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Background Malnutrition leads to accelerated tumor progression through the suppression of tumor immunity. The present study examined the significance of the preoperative prognostic nutritional index (PNI) for predicting postoperative survival outcomes in gastric cancer (GC). Methods A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. PNI was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte counts (per mm 3 ). The prognostic impact of preoperative PNI was examined using two multivariate analysis models. Results The optimal cutoff value of preoperative PNI for predicting overall survival (OS) was 48 based on a receiver operating characteristic curve. The 5-year OS rate was 59.5% in the PNI<48 group and 91.3% in the PNI≥48 group ( p <0.001). In the first multivariate survival analysis where all explanatory variables were composed of preoperative factors alone, a PNI<48 (hazard ratio [HR] 3.33; 95% confidence interval [CI] 2.01–5.56, p <0.001), upper-third GC and cT2–T4 were identified as independent indicators of a poor OS. In the second survival analysis where explanatory variables were composed of preoperative, intraoperative, and pathological factors, a PNI<48 (HR 2.80; 95% CI 1.65–4.78, p <0.001), hypertension, open gastrectomy, intraoperative blood loss≥100g, pT2–T4, and pN+ were independent prognostic factors. Conclusion Preoperative PNI may be a useful predictor of postoperative survival outcomes both before and immediately after surgery in GC. Appropriate perioperative interventions and the meticulous surveillance of GC relapse are necessary for patients with PNI<48.

Esophageal cancer (EC) is the sixth leading cause of cancer‐related death worldwide. Recently, neoadjuvant chemotherapy (NAC) before curative surgery has become a standard treatment for clinical stage II or III EC patients. Some EC patients receive a complete response (CR) by NAC; thus, curative surgery may be unnecessary for such patients. MicroRNA levels in plasma have the potential to be a predictor of response to NAC. In the present study, we focused on miR‐192‐5p, which is highly expressed in EC tissue. The purpose was to investigate the correlations between levels of plasma miR‐192‐5p and the response to NAC. Furthermore, molecular functions of miR‐192‐5p associated with chemosensitivity were examined using EC cell lines. The levels of miR‐192‐5p in plasma before surgery were evaluated in 113 EC patients. Sixty‐nine patients received NAC. miR‐192‐5p levels in the CR group were significantly higher than in the other groups (p = 0.002). The downregulation of miR‐192‐5p in the EC cell line inhibited sensitivity to cisplatin, and the overexpression of miR‐192‐5p in the EC cell line promoted sensitivity to cisplatin. miR‐192‐5p regulated sensitivity to cisplatin by targeting ERCC3 and ERCC4. Plasma miR‐192‐5p could be used as a predictor of response to chemotherapy and prognosis in EC patients. Expression of miR‐192 in esophageal cancer regulated sensitivity to cisplatin by targeting ERCC3 and ERCC4. Plasma miR‐192 may be used as a predictor of response to chemotherapy in esophageal cancer patients.

Patients with gastric cancer are often malnourished during tumor progression. Malnutrition is a risk factor for postoperative complications and a poor prognosis. Early evaluation and management of nutrition can improve these outcomes. Various combined indices in which albumin is the primary component are used to evaluate the nutritional status, including the Prognostic Nutritional Index, Glasgow Prognostic Score, and Controlling Nutritional Status score. Both the American Society for Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism guidelines recommend immediate and early oral/enteral nutrition. However, few reports have described the additional effects of preoperative immunonutrition on clinical outcomes of gastric cancer surgery. Gastrectomy types and reconstruction methods that consider the postoperative nutritional status have been used when oncologically acceptable. Total gastrectomy has recently tended to be avoided because of its negative impact on nutritional status. New findings obtained from the emergence of continuous glucose measurement, such as glucose fluctuation and nocturnal hypoglycemia, may affect nutritional management after gastrectomy. Some prospective clinical studies on perioperative nutritional intervention have set postoperative body weight loss as a primary endpoint. It seems important to continue oral nutritional supplement, even in small doses, to reduce body weight loss after gastrectomy. Evidence generated by prospective, well‐developed randomized controlled studies must be disseminated so that nutritional therapy is widely recognized as an important multimodal therapy in patients undergoing gastric cancer surgery. Evaluating and addressing the issue of nutrition early can improve outcomes of gastric cancer surgery. For surgical procedures, gastrectomy types and reconstruction methods that consider postoperative nutritional status have been conducted. Evidence needs to be disseminated so that nutritional therapy is widely recognized as an important multimodal therapy for gastric cancer.

BackgroundThe membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs).MethodsCells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis.ResultsAmong MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone.ConclusionsThe present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer.

BackgroundCircular RNA is a novel endogenous non-coding RNA with a stable loop structure, and theories for its biogenesis and usefulness as a biomarker in various cancers have been proposed. The present study investigated the significance of circular FAT1 (circFAT1) as a novel biomarker in esophageal squamous cell carcinoma (ESCC).MethodCircFAT1 expression levels were measured in ESCC cell lines and the effects of downregulating circFAT1 on cell migration and invasion were examined using a transwell assay. The functions of miR-548g, which will be sponged by circFAT1, were assessed. Furthermore, the expression of circFAT1 was evaluated in 51 radically resected ESCC tissue samples using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationships between circFAT1 expression, clinicopathological factors, and patient prognosis were analyzed.ResultsCircFAT1 expression levels were significantly lower in tumor tissue than in adjacent non-tumorous mucosal tissue (p = 0.01). The downregulation of circFAT1 expression promoted ESCC cell migration and invasive ability, but not proliferation. The expression of miR-548g was upregulated by the downregulation of circFAT1. The overexpression of miR-548g also promoted ESCC cell migration and invasion. Recurrence-free survival (p = 0.02) and cancer-specific survival (p = 0.04) rates were significantly higher in patients with elevated circFAT1 expression levels.ConclusionThe expression level of circFAT1 is a novel prognostic marker in ESCC patients. New treatment strategies may be developed using the tumor suppressive functions of circFAT1.

BackgroundThe cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride (Cl−) anion conducting channel, and its role in esophageal squamous cell carcinoma (ESCC) was examined in the present study.MethodsOverexpression experiments were conducted on human ESCC cell lines following the transfection of a CFTR plasmid, and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. A microarray analysis was performed to examine gene expression profiles. Fifty-three primary tumor samples collected from ESCC patients during esophagectomy were subjected to an immunohistochemical analysis.ResultsTransfection of the CFTR plasmid into the ESCC KYSE 170 and KYSE 70 cell lines suppressed cell proliferation, migration, and invasion and induced apoptosis. The microarray analysis showed the up-regulated expression of genes involved in the p38 signaling pathway in CFTR plasmid-transfected KYSE 170 cells. Immunohistochemical staining revealed a relationship between the CFTR expression pattern at the invasive front and the pN category. A relationship was also observed between the weak expression of CFTR at the invasive front and a shorter postoperative survival in a prognostic analysis.ConclusionsThe overexpression of CFTR in ESCC activated the p38 signaling pathway and was associated with a good patient prognosis. These results indicate the potential of CFTR as a mediator of and/or a biomarker for ESCC.

BackgroundSystemic inflammatory response is strongly linked to among cancer development, progression and poor prognosis. The aim of this study was to clarify the impact of postoperative serum C-reactive protein (CRP) levels on the prognoses of patients with colorectal cancer (CRC).MethodsA total of 467 patients with stage I–III CRC who underwent curative surgery were retrospectively analyzed. To precisely evaluate the effect of postoperative inflammatory status on prognosis in CRC patients, we excluded patients with postoperative complication or elevated preoperative CRP level (CRP > 1.0 mg/dL). Patients were divided into two groups based on their highest post-resection CRP levels (max CRP): the low CRP group (LCG; < 9.0 mg/dL, n = 385) and high CRP group (HCG; ≥ 9.0 mg/dL, n = 82). Furthermore, the effect of inflammation on malignant potential of CRC cells was evaluated using in vitro peritoneal dissemination model.ResultsHCG patients showed significantly worse recurrence-free survival (RFS) than LCG patients (p = 0.012). Multivariate analysis revealed that a higher max CRP was an independent prognostic factor for RFS (HR: 2.07, 95% CI 1.04–3.96, p = 0.038). Concerning the risk factors for high max CRP level, multivariate analysis revealed that older age (p < 0.001), male sex (p < 0.001), higher BMI (p = 0.005), right-sided colorectal cancer (p = 0.008), and longer operative time (p = 0.007) were independent risk factors. A higher max CRP was also significantly associated with peritoneal recurrence (p < 0.001). Additionally, recombinant cytokines enhanced the adhesive ability of CRC cells to mesothelial cell in vitro (p < 0.05).ConclusionsPostoperative inflammation may be a possible mechanism portending the poor prognosis of CRC patients.

BackgroundCalcium voltage-gated channel auxiliary subunit alpha 2/delta 1 (CACNA2D1), a gene encoding a voltage-gated calcium channel, has been reported as an oncogene in several cancers. However, its role in colon cancer (CC) remains unclear. This study aimed to investigate the function of CACNA2D1 and its effect on the microenvironment in CC.MethodsImmunohistochemistry (IHC) analysis was performed on samples collected from 200 patients with CC who underwent curative colectomy. Knockdown experiments were performed using CACNA2D1 siRNA in the human CC cell lines HCT116 and RKO, and cell proliferation, cycle, apoptosis, and migration were then analyzed. The fibroblast cell line CCD-18Co was co-cultured with CC cell lines to determine the effect of CACNA2D1 on fibroblasts and the relationship between CACNA2D1 and the cancer microenvironment. Gene expression profiles of cells were analyzed using microarray analysis.ResultsIHC revealed that high CACNA2D1 expression was an independent poor prognostic factor in patients with CC and that CACNA2D1 expression and the stroma are correlated. CACNA2D1 depletion decreased cell proliferation and migration; CACNA2D1 knockdown increased the number of cells in the sub-G1 phase and induced apoptosis. CCD-18Co and HCT116 or RKO cell co-culture revealed that CACNA2D1 affects the cancer microenvironment via fibroblast regulation. Furthermore, microarray analysis showed that the p53 signaling pathway and epithelial–mesenchymal transition-associated pathways were enhanced in CACNA2D1-depleted HCT116 cells.ConclusionsCACNA2D1 plays an important role in the progression and the microenvironment of CC by regulating fibroblasts and may act as a biomarker for disease progression and a therapeutic target for CC.