Exploring the association between inflammatory biomarkers and gastric cancer development: A two-sample mendelian randomization analysis.

This study aimed to elucidate the potential causative links between inflammatory biomarkers and gastric cancer risk via a two-sample Mendelian randomization approach. Leveraging genome-wide association study (GWAS) data, we conducted a two-sample Mendelian randomization analysis. Instrumental variable selection for inflammatory markers - namely, tissue factor, monocyte chemotactic protein-1, E-selectin, interleukin 6 receptor, and fatty acid-binding protein 4 - was informed by SNP data from the IEU database. Strongly associated SNPs served as instrumental variables. We applied a suite of statistical methods, including Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger, and mode-based estimates, to compute the odds ratios (ORs) that articulate the impact of these markers on gastric cancer susceptibility. The IVW method revealed that the interleukin 6 receptor was inversely correlated with gastric cancer progression (OR = 0.86, 95% CI = 0.74-0.99, P = .03), whereas fatty acid-binding protein 4 was found to elevate the risk (OR = 1.21, 95% CI = 1.05-1.39, P = .03). Instrumental variables comprised 5, 4, 7, 2, and 3 SNPs respectively. Convergent findings from WME, MR-Egger, and mode-based analyses corroborated these associations. Sensitivity checks, including heterogeneity, horizontal pleiotropy assessments, and leave-one-out diagnostics, affirmed the robustness and reliability of our instruments across diverse gastric malignancy tissues without substantial bias. Our research suggests that the interleukin 6 receptor potentially mitigates, while fatty acid-binding protein 4 may contribute to the pathogenesis of gastric cancer (GC). Unraveling the intricate biological interplay between inflammation and oncogenesis offers valuable insights for preemptive strategies and therapeutic interventions in gastric malignancy management.

First-line induction chemotherapy with high-dose methotrexate versus teniposide in patients with newly diagnosed primary central nervous system lymphoma: a retrospective, multicenter cohort study.

BACKGROUND: This study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs). METHODS: The study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort. RESULTS: A total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7-51.2] in the MTX cohort and 24.3 months (95% CI: 16.6-32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8-35.2) in the MTX cohort and 32 months (95% CI: 27.6-36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts. CONCLUSIONS: This was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate - based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

Knockout of Calcyclin Binding Protein Impedes the Growth of Breast Cancer Cells by Regulating Cell Apoptosis and ß-Catenin Signaling.

Breast invasive carcinoma (BRCA) is becoming the most common malignant disease worldwide, and there is intense interest in identifying diagnostic biomarkers that can be targeted for treatment of BRCA. Recent evidence has shown that calcyclin binding protein (CacyBP) can function as either a tumor promoter or suppressor during carcinogenesis. Data in The Cancer Genome Atlas (TCGA) database show that CacyBP is overexpressed in human BRCA tissues, and high levels of CacyBP are associated with shorter overall survival. Immunohistochemical staining has shown that CacyBP levels are high in cancer tissue samples and associated with a higher likelihood of disease progression. We, therefore, conducted a knockout assay to determine the role of CacyBP in the development of BRCA. Knockout of CacyBP significantly inhibited MCF7 cell proliferation and colony formation. Apoptosis was higher in CacyBP knockout cells compared with control cells. Microarray analysis showed that the CacyBP knockout caused dysregulation of numerous genes closely related to ß-catenin signaling, whereas quantitative reverse-transcription PCR and immunoblotting showed that it to be inactivated. In summary, we conclude that when overexpressed, CacyBP acts as a potential oncogene for BRCA by regulating ß-catenin signaling.

Primary breast diffuse large B-cell lymphoma in the rituximab era: Therapeutic strategies and patterns of failure.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB-DLBCL patients. We retrospectively reviewed data on 108 PB-DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow-up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5-year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5-year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10-year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB-DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB-DLBCL patients.

A fixed inhaled nitrous oxide/oxygen mixture as an analgesic for adult cancer patients with breakthrough pain: study protocol for a randomized controlled trial.

BACKGROUND: The management of breakthrough pain in cancer patients is always a challenge for medical professions. Occurring in 80% of cancer patients with advanced disease, breakthrough pain significantly decreases both patient's and caregiver's quality of life. The aim of this study is to assess the analgesic efficacy of a fixed inhaled nitrous oxide/oxygen mixture for adult cancer patients with breakthrough pain. METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind study; it will be conducted in the General Hospital of Ningxia Medical University. The target study subjects are at least 18 years old, and are hospitalized cancer patients who are receiving routine opioids to control cancer-related pain but still experience breakthrough pain. A total of 240 patients will be recruited and randomly allocated between three treatment groups (A, B, C) and a control group (group D) in a ratio of 3:1. All treatment groups (A, B, C) will receive standard pain treatment (oral immediate-release morphine) plus a pre-prepared nitrous oxide/oxygen mixture, and the control group (D) will receive the standard pain treatment plus oxygen. Patients, doctors, nurses, and data collectors are all blind to the experiment. Assessments will be taken before treatment (T0), at 5 min (T1) and 15 min (T2) during treatment, and at 5 min after treatment (T3). The primary endpoint measures will be the percentage of patients whose pain is relieved at T1, T2, and T3. Secondary outcome measures will include the safety of treatment, adverse events, and satisfaction from both health professionals and patients. DISCUSSION: This study aims to provide an effective and practical intervention for a fast breakthrough pain relief and to improve cancer patients' quality of life significantly. The Evidence-Based Medicine Working Group claim that a randomized, double-blind, placebo-controlled experimental intervention is the most appropriate design to demonstrate its efficacy, so this study could give a new approach to controlling breakthrough pain episodes. TRIAL REGISTRATION: ChiCTR-INC-16008075 . Registered on 8 March 2016.

Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction.

PURPOSE: There is currently no standard treatment strategy for patients with advanced metastatic gastric cancer experiencing progression after two or more lines of chemotherapy. We assessed the efficacy and safety of apatinib, a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, in patients with advanced gastric or gastroesophageal junction adenocarcinoma for whom at least two lines of prior chemotherapy had failed. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled phase III trial. Patients from 32 centers in China with advanced gastric or gastroesophageal junction adenocarcinoma, for whom two or more prior lines of chemotherapy had failed, were enrolled. Patients were randomly assigned to oral apatinib 850 mg or placebo once daily. The primary end points were overall (OS) and progression-free survival (PFS). RESULTS: Between January 2011 and November 2012, 267 patients were enrolled. Median OS was significantly improved in the apatinib group compared with the placebo group (6.5 months; 95% CI, 4.8 to 7.6 v 4.7 months; 95% CI, 3.6 to 5.4; P = .0149; hazard ratio, 0.709; 95% CI, 0.537 to 0.937; P = .0156). Similarly, apatinib significantly prolonged median PFS compared with placebo (2.6 months; 95% CI, 2.0 to 2.9 v 1.8 months; 95% CI, 1.4 to 1.9; P < .001; hazard ratio, 0.444; 95% CI, 0.331 to 0.595; P < .001). The most common grade 3 to 4 nonhematologic adverse events were hand-foot syndrome, proteinuria, and hypertension. CONCLUSION: These data show that apatinib treatment significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy.

Inhibition of mitotic Aurora kinase A by alisertib induces apoptosis and autophagy of human gastric cancer AGS and NCI-N78 cells.

Gastric cancer is one of the most common cancers and responds poorly to current chemotherapy. Alisertib (ALS) is a second-generation, orally bioavailable, highly selective small-molecule inhibitor of the serine/threonine protein kinase Aurora kinase A (AURKA). ALS has been shown to have potent anticancer effects in preclinical and clinical studies, but its role in gastric cancer treatment is unclear. This study aimed to investigate the cancer cell-killing effect of ALS on gastric cancer cell lines AGS and NCI-N78, with a focus on cell proliferation, cell-cycle distribution, apoptosis, and autophagy and the mechanism of action. The results showed that ALS exhibited potent growth-inhibitory, proapoptotic, and proautophagic effects on AGS and NCI-N78 cells. ALS concentration-dependently inhibited cell proliferation and induced cell-cycle arrest at G2/M phase in both cell lines, with a downregulation of cyclin-dependent kinase 1 and cyclin B1 expression but upregulation of p21 Waf1/Cip1, p27 Kip1, and p53 expression. ALS induced mitochondria-mediated apoptosis and autophagy in both AGS and NCI-N78 cells. ALS induced the expression of proapoptotic proteins but inhibited the expression of antiapoptotic proteins, with a significant increase in the release of cytochrome c and the activation of caspase 9 and caspase 3 in both cell lines. ALS induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) signaling pathways while activating the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway as indicated by their altered phosphorylation, contributing to the proautophagic effects of ALS. SB202191 and wortmannin enhanced the autophagy-inducing effect of ALS in AGS and NCI-N78 cells. Notably, ALS treatment significantly decreased the ratio of phosphorylated AURKA over AURKA, which may contribute, at least in part, to the inducing effects of ALS on cell-cycle arrest and autophagy in AGS and NCI-N78 cells. Taken together, these results indicate that ALS exerts a potent inhibitory effect on cell proliferation but inducing effects on cell-cycle arrest, mitochondria-dependent apoptosis, and autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AURKA-mediated signaling pathways in AGS and NCI-N78 cells.

Association Between p21 Ser31Arg Polymorphism and Gastrointestinal Tract Tumor Risk: A Meta-analysis.

Human p21 gene is characterized by a polymorphism at codon 31 leading to a Serine-to- Arginine (S/R), two different alleles of p21 Ser31Arg (rs 1801270) polymorphism have been shown to differ significantly in their transcriptional efficiency. More and more investigations are now being carried out to examine a possible link between the p21 Ser31Arg polymorphism and cancer. However, the results were inconclusive. Therefore, we carried out a systematic review and meta-analysis to examine whether this polymorphism is associated with gastrointestinal tract tumor in Asian. Seven studies (n = 2690), comprising 967 cases and 1723 controls in Asian population, were included in our study. The meta-analysis showed significant association between Ser-allele or Ser/Ser genotype and the susceptibility to gastrointestinal tract tumor in overall studies (Ser-allele vs. Arg-allele: OR = 1.17, 95% CI: 1.04-1.31; Ser/Ser vs. Arg/Arg: OR = 1.38, 95% CI: 1.09-1.75; Ser/Ser vs. Arg/Ser: OR = 1.27, 95% CI: 1.05-1.53; Ser/Ser vs. Arg/Ser + Arg/Arg: OR = 1.29, 95% CI: 1.07-1.54). Despite the limitations, the results of the present meta-analysis suggested that, in the p21 Ser31Arg polymorphism, Ser-allele and Ser/Ser genotype might be risk factors for gastrointestinal tract tumor in Asian populations.

A novel tri-allelic insertion/deletion polymorphism in the promoter of p21(Waf1/Cip1) and the association with gastric cancer.

AIMS: p21(Waf1/Cip1) is a cyclin-dependent kinase inhibitor that is pivotal in arresting cellular growth in terminal cell differentiation and apoptosis. Thus, the existence of natural variants of p21(Waf1/Cip1) could be linked to specific cancer. The purpose of this report was to identify a novel tri-allelic insertion/deletion (INDEL) polymorphism (rs4135235) involving a poly-T sequence in the promoter region of p21(Waf1/Cip1) gene and to explore its role in gastric cancer (GC). METHOD: A total of unrelated 676 subjects (376 GC patients; 300 cancer-free controls) were enrolled in the study, and genomic DNA was obtained from each subject for genotyping. PCR-directed sequencing technique was used to detect the genotypes of the polymorphism. TA cloning was used to confirm the existence of three alleles. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis. RESULTS: Six genotypes (9T/9T, 10T/10T, 11T/11T, 9T/10T, 10T/11T, and 9T/11T) and three alleles (9Ts, 10Ts, and 11Ts) were identified among all study subjects. GC cases were different from the control group with over-representation of 9T/11T heterozygotes (19.7% vs. 12.3%) and under-representation of 10T/10T homozygotes (18.4% vs. 20.7%). Compared with those carrying 10T/10T, individuals with 9T/11T increased the susceptibility for GC (OR=1.797, 95%CI=1.065-3.031). CONCLUSION: Our findings confirmed the existence of a tri-allelic polymorphism in the promoter of p21(Waf1/Cip1). It has also shown the heterozygous genotype 9T/11T to be a potential risk factor for GC in the Chinese population.

[Comparison of biological behavior between triple-negative breast cancer and non-triple- negative breast cancer].

OBJECTIVE: To summarize the epidemiological and biological features of triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) to provide reference for devising individualized therapy and making prognostic evaluation. METHODS: The 5-year follow-up data were collected from 231 patients with pathologically established diagnosis of breast cancer treated in the Affiliated Hospital of Ningxia Medical University and Yinchuan People's Hospital between Jan. 2002 and Dec. 2004. The epidemiological and clinicopathological characteristics as well as the recurrence, metastasis and 5-year survival were compared between TNBC group and non-TNBC group. RESULTS: TNBC accounted 17.3% of the total breast cancer cases enrolled in this study. The tumor size and rates of recurrence and metastasis (especially visceral metastasis) were significantly greater in TNBC group than in non-TNBC group (P<0.05). The TNBC patients showed significantly lower 3- and 5-year survival rates than the non-TNBC patients (P<0.05), and TNBC patients with positive lymph nodes in clinical stage II had also a lower 5-year survival (P<0.05). Cox regression model analysis identified the patients' age, primary tumor size, clinical stages and triple-negativity as the independent risk factors for breast cancer. CONCLUSION: Compared to non-TNBC patients, patients with TNBC have higher rates of local recurrence and invasion, visceral metastasis and poorer prognosis, and a lower rate of 5-year survival. The triple negativity represents an independent factor for prognosis evaluation of breast cancer.

CacyBP/SIP expression is involved in the clinical progression of breast cancer.

OBJECTIVE: Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is a target protein of the S100A6, which is a member of the S100 family. It has been shown that CacyBP/SIP plays important roles in cell cycle progression, differentiation, and carcinogenesis. The purpose of this study was to explore the correlation of CacyBP/SIP expression and clinical significance in breast cancer. METHODS: Immunohistochemistry was performed to detect the CacyBP/SIP expression in 79 pairs of breast cancer tissues and adjacent nontumor tissues. Western blot analysis and semiquantitative RT-PCR were used to measure CacyBP/SIP protein and mRNA levels in three pairs of fresh breast cancer tissues and adjacent nontumor tissues. The clinical data were collected by telephone follow-up for 5 years. RESULTS: CacyBP/SIP mRNA and protein levels in breast cancer tissues were significantly higher compared with adjacent nontumor tissues. Poor cellular differentiation, lymph node invasion, and clinicopathological staging in breast cancer were associated with CacyBP/SIP expression. Other factors, such as age, menses, and tumor size, were not related to CacyBP/SIP expression. The up-regulation of CacyBP/SIP expression also was shown to increase recurrence and metastasis of breast cancer and to correlate with short overall survival rate. CONCLUSIONS: CacyBP/SIP expression is evident in more advanced clinical progression of breast cancer, and it might be a biomarker for poor prognosis and a potential therapeutic target in breast cancer.