Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment.

Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics.

Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.

BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Prognostic impact of examined lymph-node count for patients with esophageal cancer: development and validation prediction model.

Esophageal cancer (EC) is a malignant tumor with high mortality. We aimed to find the optimal examined lymph node (ELN) count threshold and develop a model to predict survival of patients after radical esophagectomy. Two cohorts were analyzed: the training cohort which included 734 EC patients from the Chinese registry and the external testing cohort which included 3208 EC patients from the Surveillance, Epidemiology, and End Results (SEER) registry. Cox proportional hazards regression analysis was used to determine the prognostic value of ELNs. The cut-off point of the ELNs count was determined using R-statistical software. The prediction model was developed using random survival forest (RSF) algorithm. Higher ELNs count was significantly associated with better survival in both cohorts (training cohort: HR = 0.98, CI = 0.97-0.99, P < 0.01; testing cohort: HR = 0.98, CI = 0.98-0.99, P < 0.01) and the cut-off point was 18 (training cohort: P < 0.01; testing cohort: P < 0.01). We developed the RSF model with high prediction accuracy (AUC: training cohort: 87.5; testing cohort: 79.3) and low Brier Score (training cohort: 0.122; testing cohort: 0.152). The ELNs count beyond 18 is associated with better overall survival. The RSF model has preferable clinical capability in terms of individual prognosis assessment in patients after radical esophagectomy.

Dynamic peripheral blood immune cell markers for predicting the response of patients with metastatic cancer to immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) have shown durable responses in various malignancies. However, the response to ICI therapy is unpredictable, and investigation of predictive biomarkers needs to be improved. EXPERIMENTAL DESIGN: In total, 120 patients receiving ICI therapy and 40 patients receiving non-ICI therapy were enrolled. Peripheral blood immune cell markers (PBIMs), as liquid biopsy biomarkers, were analyzed by flow cytometry before ICI therapy, and before the first evaluation. In the ICI cohort, patients were randomly divided into training (n = 91) and validation (n = 29) cohorts. Machine learning algorithms were applied to construct the prognostic and predictive immune-related models. RESULTS: Using the training cohort, a peripheral blood immune cell-based signature (BICS) based on four hub PBIMs was developed. In both the training and the validation cohorts, and the whole cohort, the BICS achieved a high accuracy for predicting overall survival (OS) benefit. The high-BICS group had significantly shorter progression-free survival and OS than the low-BICS group. The BICS demonstrated the predictive ability of patients to achieve durable clinical outcomes. By integrating these PBIMs, we further constructed and validated the support vector machine-recursive and feature elimination classifier model, which robustly predicts patients who will achieve optimal clinical benefit. CONCLUSIONS: Dynamic PBIM-based monitoring as a noninvasive, cost-effective, highly specific and sensitive biomarker has broad potential for prognostic and predictive utility in patients receiving ICI therapy.

Megestrol acetate dispersible tablets with a 5-HT3 receptor antagonist and dexamethasone vs. 5-HT3 receptor antagonist plus dexamethasone, can better control chemotherapy-induced nausea and vomiting: a randomized controlled study.

Background: A reasonable and effective control of chemotherapy-induced nausea and vomiting (CINV) plays an important role in the comprehensive treatment of cancer. Megestrol belongs to the 17α-hydroxyprogesterone derivative and is a highly effective synthetic progesterone. Recorded in the instructions may improve appetite and cachexia in patients with advanced tumors. In recent years, clinical practice and small sample studies have shown that megestrol combined with chemotherapy can improve CINV. This randomized controlled trial aimed to evaluate the clinical efficacy and safety of megestrol acetate combined with a 5-Hydroxytryptamine (5-HT3) receptor antagonist and dexamethasone in patients with CINV. Methods: Patients with malignant tumors who were treated with cisplatin-containing chemotherapy in our hospital from September 2018 to December 2019 were enrolled. A total of 120 patients were selected and randomly assigned to receive either megestrol acetate dispersible tablets with a 5-HT3 receptor antagonist and dexamethasone (megestrol group) or a 5-HT3 receptor antagonist plus dexamethasone (control group). Megestrol acetate dispersible tablets: 160 mg orally every morning from the day of chemotherapy until it lasts for ten days. Abstract IV of the quality-of-life scale for cancer patients in China was used to assess the quality of life (QOL) of the participants. All adverse reactions during chemotherapy were assessed according to the CTCAE 4.03 evaluation standard issued by the National Cancer Institute and divided into five grades according to severity. Results: For the control of nausea, the rates of complete prevention were significantly higher in the megestrol group than in the control patients during the delayed [53.3% (31/60) vs. 30.0% (18/60), P=0.012] and overall [40.0% (24/60) vs. 15.0% (9/60), P=0.002] observation periods. Moreover, the megestrol combination treatment group also achieved markedly higher rates of complete remission of vomiting than the control group during the delayed observation period [76.7% (46/60) vs. 51.7% (31/60), P=0.001], achieving an overall higher proportion of remission during the study period [68.3% (41/60) vs. 46.6% (28/60), P=0.0016]. Conclusions: The triple antiemetic protocol using megestrol acetate with a 5-HT3 receptor antagonist plus dexamethasone can improve CINV symptoms caused by highly emetogenic chemotherapy (HEC) with cisplatin, with an excellent control effect and few adverse reactions, especially for delayed CINV. Trial Registration: Chinese Clinical Trial Registry ChiCTR1800017953.

A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies.

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.

Joint associations among prenatal metal mixtures and nutritional factors on birth weight z-score: Evidence from an urban U.S. population.

The benefits of nutritional factors on birth outcomes have been recognized, however, limited studies have examined the role of nutritional factors in mitigating the detrimental effects of metals exposure during gestation. We used data collected from 526 mother-infant dyads enrolled in the Programming of Intergenerational Stress Mechanisms longitudinal pregnancy cohort to examine the joint effects of prenatal exposure to metals and maternal nutrition on birth weight for gestational age (BWGA) z-scores. We measured concentrations of twelve metals and trace elements in urine samples collected during pregnancy. Maternal nutritional intake was measured using the Block98 Food Frequency Questionnaire and converted into energy-adjusted consumption of individual nutrients. Using multivariable linear regression and Bayesian Kernel Machine Regression, we found that three metals [cobalt (Co), nickel (Ni), and lead (Pb)] and five metals [barium (Ba), caesium (Cs), copper (Cu), Ni, and zinc (Zn)] were associated with BWGA z-score in male and female infants, respectively. When examining the sex-specific interactions between these metals and nutrient groups [macro nutrients, minerals, A vitamins, B vitamins, anti-oxidant, methyl-donor nutrients, and inflammatory (pro- and anti-)] using a Cross-validated Kernel Ensemble model, we identified significant interactions between the macro nutrients and Co (p = 0.05), minerals and Pb (p = 0.04), and A vitamins and Ni (p = 0.001) in males. No significant interactions were found in females. Furthermore, three minerals (phosphorus, iron, potassium) and vitamin A were found to be more crucial than other nutrients in modifying the association between each respective metal and BWGA z-score in males. A better understanding of the sex-specific interactions between nutrients and metals on birth weight can guide pregnant women to protect their neonates from the adverse health impacts of metal exposures by optimizing nutrient intakes accordingly.

Characterization of gastric cancer stem-like molecular features, immune and pharmacogenomic landscapes.

Cancer stem cells (CSCs) actively reprogram their tumor microenvironment (TME) to sustain a supportive niche, which may have a dramatic impact on prognosis and immunotherapy. However, our knowledge of the landscape of the gastric cancer stem-like cell (GCSC) microenvironment needs to be further improved. A multi-step process of machine learning approaches was performed to develop and validate the prognostic and predictive potential of the GCSC-related score (GCScore). The high GCScore subgroup was not only associated with stem cell characteristics, but also with a potential immune escape mechanism. Furthermore, we experimentally demonstrated the upregulated infiltration of CD206+ tumor-associated macrophages (TAMs) in the invasive margin region, which in turn maintained the stem cell properties of tumor cells. Finally, we proposed that the GCScore showed a robust capacity for prediction for immunotherapy, and investigated potential therapeutic targets and compounds for patients with a high GCScore. The results indicate that the proposed GCScore can be a promising predictor of prognosis and responses to immunotherapy, which provides new strategies for the precision treatment of GCSCs.

Anlotinib is effective in the treatment of advanced pancreatic cancer: a case report.

Effective treatments are urgently needed for patients with advanced pancreatic cancer. Anlotinib is a novel small-molecule multitarget tyrosine kinase inhibitor with broad inhibitory effects on tumor growth and angiogenesis. Here, we present an advanced pancreatic cancer patient, who respond to anlotinib targeted therapy after the failure of multiline chemotherapy and apatinib targeted therapy. Anlotinib was given orally at a dose of 10 mg once daily (2 weeks on/1 week off), and progression-free survival was 5.6 months. The adverse reaction of anlotinib was elevated aminotransferase and fatigue, but it was tolerable and reversible. Our case indicates that anlotinib might be effective in the treatment of advanced pancreatic cancer. This case report may offer a new targeted treatment option for heavily treated advanced pancreatic cancer.

Health effects of air pollutant mixtures on overall mortality among the elderly population using Bayesian kernel machine regression (BKMR).

It is well documented that fine particles matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) are associated with a range of adverse health outcomes. However, most epidemiologic studies have focused on understanding their additive effects, despite that individuals are exposed to multiple air pollutants simultaneously that are likely correlated with each other. Therefore, we applied a novel method - Bayesian Kernel machine regression (BKMR) and conducted a population-based cohort study to assess the individual and joint effect of air pollutant mixtures (PM2.5, O3, and NO2) on all-cause mortality among the Medicare population in 15 cities with 656 different ZIP codes in the southeastern US. The results suggest a strong association between pollutant mixture and all-cause mortality, mainly driven by PM2.5. The positive association of PM2.5 with mortality appears stronger at lower percentiles of other pollutants. An interquartile range change in PM2.5 concentration was associated with a significant increase in mortality of 1.7 (95% CI: 0.5, 2.9), 1.6 (95% CI: 0.4, 2.7) and 1.4 (95% CI: 0.1, 2.6) standard deviations (SD) when O3 and NO2 were set at the 25th, 50th, and 75th percentiles, respectively. BKMR analysis did not identify statistically significant interactions among PM2.5, O3, and NO2. However, since the small sub-population might weaken the study power, additional studies (in larger sample size and other regions in the US) are in need to reinforce the current finding.

Apatinib in the treatment of gastric cancer in Henan Province: a multicenter prospective real-world observational study (Ahead-HAP01).

Background: Apatinib is approved in China for the treatment of advanced gastric adenocarcinoma that had progressed or relapsed after standard systemic chemotherapy treatments. However, the effectiveness of Apatinib under real-world condition has not been evaluated and the drug performance under ideal and controlled circumstances has not been validated. In fact, genetic factors, poor healthcare access, social economic status, comorbidities compliance and other factors play significant role in drug performance under "real-world" conditions. Real-world experience can help validate the safety and efficacy of apatinib. Methods: In this observational, prospective study we evaluated the safety and efficacy of Apatinib in patient treated in China. Between March 2018 and March 2019, a total of 943 patients with gastric cancer treated with Apatinib were enrolled. Response Evaluation Criteria in Solid Tumors, version 1.1 and Common Terminology Criteria for Adverse Events, version 4.0 were used to evaluate efficacy and adverse effects. Results: The median progression-free survival (PFS) was 5.65 months (5.22-6.05 months), and the median overall survival (OS) was 11.47 months (10.41-12.52 months). Apatinib in combination with more than two agents was superior to single agent apatinib in overall response rate (ORR) [18.18% vs. 9.43%, 95% confidence interval (CI): 1.03-5.90] and disease control rate (DCR) (82.82% vs. 77.87%, 95% CI: 1.21-2.59). Apatinib in combination with single agent chemotherapy was also superior to apatinib alone with DCR (86.29% vs. 77.87%, 95% CI: 1.47-2.99) irrespective of the dose (250 or 500 mg). In the patient cohort who received a starting dose of 250 mg, the DCRs of the combined treatment and monotherapy groups were 86.22% vs. 80.00% (95% CI: 1.18-3.09), respectively. The most common treatment-emergent adverse events were anemia, anorexia and thrombocytopenia (66.28%, 37.75%, 36.06%, respectively). Conclusions: Efficacy of Apatinib in this observational study is promising and toxicities are manageable. Combination of Apatinib with chemotherapy agents has a higher response rate and better disease control at the expense of increased serious adverse events. Better OS can be achieved by receiving apatinib treatment earlier. As a supplement and further validation of explanatory randomized controlled trials, the real-world study reflects the real efficacy of apatinib in practical application.

Efficacy of Chemotherapy versus Transcatheter Arterial Chemoembolization in Patients with Advanced Primary Hepatic Neuroendocrine Carcinoma and an Analysis of the Prognostic Factors: A Retrospective Study.

BACKGROUND: Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare liver tumor, and there is no clear therapeutic recommendation for patients with advanced PHNEC. This study aims to compare the efficacy of platinum-based chemotherapy (etoposide combined with cisplatin/carboplatin, EP/EC) and transcatheter arterial chemoembolization (TACE) in patients with advanced PHNEC, and to evaluate the relevant prognostic factors. PATIENTS AND METHODS: The clinical data of 41 patients with advanced PHNEC from June 2014 to October 2019 were retrospectively reviewed. RESULTS: At a median follow-up time of 13.9 months, the median overall survival (OS) was 14.8 months in the EP/EC group and 12.2 months in the TACE group (P = 0.040). The median progression-free survival (PFS) was 4.4 months and 2.7 months in the EP/EC group and the TACE group, respectively (P = 0.005). No significant differences in the overall response rate and disease control rate were observed between the EP/EC group and the TACE group (26.1% vs 11.1%, P = 0.429; 73.9% vs 44.4%, P = 0.055, respectively). A univariate analysis indicated that the Eastern Cooperative Oncology Group performance status (ECOG PS), Ki-67, tumor number, and treatment options were prognostic factors for OS. A multivariate analysis further showed that ECOG PS (P < 0.001), Ki-67 (P = 0.003), and treatment options (P = 0.022) were independent prognostic factors for OS. CONCLUSION: Ki-67, ECOG PS, and treatment options were the independent prognostic factors for OS in patients with advanced PHNEC. EP/EC may be a better choice for patients with advanced PHNEC.

Low-Dose Apatinib Combined With S-1 in Refractory Metastatic Colorectal Cancer: A Phase 2, Multicenter, Single-Arm, Prospective Study.

PURPOSE: Apatinib is an approved third-line treatment for metastatic gastric cancer in China and demonstrates good safety, tolerability, and efficacy in other advanced solid tumors. The aim of this prospective, single-arm, multicenter, phase 2 study was to assess the efficacy and safety of low-dose apatinib combined with S-1 in the treatment of refractory mCRC. PATIENTS AND METHODS: Patients with refractory mCRC were enrolled and administered apatinib combined with S-1 until disease progression, patient decision to withdraw, or unacceptable toxic effects. The primary endpoint was investigator-evaluated progression-free survival (PFS) and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR). RESULTS: From December 2017 to December 2018, 30 patients were enrolled and 29 patients were eligible for the evaluation of efficacy and safety. The median PFS (mPFS) and OS (mOS) were 7.9 and 12.9 months, respectively. Exploratory analysis revealed that patients administered S-1 ≥ 70 days achieved longer mPFS and mOS. Four patients achieved a partial response, 22 achieved stable disease, and three had progressive disease, attributing to an ORR of 13.79% and a DCR of 89.66%. Ten grade 3 adverse events were reported and the frequency of each grade 3 adverse event was less than 5%. No grade 4 side events were observed. CONCLUSIONS: These results indicated that apatinib combined with S-1 showed promising efficacy and manageable toxicity in patients with progressive mCRC after at least 2 prior lines of therapy, making it a promising therapeutic option for mCRC treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03397199, identifier NCT03397199.

BTOB: Extending the Biased GWAS to Bivariate GWAS.

In recent years, a number of literatures published large-scale genome-wide association studies (GWASs) for human diseases or traits while adjusting for other heritable covariate. However, it is known that these GWASs are biased, which may lead to biased genetic estimates or even false positives. In this study, we provide a method called "BTOB" which extends the biased GWAS to bivariate GWAS by integrating the summary association statistics from the biased GWAS and the GWAS for the adjusted heritable covariate. We employ the proposed BTOB method to analyze the summary association statistics from the large scale meta-GWASs for waist-to-hip ratio (WHR) and body mass index (BMI), and show that the proposed approach can help identify more susceptible genes compared with the corresponding univariate GWASs. Theoretical results and simulations also confirm the validity and efficiency of the proposed BTOB method.

Discovering the mechanism and involvement of the methylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and its special locus region in gastric cancer.

Cyclin-dependent kinase inhibitor 2A (CDKN2A) gene methylation has been paramount in the development of malignant masses. The purpose of the conducted research was to evaluate the mechanism and involvement of methylation in regards to the CDKN2A gene and the specific locus region in gastric cancer (GC) with comprehensive statistical analysis utilizing statistics acquired from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) revealed that the level of CDKN2A gene methylation and its locus in GC tissues was increased compared to para-cancerous tissues. In multivariate analysis, low methylation of CDKN2A gene, cg03079681, cg04026675, cg07562918, and cg13601799 locus were independently linked to better OS. In addition, the methylation of CDKN2A gene, cg00718440, cg03079681, cg04026675, cg07562918, cg10848754, cg14069088 and cg14430974 locus were negative correlated with CDKN2A gene expression. Meanwhile, the methylation of cg12840719 locus was positively correlated with CDKN2A gene expression. GSEA showed that hallmark_kras_signaling_dn, hallmark_myogenesis, and hallmark_epithelial_mesenchymal_transition pathways were enriched in the CDKN2A gene hypermethylation phenotype. Taken together, the low methylation of CDKN2A gene, cg03079681, cg04026675, cg07562918, and cg13601799 locus indicated a better prognosis in GC. The methylation levels of cg14069088 were most negatively correlated with CDKN2A gene expression. Hallmark_kras_signaling_dn, Hallmark_myogenesis, and hallmark_epithelial_mesenchymal_transition pathways might be important in the regulation of CDKN2A gene hypermethylation.

Long noncoding RNA FER1L4 suppresses proliferation, invasion, migration and lymphatic metastasis of gastric cancer cells through inhibiting the Hippo-YAP signaling pathway.

Gastric cancer (GC) is one of the most malignant tumors in the world. Growing evidence has highlighted the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis of GC. The aim of the research was to elucidate the effects of lncRNA Fer-1-like family member 4 (FER1L4) in GC and identify the potential mechanisms. The present study investigated FER1L4 controlling cell survival and migration of SGC-7901 cells. Results indicated that the expression level of FER1L4 was distinctly decreased in GC cells, as evidenced by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. By using cell proliferation assay, Transwell assay, wound healing assay and western blotting, we found out that overexpression of FER1L4 in SGC-7901 cells hindered the capacities of cell proliferation, invasion, migration and lymphatic metastasis. Furthermore, results of the western blotting and immunofluorescence assay unveiled that overexpression of FER1L4 led to a notable reduction in the expression of C-X-C chemokine receptor type 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) in SGC-7901 cells. Besides, activation of Hippo pathway by upregulating Yes-associated protein (YAP) expression or treatment of CXCR4 inhibitor WZ811 reversed the inhibitory effects of FER1L4 on proliferation and metastasis of SGC-7901 cells. Moreover, co-transfection with YAP and FER1L4 overexpression plasmids abrogated the repressive effects of FER1L4 overexpression on proliferation and metastasis. Taken together, these results demonstrated that lncRNA FER1L4 suppressed cell proliferation, invasion, migration and lymphatic metastasis of GC cells by inactivation of the Hippo-YAP pathway, providing novel insights into regulatory mechanism under GC and new strategies for clinical practice.

Clinical features and the efficacy of adjuvant chemotherapy in resectable small bowel adenocarcinoma: a single-center, long-term analysis.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy. There is no standard regimen for adjuvant chemotherapy for treating SBA. This study aimed to assess the efficacy of adjuvant chemotherapy in patients with resectable SBA. METHODS: This retrospective study collected data from 148 eligible SBA patients who received radical resection at a single institution. The patients' clinicopathological characteristics were reviewed and disease-free survival (DFS) time and overall survival time (OS) were estimated by the Kaplan-Meier method. RESULTS: The patients had a median age of 57 years at the time of diagnosis. In most cases, the primary tumor was located in the duodenum (75.68%). Of the 55 patients who received adjuvant chemotherapy, 43 received the combined regimen and 12 received single agent chemotherapy. During the follow-up period, 87 patients (58.87%) relapsed. The median DFS and the median OS were 19 and 32 months for all patients, respectively. Stage, N-stage, adjuvant chemotherapy, and having more than one symptom at the time of diagnosis were factors associated with DFS and OS. The 43 patients who received combined adjuvant chemotherapy generally exhibited better DFS and OS at 3 and 5 years (DFS: 75.7% and 57.3%, respectively; OS: 75.7% and 62.5%, respectively) than the patients who did not receive the same treatment. The survival time was significantly improved in patients with initial CA19-9 of less than 300 µ/mL or CEA of less than 10 ng/mL. Multivariate analysis revealed N stage and combined adjuvant chemotherapy were independent factors for DFS. However, only combined adjuvant chemotherapy could prolong OS for patients who underwent radical resection. CONCLUSIONS: In our study, both N stage and combined adjuvant chemotherapy are found to influence postoperative recurrence of SBA. Moreover, combined adjuvant chemotherapy is an independent prognostic factor of DFS and OS.

Serum miR-191 and miR-425 as Diagnostic and Prognostic Markers of Advanced Gastric Cancer Can Predict the Sensitivity of FOLFOX Chemotherapy Regimen.

PURPOSE: miR-191 and miR-425 have been proved to be highly expressed in gastric carcinoma (GC). However, little research has been done on their clinical value in serum of patients with advanced GC. In addition, it is not clear whether they can be used as markers for the response and prognosis of GC patients treated with oxaliplatin combined with 5-fluorouracil and FOLFOX chemotherapy. PATIENTS AND METHODS: A total of 230 patients with advanced GC admitted to our hospital were selected as the study objects, all of whom received FOLFOX chemotherapy regimen. Another 100 cases of healthy subjects were included. QRT-PCR was employed to detect the serum expression of miR-191 and miR-425 in patients. RESULTS: Compared with the healthy subjects, the serum expressions of miR-191 and miR-425 in GC patients were significantly upregulated, which were correlated with differentiation degree and TNM staging, respectively. According to the ROC curve, the AUC of miR-191 and miR-425 for GC diagnosis was 0.937 and 0.901, respectively, while the AUC for differentiation degree diagnosis was 0.854 and 0.822, and that for TNM staging diagnosis was 0.860 and 0.829, respectively. The predictive AUC of miR-191 and miR-425 for chemosensitivity was 0.868 and 0.835, respectively, with a combined predictive AUC of 0.935. Low differentiation degree, high TNM staging, high miR-191 and high miR-425 expressions were independent risk factors for chemotherapy insensitivity. Differentiation degree, TNM staging, chemotherapy effect, miR-191 and miR-425 were independent influencing factors for the prognosis of GC patients. CONCLUSION: Up-regulated expression of miR-191 and miR-425 in the serum of patients with advanced GC are effective biomarkers for the diagnosis, chemotherapy and prognosis evaluation of GC.