Role of a novel circRNA-CGNL1 in regulating pancreatic cancer progression via NUDT4-HDAC4-RUNX2-GAMT-mediated apoptosis.

BACKGROUND: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ_0035435 (termed circCGNL1) in PC. METHODS: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays. RESULTS: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway. CONCLUSIONS: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC.

Vitamin C affects G0/G1 cell cycle and autophagy by downregulating of cyclin D1 in gastric carcinoma cells.

Vitamin C has re-emerged as a promising anticancer agent. This study attempts to analyze the differential gene expression of profiles GSE11919 to look for some clues, and the most significant cell cycle pathway caused by vitamin C was identified by integrated bioinformatics analysis. Inspired by this, we investigated the effect of vitamin C treatment on gastric carcinoma cells by detection of cell cycle, apoptosis, and autophagy. Vitamin C significantly elevated the percentage of cells at G0/G1 phase, whereas the percentage of S phase cells was decreased. Meanwhile, vitamin C treatment resulted in downregulation of cell cycle-related protein Cyclin D1. We deduced that the downregulation of Cyclin D1 by vitamin C accompanied by significantly increased 5'AMP-activated protein kinase and induced autophagy in MKN45 cells. These results suggest that vitamin C has the antiproliferation effect on gastric carcinoma cells via the regulation of cell cycle and autophagy by Cyclin D1.

Association of wheat chaff derived silica fiber and esophageal cancer in north China.

BACKGROUND: Despite decades of research and intervention programs, the epidemic of esophageal squamous cell carcinoma (ESCC) in the Taihang Mountain area of north China has not seen convincing explanation by any risk factor yet and the incidence has not seen a substantial decrease. Based on recently disclosed association of aridity and wheat consumption with esophageal cancer, we revisited the hypothesis of biogenic silica in esophageal cancer development. METHODS: From the archives of the Pathology Department of Heping Hospital, Changzhi Medical College, we selected three pairs of formalin-fixed samples, tumor tissues and distant normal tissues, of three patients operated for ESCC who had no history of workplace exposure to silica dust. Two pairs of dried tissue samples were used for phytolith (silica body) analysis and another pair for microanalysis with Transmission Electron Microscope (TEM). RESULTS: One of the phytoliths in ESCC tumor tissue was similar to the prickle hair on the surface of wheat bract. In the mineral particles detected in the tumor tissue the predominant elements were Si, Ca, and P, whereas Si signals were not obvious in the distant normal tissue. CONCLUSIONS: The preliminary findings on the detection of phytoliths and the higher than normal Si concentration in ESCC tumor tissue warrants further testing the role of biogenic silica in esophageal cancer.

MiR-769 Inhibits Colorectal Cancer Cell Proliferation and Invasion by Targeting HEY1.

BACKGROUND MicroRNAs (miRNAs) have been widely recognized as essential regulators in human cancers, including colorectal cancer (CRC). Whether miR-769 is implicated in CRC progression remains elusive. The present study aimed to determine the function of miR-769 in CRC. MATERIAL AND METHODS MiR-769 expression in CRC tissues and adjacent normal tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Kaplan-Meier curve analysis was utilized to determine the association between miR-769 expression and prognosis in CRC patients. The effects of miR-769 overexpression on CRC cell proliferation, cell cycle and invasion were analyzed using Cell Counting Kit-8 (CCK8), fluorescence activated cell sorting (FACS), and Transwell assays. Western blot was utilized to assess the effect of miR-769 on HEY1 expression. RESULTS MiR-769 expression was decreased in CRC tissues. MiR-769 level was negatively correlated with the prognosis of CRC patients. Additionally, miR-769 overexpression remarkably inhibited cell proliferation, arrested CRC cells in G0 stage, and reduced cellular invasion. As to the mechanism, HEY1 was a direct target of miR-769; HEY1 level was inversely correlated with that of miR-769 in CRC tissues. Finally, overexpression of HEY1 reversed the effects of miR-769 on cell proliferation and invasion in CRC. CONCLUSIONS Our findings demonstrated that miR-769 suppressed the proliferation and invasion of CRC cells through targeting HEY1, which implied that miR-769 might be a novel therapeutic target for CRC treatment.

CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) (NCT03001596).

BACKGROUND: Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). METHODS/DESIGN: CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life. DISCUSSION: The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. TRIAL REGISTRATION: NCT03001596 (December 17, 2016).

Vitamin D Signaling Pathways Confer the Susceptibility of Esophageal Squamous Cell Carcinoma in a Northern Chinese Population.

Experimental studies have determined the chemopreventive effects of vitamin D against the esophageal squamous cell carcinoma (ESCC); however, results from the epidemiological studies are not yet well established. The current study aimed to evaluate the associations between plasma vitamin D levels and variants on vitamin D metabolic-related genes with the risks for ESCC. A hospital-based case-control study was performed. Five hundred eighty-two ESCC patients and 569 controls were recruited in a Northern Chinese population. Common variants on vitamin D metabolism-related genes CYP24A1, DHCR7, GC, CYP27B1, and vitamin D receptor (VDR) and the plasma 25(OH)D level were determined. The unconditional logistic regression method was applied to determine the associations between the variants and vitamin D level and ESCC. Higher plasma 25(OH)D was associated with a reduced risk for ESCC, especially for rs2296241, rs11568820, and rs4646536. The variants rs2296241 on CYP24A1 and rs11568820 on VDR are significantly associated with ESCC cancer. Vitamin D signaling pathways may participate in the ESCC development. Further studies with larger sample size are warranted to confirm the results. Intervention studies are needed to determine whether vitamin D supplementation may reduce the ESCC risk in the Chinese population.

Theabrownin as a Potential Prebiotic Compound Regulates Lipid Metabolism via the Gut Microbiota, Microbiota-Derived Metabolites, and Hepatic FoxO/PPAR Signaling Pathways.

The dysregulation of lipid metabolism poses a significant health threat, necessitating immediate dietary intervention. Our previous research unveiled the prebiotic-like properties of theabrownin. This study aimed to further investigate the theabrownin-gut microbiota interactions and their downstream effects on lipid metabolism using integrated physiological, genomic, metabolomic, and transcriptomic approaches. The results demonstrated that theabrownin significantly ameliorated dyslipidemia, hepatic steatosis, and systemic inflammation induced by a high-fat/high-cholesterol diet (HFD). Moreover, theabrownin significantly improved HFD-induced gut microbiota dysbiosis and induced significant alterations in microbiota-derived metabolites. Additionally, the detailed interplay between theabrownin and gut microbiota was revealed. Analysis of hepatic transcriptome indicated that FoxO and PPAR signaling pathways played pivotal roles in response to theabrownin-gut microbiota interactions, primarily through upregulating hepatic Foxo1, Prkaa1, Pck1, Cdkn1a, Bcl6, Klf2, Ppara, and Pparg, while downregulating Ccnb1, Ccnb2, Fabp3, and Plin1. These findings underscored the critical role of gut-liver axis in theabrownin-mediated improvements in lipid metabolism disorders and supported the potential of theabrownin as an effective prebiotic compound for targeted regulation of metabolic diseases.

Pathologic Response of Phase III Study: Perioperative Camrelizumab Plus Rivoceranib and Chemotherapy Versus Chemotherapy for Locally Advanced Gastric Cancer (DRAGON IV/CAP 05).

PURPOSE: This multicenter, randomized phase III trial evaluated the efficacy and safety of perioperative camrelizumab (an anti-PD-1 antibody) plus low-dose rivoceranib (a VEGFR-2 inhibitor) and S-1 and oxaliplatin (SOX) (SOXRC), high-dose rivoceranib plus SOX (SOXR), and SOX alone (SOX) for locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. METHODS: Patients with T3-4aN + M0 G/GEJ adenocarcinoma were randomly assigned (1:1:1) to receive perioperative treatment with SOXRC, SOXR, or SOX. The primary end points were pathologic complete response (pCR) and event-free survival. The Independent Data Monitoring Committee recommended stopping enrollment in the SOXR group on the basis of the safety data of the first 103 randomly assigned patients in the three groups. The patients were then randomly assigned 1:1 to the SOXRC or SOX groups. This report presents the pCR results obtained per protocol for the first 360 randomly assigned patients who had the opportunity for surgery in the SOXRC and SOX groups. RESULTS: In the SOXRC and SOX groups, of the 180 patients in each group, 99% and 98% of patients received neoadjuvant therapy, 91% and 94% completed planned neoadjuvant therapy, and 86% and 87% underwent surgery, respectively. The pCR was significantly higher in the SOXRC group at 18.3% (95% CI, 13.0 to 24.8) compared with 5.0% (95% CI, 2.3 to 9.3) in the SOX group (difference of 13.7%; 95% CI, 7.2 to 20.1; odds ratio of 4.5 [95% CI, 2.1 to 9.9]). The one-sided P value was <.0001, crossing the prespecified statistical significance threshold of P = .005. Surgical complications and grade ≥3 neoadjuvant treatment-related adverse events were 27% versus 33% and 34% versus 17% for SOXRC and SOX, respectively. CONCLUSION: The SOXRC regimen significantly improved pCR compared with SOX alone in patients with G/GEJ adenocarcinoma with a tolerable safety profile.

Linc-UROD stabilizes ENO1 and PKM to strengthen glycolysis, proliferation and migration of pancreatic cancer cells.

Pancreatic cancer (PC) is a fatal malignancy, threatening human health in worldwide. Long non-coding RNAs (lncRNAs) have been acknowledged to be essential regulators in various biological processes of human cancers. However, the role of some novel lncRNAs in PC remain to be explored. In this study, we focused on the function and molecular mechanism of a novel lncRNA linc-UROD (also named TCONS_00002016 or XLOC_000166) in PC. The expression of linc-UROD was found to be upregulated in PC cells. The results of loss-of-function assays demonstrated that linc-UROD knockdown suppressed cell proliferation and migration, induced cell cycle G0/G1 arrest, and accelerated apoptosis of PC cells. Through mechanistic experiments, we found that IGF2BP3 stabilized linc-UROD through METTL3-mediated m6A modification. In addition, linc-UROD enhances the stability of ENO1 and PKM through interacting with them to inhibit ubiquitination. Detection on glucose consumption, pyruvate kinase activity and lactate production indicated that linc-UROD accelerated glycolysis of PC cells through PKM/ENO1-mediated pathway. To summarize, linc-UROD stabilized by IGF2BP3/METTL3 contributes to glycolysis and malignant phenotype of PC cells by stabilizing ENO1 and PKM. The findings suggest that linc-UROD may be a novel therapeutic target for PC patients.

circPTPN22 attenuates immune microenvironment of pancreatic cancer via STAT3 acetylation.

Accumulating research implicated that circular RNAs exhibited significant roles in cancer development. Nonetheless, the role regarding circPTPN22 in pancreatic cancer remains unclear. Expression of circPTPN22 in pancreatic cancer cell lines and normal cells was determined with quantitative real-time PCR (qRT-PCR). Cell counting kit-8 assay and colony formation assay were used to measure the proliferation of pancreatic cancer cells. RNA immunoprecipitation and Western blot were employed for investigation the binding between circPTPN22 and STAT3. circPTPN22 expression was highly upregulated in pancreatic cancer tissues and cell lines. Knockdown of circPTPN22 inhibited cell proliferation and attenuates pancreatic cancer immune microenvironment. Furthermore, STAT3 acetylation was involved in these effects. circPTPN22 promoted STAT3 acetylation via inhibiting STAT3/SIRT1 interaction. circPTPN22 attenuates pancreatic cancer immune microenvironment by promoting STAT3 acetylation via inhibiting STAT3/SIRT1 interaction.

[The relationship between C20orf54 gene rs3746804 position single nucleotide polymorphism and susceptibility to esophageal squamous cell carcinoma].

OBJECTIVE: To explore the association of C20orf54 gene rs3746804 position single nucleotide polymorphism and susceptibility to esophageal squamous cell carcinoma (ESCC). METHODS: Purification of genomic DNA from whole blood was used the Maxwell(16) System. rs3746804 in C20orf54 was detected by direct sequencing in 434 ESCC patients from Changzhi (Shanxi province) and Linzhou (Henan province) and 554 healthy controls from Changzhi, Linzhou and including immigrators from Linzhou to Changzhi. RESULTS: For rs3746804, the genotypic frequencies of CT (37.5% vs 51.0%, 37.5% vs 52.0%), CC (44.2% vs 34.8%, 44.2% vs 33.0%) in Changzhi ESCC patients showed significant differences with healthy Changzhi controls and the healthy immigrator controls (all P < 0.05), and the frequencies of TT (18.3% vs 4.1%) and CC (44.2% vs 54.6%) in Changzhi ESCC patients showed significant differences with Linzhou ESCC patients (all P < 0.05). The genotypic frequencies of TT (4.1% vs 15.0%), CT (41.2% vs 52.0%) and CC(54.6% vs 33.0%) showed significant differences between Linzhou ESCC patients and the healthy immigrator controls (all P < 0.05), and the frequencies of TT (4.1% vs 14.1%) and CC(54.6% vs 34.8%) showed significant differences between Linzhou ESCC patients and Changzhi healthy controls (all P < 0.01). Meanwhile, there were significant differences between ESCC patients (including Changzhi and Linzhou ESCC patients) and healthy controls (including the healthy Changzhi, Linzhou and immigrator controls) in genotypic frequencies of CT (39.2% vs 48.7%) and CC (48.8% vs 38.2%) (all P < 0.01). CT and CT + TT genotype could decrease the risk of ESCC compared with the CC genotype (OR = 0.630, 95%CI 0.481 - 0.826; OR = 0.654, 95%CI 0.507 - 0.844). CONCLUSION: There is a closed relationship between SNP rs3746804 in C20orf54 and susceptibility to ESCC.

Decreased Serum Exosomal microRNA-134 Expression and Its Prognostic Value in Gastric Cancer.

OBJECTIVE: Identification of reliable biomarkers for the diagnosis and prognosis of gastric cancer (GC) is very important for achieving early cancer detection and improving clinical outcomes. The aim of the present study was to explore the clinical significance of serum exosomal miR-134 in GC. METHODS: A total of 133 GC cases were enrolled in this study, and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was carried out to measure the relative serum exosomal miR-134 expression level. The association between serum exosomal miR-134 expression and clinicopathological characteristics was investigated. RESULTS: Our results showed that serum exosomal miR-134 expression was significantly lower in GC patients than in controls. In addition, serum exosomal miR-134 discriminated GC cases from healthy controls with high accuracy. Moreover, reduced serum exosomal miR-134 expression was closely associated with aggressive clinical variables including TNM stage, lymph node metastasis and invasion depth. Furthermore, Kaplan-Meier analysis revealed that GC patients with low serum exosomal miR-134 expression tended to have shorter overall survival and relapse free survival. In multivariate analysis, serum exosomal miR-134 was an independent prognostic marker for GC. CONCLUSION: In conclusion, serum exosomal miR-134 might serve as a promising diagnostic and prognostic biomarker for GC.

[A comparison and significance of plasma riboflavin levels in patients with esophageal squamous cell carcinoma versus Linzhou healthy migrants in Changzhi of Shanxi].

OBJECTIVE: To study the relationship between plasma riboflavin levels and esophageal squamous cell carcinoma. METHODS: We detected and compared plasma concentrations of riboflavin in patients with esophageal squamous cell carcinoma (ESCC) and immigrants of Linzhou living in Changzhi. Plasma riboflavin levels were quantified in 445 ESCC patients, 689 healthy control subjects and 347 immigrants of Linzhou living in Changzhi by using enzyme-linked immunosorbent assay. RESULTS: The plasma riboflavin levels in patients with ESCC were significantly lower than those in the healthy controls and immigrants of Linzhou living in Changzhi [(731.69 ± 330.67) µg/L vs (1090.43 ± 445.08) µg/L, (731.69 ± 330.67) µg/L vs (897.58 ± 177.78) µg/L, respectively, all P < 0.05], and the plasma riboflavin levels of the healthy controls were higher than those in the immigrants of Linzhou living in Changzhi (P < 0.05). CONCLUSION: Patients with ESCC have decreased plasma riboflavin levels as compared with the healthy controls and immigrants of Linzhou living in Changzhi, there exists a lack of riboflavin in ESCC patients, but the specific mechanism needs further study.

Clonal Architectures Predict Clinical Outcome in Gastric Adenocarcinoma Based on Genomic Variation, Tumor Evolution, and Heterogeneity.

Stomach adenocarcinoma (STAD) is a highly heterogeneous disease. Due to the lack of effective molecular markers and personalized treatment, the prognosis of gastric cancer patients is still very poor. The ABSOLUTE algorithm and cancer cell fraction were used to evaluate the clonal and subclonal status of 349 TCGA (The Cancer Genome Cancer Atlas)-STAD patients. Non-negative matrix factorization was used to identify the mutation characteristics of the samples. Univariate Cox regression analysis was used to determine the relationship between clonal/subclonal events and prognosis, and the Spearman correlation was used to evaluate the relationship of clonal/subclonal events to tumor mutation burden (TMB) and neoantigens. The evolution pattern of STAD demonstrated great tumor heterogeneity. TP53, USH2A, and GLI3 appeared earliest in STAD and may drive STAD. CTNNB1, LRP1B, and ERBB4 appeared the latest in STAD, and may be related to STAD's progress. Univariate Cox regression analysis identified four early genes, eight intermediate genes, and seven late genes significantly associated with overall survival. The number of subclonal events in the T stage was significantly different. The N stage, gender, and histological type were significantly different for clonal events, and there was a significant correlation between clonal/subclonal events and TMB/neoantigens. Our results highlight the importance of systematic evaluation of evolutionary models in the clinical management of STAD and personalized gastric cancer treatment.

Clinical Significance of Monitoring Circulating Free DNA and Plasma Heat Shock Protein 90alpha in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal cancer in China and has an extremely poor prognosis. Circulating free DNA (cfDNA) and plasma heat shock protein 90alpha (Hsp90a) are two novel noninvasive biomarkers for diagnosis and prognostic prediction of several types of cancer. However, to the best of our knowledge, the roles of the two biomarkers in ESCC are still unknown. METHODS: Here, we recruited 93 primary ESCC patients and detected plasma concentrations of the two markers at different time points, including 1-3 days pre-chemotherapy, 1-7 days pre-surgery and 7-14 days post-surgery. Baseline concentrations of the two markers were associated with main characteristics of ESCC patients which were collected at first diagnosis. Correlation between the two markers and traditional serum biomarkers at baseline was also examined. Furthermore, dynamic changes of the cfDNA and Hsp90α concentrations among different time points and the potential clinical significance were assessed. RESULTS: Consequently, there was no significant association between baseline concentrations of the two markers and clinical features. Especially, cfDNA demonstrated stronger correlation with other circulating biomarkers than Hsp90α at baseline level. Importantly, both cfDNA and Hsp90α concentrations were significantly increased after surgery. Kaplan-Meier survival analysis showed that a change in concentration of cfDNA (ΔcfDNA) but not Hsp90α (ΔHSP90ɑ) between pre-surgery and post-surgery had significant effect on the overall survival of surgical patients with ESCC. CONCLUSION: Thus, ΔcfDNA evaluation could be a promising prognostic marker for surgical ESCC patients. Our findings may improve the understanding of the function of cfDNA and Hsp90α in ESCC.

Morbidity and Mortality of Patients Who Underwent Minimally Invasive Esophagectomy After Neoadjuvant Chemoradiotherapy vs Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) vs neoadjuvant chemotherapy (nCT) for treatment of locally advanced esophageal squamous cell carcinoma (ESCC) remain uncertain given lack of high-level clinical evidence. Objective: To compare safety and long-term survival of nCRT followed by minimally invasive esophagectomy (MIE) with that of nCT followed by MIE for patients with locally advanced ESCC. Design, Setting, and Participants: A prospective, multicenter, open-label, randomized clinical trial that compared safety and efficacy of nCRT vs nCT followed by MIE for patients with locally advanced ESCC. From January 1, 2017, to December 31, 2018, 264 patients with ESCC of clinical stages from cT3 to T4aN0 to 1M0 were enrolled. Analysis was performed on an intention-to-treat basis from January 1, 2017, to August 30, 2020. Interventions: Eligible patients were randomized to the nCRT group (n = 132) or the nCT group (n = 132) by a computer-generated random system. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while 40 Gy of concurrent radiotherapy was added for the nCRT group. At about 6 weeks after neoadjuvant therapy, MIE via thoracoscopy and laparoscopy was performed for the patients in both groups. Main Outcomes and Measures: The primary outcome was 3-year overall survival. Secondary outcomes included postoperative complications, mortality, postoperative pathologic outcome, recurrence-free survival time, and quality of life. Results: Among 264 patients (226 men [85.6%]; mean [SD] age, 61.4 [6.8] years), postoperative morbidity was 47.4% in the nCRT group (54 of 114) and 42.6% in the nCT group (46 of 108), with no significant difference between groups (difference, 4.8%; 95% CI, -8.2% to 17.5%; P = .48). Distribution of the severity of complications was similar between the 2 groups based on Clavien-Dindo classification. The 90-day perioperative mortality rate was 3.5% for the nCRT group (4 of 114) and 2.8% for the nCT group (3 of 108) (P = .94). The R0 resection rates were similar between groups (109 of 112 [97.3%] vs 100 of 104 [96.2%]; P = .92). However, patients in the nCRT group had a higher pathologic complete response (residual tumor, 0%) rate (40 of 112 [35.7%] vs 4 of 104 [3.8%]; P < .001) and a higher rate of negative lymph nodes (ypN0, 74 of 112 [66.1%] vs 48 of 104 [46.2%]; P = .03) than those in the nCT group. One-year overall survival using intention-to-treat analysis was 87.1% in the nCRT group (115 of 132) and 82.6% in the nCT group (109 of 132) (P = .30). Furthermore, deaths caused by tumor progression or recurrence were significantly less in the nCRT group than in the nCT group (9 of 132 [6.8%] vs 19 of 132 [14.4%]; P = .046); however, deaths from nontumor causes were similar (8 of 132 [6.1%] vs 4 of 132 [3.0%]; P = .24). Conclusions and Relevance: Initial results of the trial showed that nCRT followed by MIE has similar safety to and better histopathologic outcome than nCT followed by MIE for treatment of locally advanced ESCC. Trial Registration: ClinicalTrials.gov Identifier: NCT03001596.

The efficacy and safety of neoadjuvant chemotherapy on patients with advanced gastric cancer: A multicenter randomized clinical trial.

OBJECTIVES: Exploring the efficacy and safety of perioperative chemotherapy on patients with AGC at different clinical and pathological stages. METHODS: A phase III randomized, multicenter, trial comparing adjuvant (arm A) or perioperative S-1 plus oxaliplatin (SOX, arm B), and perioperative capecitabine plus oxaliplatin (XELOX, arm C) was initiated in T3/4, node + gastric cancer patients (unclear). Each patient received an 8-cycle chemotherapy (3 weeks for one cycle). Group arms B and C received two cycles preoperatively, and six cycles postoperatively. Primary endpoints were R0 resection rate and DFS, and secondary endpoints included OS, ORR, DCR, and safety. This study was registered on Clinicaltrials.gov. NCT01516944. RESULTS: A total of 749 patients were randomly assigned into groups A, B, and C. Group A received 1460 circles chemotherapy and group B received 1177 circles while group C received 1200 circles. R0 resection rates in the three groups were 81.7%, 88.7%, and 83.1%, respectively. The difference between groups A and B was considered to be statistically significant (P = .018), and no significant difference between groups B and C (P = .051). Hazard ratio were compared between groups B and C and DFS showed 0.72 (0.67-0.77 with 95% CI), Pnon-inferiority  < .0001, Plog-rank  = .064). The CI top limit actually lower than the estimated value of 1.38, which indicated noninferiority of SOX to XELOX. CONCLUSIONS: Compared with PAC, perioperative chemotherapy showed a significant improvement in R0 resection rates and prognosis in AGC patients with higher safety rates. This study was powered to show superiority of perioperative over adjuvant SOX, and noninferiority of SOX to XELOX. Volume measurement, repeated laparoscopic exploration combined with exfoliative cytology can be used as a supplementary method in the clinical staging and efficacy evaluation of AGC.

A possible role of biogenic silica in esophageal cancer in North China?

Certain areas in North China have the highest incidence of esophageal squamous cell carcinoma (ESCC) in the world, which has not seen convincing explanation by any risk factor yet. Biogenic silica in millet bran was linked to ESCC in the early 1980s but the hypothesis was largely dismissed because of the lack of geographic correlation between millet consumption and ESCC. Later epidemiological studies disclosed the linkage of wheat consumption in North China to ESCC instead. Now, we hypothesize silica phytoliths (silicified bodies that have definite shapes) from wheat chaff are a major etiologic factor of ESCC in this region. This hypothesis is supported by the potentially high abundance of silica phytoliths on the bracts of wheat (Triticum aestivum) in North China due to favorable Si-accumulation genotype, arid climate, and siallitic soil with bioavailable Si. These silica phytoliths can contaminate wheat flour and cause repeated local injuries in the esophagus and stimulate proliferation by providing anchorage.

Fibulin-2 inhibits development of gastric cancer by downregulating ß-catenin.

The aim of the present study was to investigate the expression of fibulin-2 and ß-catenin in gastric cancer tissues and the association to mutual regulation. Forty-nine cases of gastric cancer specimens obtained via surgical resection in the Pathology Department of Heping Hospital Affiliated to Changzhi Medical College from March 2013 to August 2017 were collected. The expression levels of fibulin-2 and ß-catenin in 49 cases of gastric cancer and para-carcinoma tissues were detected via quantitative polymerase chain reaction and immunohistochemistry. The correlation of expression of fibulin-2 and ß-catenin proteins in gastric cancer was detected via Spearman's analysis. The correlation of fibulin-2 and ß-catenin protein expression with clinicopathological indexes of patients was also analyzed. Moreover, the fibulin-2 overexpression plasmid was constructed and transfected into human gastric cancer AGS and SGC-790 cell lines, so as to observe changes in ß-catenin and its downstream indexes. Fibulin-2 messenger ribonucleic acid (mRNA) level in gastric cancer tissues was significantly lower than that in para-carcinoma tissues, while ß-catenin mRNA level was significantly increased (P<0.05). The positive rate of fibulin-2 protein was 73.47% (36/49) in gastric cancer tissues and 16.33% (8/49) in para-carcinoma tissues, while that of ß-catenin was 77.55% (38/49) in gastric cancer tissues and 28.57% (14/49) in para-carcinoma tissues, indicating that fibulin-2 protein is significantly deleted in gastric cancer tissues, and ß-catenin protein is significantly upregulated (P<0.001). Fibulin-2 and ß-catenin had a negative correlation (r=-0.361, P=0.003), but was closely correlated with the tumor size and lymph node metastasis (P<0.05). After overexpression of fibulin-2, expression of ß-catenin, cyclin D1 and c-Myc protein was obviously downregulated (P<0.05). The tumor suppressor gene, fibulin-2, is significantly deleted in gastric cancer tissues, while ß-catenin is remarkably enriched. Overexpression of fibulin-2 can inhibit the development of gastric cancer by downregulating ß-catenin.