice were employed to induce AGI by performing colon ascendens stent surgery, with sham-operated as control. Exogenous C3 treatment was applied at 6-h postsurgery. After 48 h, overall survival, intestinal damage severity, and C3 intracellular activation were assessed in both epithelial cells and PCs. RESULTS: AGI caused a high mortality, while C3 therapy significantly attenuated epithelial damages and improved survival. Besides, exogenous C3 in vitro enhanced the proliferation and activity of PCs. Importantly, intracellular C3 activation was observed inside of PCs under C3 co-stimulation in vitro. CONCLUSION: C3 immunotherapy might play a valuable role in turnover of gut epithelia through intracellular activation in PCs.