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BackgroundThe systemic inflammation score (SIS), based on preoperative serum albumin (Alb) level and lymphocyte-to-monocyte ratio (LMR), has been shown to be a novel prognostic score for some tumors. We investigate the prognostic value of the SIS in patients with resectable gastric cancer (GC).MethodsPatients with GC who underwent curative resection between December 2008 and December 2013 were included. Time-dependent receiver operating characteristics analysis (t-ROC), concordance index (C-index) and AUC were used to compare the prognostic impact.ResultsTotally, 1786 patients with resectable GC were included in the study. By multivariate analysis, the SIS was not an independent prognostic factor. However, the normal Alb level (≥ 40 g/l) and LMR ≥ 3.4 both remained independent protective factors for GC (both P < 0.05). Due to the similar survival of patients with LMR ≥ 3.4 and LMR < 3.4 in the normal Alb group, we combined the two subgroups to establish the modified SIS (mSIS). Multivariate analysis revealed that the mSIS was the only significant independent biomarker (P < 0.05). The t-ROC curve and C-index for the mSIS were superior to those of the SIS throughout the observation period. Furthermore, the AUC of the mSIS was significantly greater than that of the SIS at 3 and 5 years after operation (both P < 0.05).ConclusionThe preoperative mSIS is a novel, simple and useful prognostic factor for postoperative survival in patients with GC and can be used as a part of the preoperative risk stratification process to improve the prediction of clinical outcomes.

Background We sought to investigate the prognostic value of complete blood count (CBC)-based biomarkers for patients with resectable gastric cancer (GC). Methods Patients with GC who underwent primary surgical resection between December 2008 and December 2013 were included. The estimated area under the curve (AUC) and multivariate Cox regression models were used to identify the best CBC-based biomarker. Time-dependent receiver operating characteristic (t-ROC) curve analysis was used to predict overall survival and compare the prognostic impact. Results In the 1810 patients analyzed, the median follow-up period was 51.0 months (range 1–101 months). Based on multivariate analysis, the lymphocyte-monocyte ratio (LMR) and hemoglobin (Hb) level were independent prognostic factors (both P  < 0.05). Based on the LMR and Hb level, we established the CBC-based inflammatory score (CBCS). A higher CBCS was associated with older age, female sex, higher American Society of Anesthesiologists (ASA) score, proximal tumor location, larger tumor size, later stage and vascular involvement (all P  < 0.05). Univariate analyses showed that a higher CBCS was also associated with worse overall survival (OS), which was consistent in each stage (all P < 0.05). Multivariate analysis revealed that the CBCS was a significant independent biomarker (P < 0.05). The AUC for the CBCS (0.627) was significantly higher than the AUCs for the LMR (0.573) and Hb level (0.605) (both P < 0.05). Furthermore, the t-ROC curve of the CBCS was superior to that of the prognostic nutritional index (PNI), systemic immune-inflammation index (SII), modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin ratio (CRP/Alb) throughout the observation period. Conclusion The preoperative LMR and Hb level were optimal CBC-based biomarkers for predicting OS in GC patients after curative resection. Based on the LMR and Hb, we developed a novel and easily obtainable prognostic score called the CBCS, which may improve the prediction of clinical outcomes.

BackgroundWhile p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.ObjectiveThis study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.DesignWe used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r+ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.ResultsThe p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors’ organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.Conclusionsp53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

Background The effects of preoperative malnutrition and preoperative correction of hypoalbuminemia (PCH) on the short- and long-term outcomes in patients with gastric cancer are unclear. Objective This study aimed to examine the effect of preoperative nutritional status on short- and long-term outcomes in patients who underwent radical gastrectomy, and also explored the role of PCH in malnourished patients with gastric cancer. Methods We prospectively reviewed data from patients with gastric cancer who were treated in our department between January 2009 and December 2014. The effect of preoperative nutritional status on short- and long-term outcomes in patients who underwent radical gastrectomy was investigated, and we explored whether PCH could improve the short- and long-term outcomes of these patients. Results A total of 1976 patients were analyzed, including 412 patients in the malnourished group and 1564 in the well-nourished group. The overall incidence of complications in the malnourished group was significantly higher than the well-nourished group (21.4 vs. 15.5%, p  = 0.005). Except for incision infection (3.2 vs. 1.6%, p  = 0.041), there were no significant differences for other complications. In the malnourished group, 98 cases of preoperative hypoproteinemia were corrected (PCH group), whereas 314 cases were not (NPCH group). The incidence of incision infection in the PCH group was significantly lower than in the NPCH group (0 vs. 4.1%, p  = 0.041). The median follow-up time was 39 months (1.0–88.0 months), and the 3-year overall survival (OS; 59.1 vs. 75%, p  < 0.001) and disease-free survival (DFS; 54.8 vs. 72.5%, p  < 0.001) rates were significantly lower in the malnourished group than in the well-nourished group. A multivariate Cox regression analysis showed that malnutrition was an independent prognostic factor for 3-year OS (hazard ratio [HR] 1.211, 95% confidence interval [CI] 1.01–1.452, p  = 0.039) and DFS (HR 1.168, 95% CI 1.013–1.398, p  = 0.043). For the malnourished group with stage I gastric cancer, the PCH and NPCH groups showed no significant differences in 3-year OS (90.0 vs. 89.0%, p  = 0.227) or DFS (90.0 vs. 87.3%, p  = 0.363); however, for the malnourished group with stages II–III gastric cancer, the 3-year OS (69.9 vs. 47.6%, p  = 0.013) and DFS (55.4 vs. 43.6%, p  = 0.046) rates were significantly higher in the PCH group than in the NPCH group. Conclusions The incidence of incision infection was significantly higher in patients with malnutrition than in well-nourished patients. The 3-year OS and DFS rates were significantly lower in malnourished patients than in well-nourished patients. PCH may both reduce the incidence of incisional infection in patients with malnutrition and improve 3-year OS and DFS rates for malnourished patients with stages II–III gastric cancer; however, to confirm our findings, further studies are warranted.

ObjectiveThe aim of this study was to determine the prognostic significance of preoperative carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels in patients with resectable gastric cancer (GC).Patients and MethodsPatients who underwent a radical resection for GC at the Fujian Medical University Union Hospital between 2007 and 2014 were included in this study. The estimated area under the curve (AUC) was compared to evaluate the discriminatory ability of tumor makers. Additional external validation was performed using a dataset from Sun Yat-sen University Cancer Center.ResultsPreoperative CEA/CA19-9 levels were identified as an independent predictor of overall survival (OS) and disease-specific survival (DSS) (both p < 0.05) in the development group. In a subgroup analysis based on TNM stage, preoperative CEA/CA19-9 levels clearly stratified the survival rates for stage III GC (p < 0.05). A multivariate analysis revealed that preoperative CEA/CA19-9 levels were an independent prognostic factor (p < 0.05) in stage III; the AUC of the preoperative CEA/CA19-9 was equivalent to that of T stage. A prediction model (TNMC) for stage III GC was developed by incorporating preoperative CEA/CA19-9 levels into the American Joint Committee on Cancer (AJCC) staging system. The AUC of the TNMC was significantly higher than that of the TNM staging system at 1, 3, and 5 years postoperatively (all p < 0.05), with similar results also being obtained in the external validation set.ConclusionPreoperative CEA/CA19-9 levels are an independent predictor of OS and DSS in stage III GC patients. The inclusion of preoperative CEA/CA19-9 levels in AJCC TNM staging provided an optimal prognosis in stage III GC.

Carcinoembryonic antigen (CEA) is one of the important indexes for the diagnosis and prognosis of gastrointestinal cancer. Systemic inflammatory response (SIR) is closely related to the occurrence and development of gastrointestinal cancer. A total of 803 patients who underwent radical gastrectomy in Qinghai University Affiliated Hospital from January 2012 to December 2016 were included as training set. Multivariable Cox proportional hazard regression was used to identify associations with outcome of gastric cancer (GC). CNLR was established by combining CEA and the neutrophils to lymphocytes ratio (NLR, a typical parameter in SIR) to generate a novel prognostic score system and its prognostic value was externally validated. Multivariate analysis showed that CEA and NLR were independent prognostic factors for GC patients (both < 0.05). A higher CNLR was significantly associated with older age, male sex, larger tumor size, vascular invasion and advanced stages (all < 0.05). Patients with higher CNLR had poor prognosis than those with lower CNLR ( < 0.05). Multivariate analysis showed that CNLR was an independent prognostic factor ( < 0.05). Incorporation of the CNLR into a prognostic model including age and TNM stage generated a nomogram, which predicted accurately 3- and 5-year survival for GC patients. And similar results were obtained in the external validation set. The CNLR prognostic scoring system established by combining CEA and NLR is an independent prognostic factor for GC, which can be incorporated into the traditional TNM staging to improve the prediction of long-term survival outcomes.

Background Previous studies have suggested that preoperative anemia negatively influences survival in patients with gastric cancer (GC). We sought to investigate which anemic markers can better predict the prognosis of patients with resectable GC. Methods The study involved 2277 GC patients who underwent curative resection between December 2008 and December 2014. Cox regression models were used to identify the best anemic markers associated with prognosis. Time-dependent receiver operating characteristics analysis (t-ROC) and the estimated area under the curve (AUC) were used to compare the prognostic values. Results Of all patients, 1709 (75.1%) were male, and the median age was 61 years. Univariate analyses showed that preoperative hematocrit (HCT), hemoglobin, and mean corpuscular volume were associated with OS (all P  < 0.05). However, in a separate analysis of individual stages, only HCT was shown to be significantly prognostic across all tumor stages (all P  < 0.05). In the multivariate analysis, preoperative HCT remained an independent prognostic factor for GC. Low HCT was significantly associated with older age, female sex, lower body mass index, higher American Society of Anesthesiologists score, higher preoperative transfusion rate, 90-day mortality, adjuvant chemotherapy, larger tumor size, lymph node metastasis, later stage, and vascular involvement. The t-ROC curve and AUC for HCT were similar to those for the controlling nutritional status and prognostic nutritional index throughout the observation period. Conclusions The preoperative HCT is a novel, simple, and powerful prognostic indicator of poor outcome in patients with GC and can be used as a part of the preoperative risk stratification process.

Objective To validate the efficacy and safety of laparoscopic total gastrectomy (LTG) for advanced gastric cancer (AGC). Background Laparoscopic distal gastrectomy (LDG) in the treatment of patients with local AGC is becoming increasingly popular, and there have been several multicenter randomized controlled trials focused on this treatment. However, few reports on the procedure of LTG for AGC exist. Methods The data of 976 patients who underwent LTG for AGC were retrieved from a prospectively constructed database of 2170 patients who underwent laparoscopic gastrectomy between 2007 and 2013. Surgical outcomes of LTG were investigated and compared with those of patients who underwent LDG. Results LTG was associated with significantly longer operation time, number of dissected lymph nodes, and time of resume soft diet compared with the LDG group. According to Clavien–Dindo classification, the morbidity and mortality rates of the LTG group were comparable to those of the LDG group. Multivariate analyses revealed that elderly patients, more comorbidities, and longer operation time were the significant independent risk factors for determining postoperative complications. The difference in overall survival rates between the two groups was statistically significant. However, a comparative analysis of overall survival showed no statistical significance for any of the stages of cancer between the LTG and LDG groups. Conclusions The study findings suggest that LTG is an oncologically safe procedure for AGC yields comparable surgical outcomes. A well-designed phase III trial can be carried out to provide valuable evidence for the oncologic safety of LTG for the treatment of AGC.

: To compare the clinicopathologic data and short-term surgical outcomes of laparoscopic gastrectomy (LG) for gastric cancer (GC) between the east and west. : Patient demographics, surgical procedures, pathological information, and postoperative recovery were compared among gastric cancer patients who underwent LG in the clinical trial of IMIGASTRIC (NCT02325453) between 2009 and 2016. : More younger males, higher BMI, lower ASA score and less neoadjvant chemotherapy were evident in east patient cohort. Eastern patients had a higher proportion of proximal, differentiated and advanced gastric cancers. More total gastrectomies, larger extent of lymph node (LN) dissection, and higher number of retrieved LNs were found in the eastern patients. However, more Roux-en-Y anastomosis procedures during distal gastrectomy and intra-corporeal anastomosis were performed in the western patients. The west patients showed faster postoperative recovery than the eastern patients. The mortality rates of the western patients were comparable to those of the eastern patients. However, fewer III-IV complications were evident in the eastern centers. Multivariate analyses revealed that an elderly age, higher ASA score, and more blood loss were the significant independent risk factors of postoperative complications for eastern patients. However, for the western patients, the independent risk factors were neoadjuvant therapy, more retrieval LNs, and pT3-4 stage. : The selections and short-term surgical outcomes of LG for GC were widely different between East and West. To obtain more objective and accurate results, these differences should be considered in future international prospective studies.

Tu et al. show that Tff2 corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. Tff2 corpus cells are TA progenitors that give rise to secretory cells. Tff2 progenitors, not chief cells, are the primary source of SPEM after injury. Kras-mutant Tff2 progenitors progress directly to dysplasia, bypassing metaplasia. Multi-omics analysis reveals distinct trajectories for SPEM and gastric cancer. Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using knockin mice, we identified highly proliferative Tff2 progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2 corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2 progenitors abrogated SPEM formation, while genetic ablation of GIF chief cells enhanced SPEM formation from Tff2 progenitors. In response to infection, Tff2 progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of Kras mutations in Tff2 progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2 progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.