Purpose The significance of neuroendocrine differentiation (NED) in gastric carcinoma (GC) is controversial, leading to ambiguous concepts in traditional classifications. This study aimed to determine the prognostic threshold of meaningful NED in GC and clarify its unclear features in existing classifications. Materials and Methods Immunohistochemical staining for synaptophysin, chromogranin A, and neural cell adhesion molecule was performed for 945 GC specimens. Survival analysis was performed using the log-rank test and univariate/multivariate models with percentages of NED (P NED ) and demographic and clinicopathological parameters. Results In total, 275 (29.1%) cases were immunoreactive to at least 1 neuroendocrine (NE) marker. GC-NED was more common in the upper third of the stomach. P NED , and Borrmann's classification and tumor, lymph node, metastasis stages were independent prognostic factors. The cutoff P NED was 10%, beyond which patients had significantly worse outcomes, although the risk did not increase with higher P NED . Tumors with ≥10% NED tended to manifest as Borrmann type III lesion with mixed/diffuse morphology and poorer histological differentiation; the NE components in this population mainly grew in insulae/nests, which differed from the predominant growth pattern (glandular/acinar) in GC with <10% NED. Conclusions GC with ≥10% NED should be classified as a distinct subtype because of its worse prognosis, and more attention should be paid to the necessity of additional therapeutics for NE components.

Highlights The serum lipid patterns of GCNEI differed from those of pure gastric adenocarcinoma significantly. Serum lipid levels correlated to the progression of GCNEI. Serum lipid levels impacted the risk of the occurrence of GCNEI.

Background: Early gastric cancer (EGC) with undifferentiated component (UDC) is a more aggressive entity, where the significance of preoperative data to tumor invasion and lymph node metastasis (LNM) remains unclarified.Methods: A total of 5,020 GC patients undergoing radical gastrectomy in three centers were reviewed, of which, EGC with UDC in preoperative biopsy specimens were enrolled. The histology of biopsy and surgical specimens was graded according to the proportion of UDC and signet ring cells (SRCs). Risk factors of tumor invasion and LNM were evaluated with histological, clinical and demographic data.Results: Lower body mass index (BMI), melena and larger tumor size were the independent preoperative risk factors of both LNM and LVI, while ulcerative lesion (UL) and the lower third stomach were only correlated with LNM. No relevance was found between the histological features of biopsy specimens and LNM, but SRC or >50% UDC lowered the risk of lymphovascular invasion (LVI) and/or submucosal (SM) invasion. When surgical data (depth of invasion and LVI included) were added, lower BMI, melena and the lower third stomach were still the independent preoperative risk factors of LNM, and LVI, SRC and SM invasion also showed relevance to LNM. The performance of predictive models using pre-or postoperative histological data was comparable. Conclusions:The preoperative data were significantly relevant to tumor invasion and LNM, showing comparable risk strength with surgical specimens in histology.

Background: Many studies have shown an elevated level of cholesterol in colon tumors as compared to normal tissue. Obesity and high low-density lipoprotein cholesterol (LDL-C) are known risk factors for colon cancer. However, the role of LDL-C in colon cancer patients with normal body mass index (BMI) remains elusive.Methods: Levels of serum cholesterol and oxysterols were quantified by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) from 129 individuals with normal BMI, including 32 with solitary polyp, 36 with multiple polyps, and 31 with adenocarcinoma as well as 32 healthy controls. In vitro, colon cancer cells were treated with LDL-C and assayed for chemokines via RNA-Seq and mitochondrial morphology via transmission electron microscopy and immunofluorescence. Additionally, correlation analysis was performed between LDL-C-induced chemokines and the overall survival of colon cancer patients from the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA) database. Results:The serum cholesterol level was significantly higher in colon adenocarcinoma patients with normal BMI than that in healthy controls (P<0.001). LDL-C potentiated colon cancer cell invasion and resistance to glucose-deprivation in vitro via chemokine-mediated signaling, mainly upregulation of CC chemokine ligand (CCL) 5 and downregulation of CCL 11. By analyzing the RNA expression data of colorectal cancer from TCGA, GTEx, and HPA, we demonstrated that the CCL5 level in colorectal adenocarcinoma tissues was significantly increased relative to adjacent normal tissues (P=0.01) while the CCL11 level was decreased (P=0.01). Both increased CCL5 and decreased CCL11 showed a negative correlation with the 5-year overall survival in tumor node metastasis (TNM) stage II colon cancer patients (P=0.0032, 0.026 for CCL5 and CCL11, respectively). Conclusions:Our study supports the idea that LDL-C regulates the expression of CCL5 and CCL11 chemokines, which may have predictive values for survival in colon cancer patients with normal BMI, especially for patients in TNM stage II.