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Background Radiation pneumonitis (RP) is a common side effect in lung cancer patients who received radiotherapy. Our previous study found genetic variations in DNA repair gene NEIL1 may be a predictor of RP in patients with esophageal cancer. So, we hypothesis genetic variations in NEIL1 gene could affect the risk of RP in lung cancer patients following radiotherapy. Methods Genetic variations rs4462560 G>C and rs7402844 C>G in NEIL1 gene were genotyped in 174 lung cancer patients received radio(chemo)therapy. Luciferase assay, real‐time PCR and Western blot were used to access the effect of the variants on NEIL1 in HELF and HEF cell lines which were transfected with plasmids containing rs4462560 G>C and rs7402844 C>G. Results Patients with rs4462560 CC genotype had a lower risk of RP grade ≥2 than GG genotype. Compared with the CC genotype, rs7402844 GG genotype was associated with an increased RP grade ≥2 risk. What is more, rs4462560 G decreased the relative luciferase activity of NEIL1 gene promoter compared with the negative control in vitro, while rs4462560 C can increase the relative luciferase activity. The mRNA and protein level of the NEIL1 gene in rs4462560 G were lower than rs4462560 C. Conclusions Genetic variants of NEIL1 are associated with RP risk through regulation of NEIL1 expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy., We found genetic variants of NEIL1 are associated with RP risk in the study. These variants might exert their effect through regulation of NEIL1 expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.

Yeqi Sun,1,*Wenwei Yu,1,*Wenbin Guan,1,*Lei Cai,1 Meng Qiao,1 Leizhen Zheng,2 Ruiqi Jiang,1 Ruifen Wang,1 Lifeng Wang11Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, People’s Republic of China; 2Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, People’s Republic of China*These authors contributed equally to this workPurpose: Targeting the PD-1/PD-L1 pathway has emerged as a novel therapy for cancer. To identify rational candidates for anti-PD-1/PD-L1 immunotherapy in gastric cancer (GC), the abundance of PD-L1 expression was evaluated on a kind of biomarker-based molecular classification for shaping prognosis and treatment planning.Methods: One hundred and sixty-five GCs were classified into five subgroups using immunohistochemistry (IHC) and in situ hybridization (ISH) methods, based on a panel of seven markers (MLH1, PMS2, MSH2, MSH6, E-cadherin, P53, and Epstein-Barr virus mRNA). The expression of PD-L1 in GC tissues was analyzed immunohistochemically.Results: The five categories (Epstein–Barr virus positivity, microsatellite instability, aberrant E-cadherin, aberrant P53 expression, and normal P53 expression) correspond to the reported molecular subgroups for similar proportions and clinicopathologic characteristics. Survival analysis indicated that subgroups with aberrant E-cadherin expression independently predicted a worse prognosis in GC patients (HR=2.51, P=0.010). The clinical and prognostic profiles produced by this stratification in nonintestinal-type GC were distinguishable from those in intestinal-type. Although PD-L1 was not a significant prognostic factor, that more frequent presence of PD-L1-positive in microsatellite instability tumors than other subtypes (P

Background Chemoresistance is the major cause of neoadjuvant treatment failure in breast cancer patients. Despite recent progress, the mechanism underlying chemoresistance remains to be further defined. Methods Expression of G protein-coupled receptor 120 (GPR120) was analyzed by immunohistochemistry in the biopsies of primary breast cancer who subsequently underwent preoperative neoadjuvant chemotherapy. In vitro and in vivo loss- and gain-of -function studies were performed to reveal the effects and related mechanism of GPR120 signaling pathway in the chemoresistance of breast cancer cells. Findings We identified that GPR120, a receptor for long-chain fatty acids, was important for the acquisition of chemoresistance in breast cancer cells. We showed that GPR120 expression was positively associated with clinical response to neoadjuvant chemotherapy in patients. In breast cancer cells, GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism. Upregulated GPR120 signaling rendered cells resistant to epirubicin-induced cell death by upregulating ABC transporters expression and thus decreasing the intracellular accumulation of epirubicin. Akt/NF-κB pathway was responsible for the GPR120-mediated expression of ABC transporters leading to modulation of the concentration of chemotherapeutic drugs in cells. The functional importance of GPR120 in chemoresistance was further validated using epirubicin-treated tumor xenografts, in which we showed that blockade of GPR120 signaling with AH7614 or GPR120-siRNA significantly compromised chemoresistance. Interpretation Our results highlight that GPR120 might be a promising therapeutic target for breast cancer chemoresistance. Fund National Natural Science Foundation of China, Ministry of Science and Technology of China, Program of Science and Technology Commission of Shanghai Municipality.

Xin Lu,1 Wanying Guo,2 Wei Xu,1 Xuelei Zhang,1 Zhijie Shi,1 Leizhen Zheng,1 Wenzhao Zhao1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; 2Department of Breast Surgery, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China Purpose: The aim of this study was to perform a systematic review and meta-analysis to evaluate the value of the Glasgow prognostic score (GPS) or modified Glasgow prognostic score (mGPS) in patients with colorectal cancer (CRC). Methods: A comprehensive medical literature search was performed using the online databases PubMed, Embase, Web of Science, and the Cochrane Library. After extracting basic characteristics and prognostic data from the included studies, overall survival (OS) and cancer-specific survival (CSS) were pooled as primary outcomes. Subgroup analyses were performed according to therapeutic strategies, models, cutoff values, regions, tumor, node, metastasis stages, sample size, and ages. Results: Forty-three independent cohorts from 41 studies with 9,839 CRC patients were included in the present study. Correlation between GPS or mGPS and OS was analyzed in 32 cohorts of 7,714 patients, and 23 independent cohorts of 5,375 patients focused on the correlation between GPS or mGPS and CSS. The overall outcomes showed that patients with elevated GPS or mGPS were associated with poor OS (HR: 2.20, 95% CI: 1.88–2.57, P

Gastric cancer is one of the most common and deadly cancer types. Currently, four subtypes have been identified with unique molecular alterations: Epstein–Barr virus (EBV)‐positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) tumors. Notably, many gastric tumors are associated with the bacterium Helicobacter pylori but the genomic landscape of this subgroup of tumors remains largely unknown. Targeted sequencing covering 425 genes was performed retrospectively on 1703 gastric tumor tissues and matched normal blood samples. Nonsynonymous mutations, copy‐number variation (CNV), and MSI status were called from human DNA reads; nonhuman DNA reads were mapped to NCBI microbial reference genome using Kraken and significant species were identified. Overall, 37 (2.76%) from a total of 1703 samples were EBV‐positive, 200 (11.74%) samples were H. pylori‐positive, and 10 samples were positive for both. Among the rest, 59 (3.46%) samples were MSI, 380 (22.31%) were CIN, and 1017 (59.72%) were GS. Most of the 200 H. pylori‐positive samples tend to be genome stable (85.5%, p, Previous group have found 4 molecular subtypes for gastric adenocarcinoma. We uncovered an additional subtype of H.pylori associated gastric cancer with distinct genomic profile.

Background Anti-apoptotic protein Bcl-2 plays a substantial role in the carcinogenesis, whereas the regulation for Bcl-2 in gastric carcinoma (GC) is poorly understood. Specifically, a role of microRNA (miR)-383 in the control of Bcl-2 has not been shown in GC and thus addressed in the current study. Methods We investigated the levels of miR-383 and Bcl-2 in 50 GC specimens, and compared them with patients’ clinical characteristics. Bioinformatics analyses and luciferase-reporter assay were applied for analyzing the relationship between Bcl-2 and miR-383. An CCK assay was used to determine the survival of Fluorouracil-treated GC cells, and apoptosis of GC cells was assessed by flow cytometric FITC Annexin V apoptosis detection assay and expression of apoptosis-associated proteins. Results The levels of miR-383 were lower while the levels of Bcl-2 levels were higher in GC specimens, compared to tissue from the adjacent non-tumor region. Low miR-383 and high Bcl-2 seemed to be associated with high malignancy and metastasis. In GC specimens, the levels of Bcl-2 and miR-383 inversely correlated. The overall survival of miR-383-low cases was poorer. Mechanistically, miR-383 targeted the 3′-UTR of Bcl-2 mRNA to inhibit its protein translation. Overexpression of miR-383 downregulated Bcl-2, resulting in reduced survival of Fluorouracil-treated GC cells. Similar conclusion was drawn through analysis of published database. Conclusion MiR-383 reduces survival of Fluorouracil-treated GC cells through downregulating of Bcl-2.

Aim: The clinicopathological and prognostic significance of C-MYC dysregulation (amplification or overexpression) in esophageal squamous cell carcinoma (ESCC) remains controversial. Therefore, we performed this meta-analysis to elucidate this relationship. Materials & methods: Available studies were retrieved from PubMed, Web of Science, EMBASE and the Cochrane Library, and ten studies with a total of 1432 patients were included in this meta-analysis. Results: Pooled results showed that C-MYC dysregulation was significantly associated with poor overall survival (hazard ratio: 1.405 [95% CI: 1.170–1.639]; p < 0.001) and lymph node metastasis (odds ratio: 1.798 [95% CI: 1.125–2.873]; p = 0.014). Subgroup analysis confirmed the results and more prominent predictive effects were observed in the C-MYC amplification group. Conclusion: C-MYC dysregulation is a promising biomarker for ESCC prognosis.

Objective: Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions in gastric cancer (GC). Previous studies demonstrated genetic variants within mTORC1 genes were associated with GC risk. However, no studies reported the associations between genetic variants within mTORC1 genes and GC prognosis. Herein, we firstly assessed the associations of genetic variants of mTORC1 genes with overall survival (OS) of GC in Chinese populations. Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in mTORC1 genes (i.e., rs2536 T>C and rs1883965 G>A for mTOR, rs3160 T>C and rs26865 A>G for MLST8, rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A for RPTOR) by the TaqMan method in 197 Chinese GC patients who had surgical resection in Xinhua Hospital. We conducted Kaplan-Meier survival plots and Cox hazards regression analysis to explore the associations of these SNPs with OS. Results: The single-locus analysis indicated that RPTOR rs1062935 T>C was associated with an increased risk of poor GC prognosis (CC vs. TT/TC: adjusted Hazard ratio (HR) = 1.71, 95% confidence interval (CI) = 1.04-2.82). The combined analysis of all eight SNPs showed that patients with more than three risk genotypes significantly increased risk of death (adjusted HR = 2.44, 95% CI = 1.30-4.58), when compared to those with three or less risk genotypes. Conclusions: Our findings indicated that genetic variants within mTORC1 genes may predict GC prognosis in Chinese populations. The results need to be validated in future studies with larger sample sizes.

Aim To confirm non-inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5-fluorouracil (5-FU)/cisplatin (FP) as first-line treatment for advanced gastric cancer (AGC) in Chinese patients. Methods In open-label phase III ML17032 trial, AGC (stage IIIA-IV) patients with or without metastases were randomized 1:1 to receive cisplatin (80 mg/m2 /day intravenous [IV] day 1) with either capecitabine (1000 mg/m2 /day oral [PO] twice daily [BID], days 1-14; XP) or 5-FU (800 mg/m2 /day continuous IV days 1-5; FP) every 3 weeks. The primary objective was to confirm the non-inferiority of XP over FP for progression-free survival (PFS). Results The intent-to-treat (ITT) population included 126 Chinese patients (XP-62, FP-64; 67.5% male, mean age 54.7 years). The primary analysis was performed on the per-protocol (PP) population (105 patients; XP-51, FP-54; 65.7% male). Median PFS in the XP and FP groups was 7.2 and 4.5 months, respectively. The adjusted hazard ratio (HR) for PFS was 0.52 (95% confidence interval [CI]: 0.32-0.83, P = 0.006). Unadjusted HR for PFS in the ITT population was 0.63 (95% CI, 0.42-0.94, P = 0.022). The most frequent drug-related grade 3/4 adverse events (AEs) were neutropenia (XP-20.7%, FP-17.7%) and gastrointestinal disorders (XP-19.0%, FP-19.4%). The overall incidence of grade 3/4 AEs (XP-43.1%, FP-46.8%), serious AEs (XP-1.7%, FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%, FP-16.1%) were comparable. Conclusion XP had a similar safety profile and may demonstrate superiority for PFS compared to FP as first-line treatment of Chinese patients with AGC (NCT02563054).

Purpose: The aim of the study was to investigate the effect of deficiency of hMLH1 and hMSH2 expression on the prognosis of early gastric cancer (EGC) in Chinese populations. Methods: A total of 160 EGC patients who underwent curative gastrectomy with lymphadenectomy from January 2011 to July 2014 at Xinhua Hospital were evaluated. The expression rates of hMLH1 and hMSH2 were examined using tissues preserved in paraffin blocks by immunohistochemical staining. The clinicopathological characteristics and prognosis of EGC with deficient hMLH1 and hMSH2 were analyzed. Results: On immunohistochemical staining, the loss expression of hMLH1 and hMSH2 were observed in 89 (55.6%) and 45 (28.1%), respectively. The hMLH1 deficiency was associated with the middle third of tumor location (P = 0.041). According to Kaplan-Meier survival analysis and Log-Rank test, the loss expression of hMLH1 and hMSH2 were associated with worse survival than positive hMLH1 (HR = 0.247, 95% CI = 0.078-0.781, P = 0.017) and hMSH2 (HR = 0.174, 95% CI = 0.051-0.601, P = 0.006) in EGC. Conclusion: The main conclusions were as follows: The hMLH1 deficiency was preferred to the middle third of EGC. Lymph node metastasis (LNM) was a prognostic factor of EGC. And the prognosis of EGC patients with deficient mismatch repair (dMMR, mainly including deficient hMLH1 and hMSH2) was obviously worse than proficient mismatch repair (pMMR).

Cervical cancer is the fourth most common female malignancy for both incidence and mortality worldwide and is one of the major threats to women's health. The role of long non‑coding RNAs (lncRNAs) in cervical cancer remains largely unknown. In the present study, the differentially expressed lncRNAs in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues were retrieved form The Cancer Genome Atlas (TCGA) and were analyzed. The expression analysis of related genes was performed with GEPIA. The proliferation and migratory and invasive abilities of MIR205HG knockdown CESC cells were analyzed using Cell Counting Kit‑8 and transwell assays. The expression of Ki‑67 and p16 was detected by immunofluorescence. A total of 203 differentially expressed lncRNAs were identified. The results demonstrated that MIR205HG was overexpressed in CESC tissues. Furthermore, the genes related to MIR205HG were enriched in cancer‑related pathways. MIR205HG knockdown significantly decreased the proliferation and migratory and invasive abilities of CESC cells. In addition, silencing of MIR205HG significantly decreased the expression of p16 in C‑33 A cells. The expression of fibroblast growth factor receptor 3, thymidine phosphorylase and GTPase HRas was downregulated in MIR205HG knockdown CESC cells. These findings revealed some potential lncRNA candidates for cervical cancer research and suggested that MIR205HG may have a pro‑tumor role in CESC.

Gastric cancer (GC) is one of the most common malignant tumors in the world. As anti-angiogenic therapy shows efficacy in the treatment of GC, but only works in certain patients, the identification of potential beneficiaries are urgently required in order to apply appropriate treatments. The Lauren classification demonstrates numerous differences in etiology, epidemiology and pathology; however, the association between Lauren classification and pro-angiogenic factors remains unclear. The present study aimed to investigate the clinicopathological factors associated with Lauren classification and the prognostic significance of Lauren classification and vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression in GC. Paraffin-embedded GC tissues and clinical information of 255 patients with GC were collected. The clinicopathological factors associated with Lauren classification were evaluated by Logistic regression analysis. Kaplan-Meier survival and Cox regression analyses were used to examine the prognostic significance of Lauren classification and of VEGF and VEGFR-2 expression in patients with GC. The results demonstrated that there was no association between Lauren classification and VEGF and VEGFR-2 expression. Furthermore, results from survival analysis demonstrated that Lauren classification (P=0.001) and Tumor-Node-Metastasis stage (stage II, P=0.002; stage III, P

Shuang-fen Tao, Wen-hua Gu, Jian-chun Gu, Mei-ling Zhu, Qing Wang, Lei-zhen Zheng Oncology Department, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, People’s Republic of ChinaCorrespondence: Lei-zhen ZhengOncology Department, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, People’s Republic of ChinaEmail zhengleizhen@xinhuamed.com.cnPurpose: This retrospective study was conducted to evaluate the safety and efficacy of high-intensity focused ultrasound (HIFU) ablation combined with Gemcitabine and Oxaliplatin (Gemox) for the treatment of middle and advanced pancreatic cancer in elderly patients.Methods: Forty-seven patients with pancreatic cancer treated with HIFU and Gemox were evaluated for inclusion, and 38 cases were finally included. The primary endpoint was safety. Secondary endpoints included the response rate, the clinical benefit response (CBR), overall survival (OS), progression-free survival (PFS).Results: After combination therapy of HIFU and Gemox, severe complications were rarely reported, and no treatment-related death occurred. The rate of three or four-degree myelosuppression was low, and no obvious impairment of hepatorenal function was observed. Pancreatitis and gastrointestinal injury did not occurred. The disease control rate (DCR) was estimated to be 76.3%, including complete remission (CR), partial remission (PR), stable disease (SD) in 1, 6, 22 cases, respectively. And the objective response rate (ORR) was 18.4%. The clinical benefit rate (CBR) was 68.4%, with the pain significantly relieved (P

The present study aimed to evaluate the efficacy and safety of acetyl-L-carnitine (ALC) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). The study was carried out as a prospective, randomized, double-blind, placebo-controlled and paralleled clinical study. A total of 239 patients with CIPN were selected as the study subjects. Of the 239 subjects, 118 subjects received 3 g/day ALC orally for 8 weeks and 121 received a placebo. The primary endpoint was improvement of peripheral neuropathy by at least one grade. Patient status was assessed at week 4, 8 and 12 after enrollment into the study. In both the full analysis set (FAS) and the per-protocol set (PPS), peripheral sensory neuropathy was significantly ameliorated in the ALC group with 50.5 and 51.6% patients meeting the primary endpoint at week 8, compared with 24.1 and 23.1% of patients in the placebo group (P

// Xueru Zhu 1, * , Zhao Wang 2, * , Jing He 2, 3 , Weiye Wang 4 , Wenji Xue 1 , Yiwei Wang 1 , Leizhen Zheng 1 , Mei-Ling Zhu 1 1 Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Yangpu, Shanghai, China 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China 3 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China 4 Shanghai Key Laboratory of Children’s Environmental Health, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Yangpu, Shanghai, China * These authors contributed equally to this work Correspondence to: Meiling Zhu, email: anniezhu_79@163.com Leizhen Zheng, email: zhengleizhen2006@126.com Keywords: CYP1A1, polymorphism, colorectal cancer, meta-analysis Received: March 22, 2016 Accepted: June 03, 2016 Published: June 30, 2016 ABSTRACT Cytochrome P450 1A1 (CYP1A1) enzyme is one of the most important metabolizing enzymes responsible for the metabolism of numerous xenobiotics. Numerous individual case-control studies have investigated the associations between the CYP1A1 rs1048943 A > G and rs4646903 T > C genetic variations and colorectal cancer (CRC) risk, but the conclusions were controversial. To obtain a scientific conclusion, we performed a meta-analysis based on a total of 26 publications, including 20 studies with 8665 cases and 9953 controls on rs1048943 A > G and 19 studies with 6416 cases and 7551 controls on rs4646903 T > C, respectively. The pooled analysis indicated that rs1048943 A > G was associated with an increased risk of CRC (G vs. A: OR = 1.28, 95% CI = 1.08−1.52; GG vs. AA: OR = 1.54, 95% CI = 1.25−1.91; GA vs. AA: OR = 1.26, 95% CI = 1.00−1.60; GG/GA vs. AA: OR = 1.31, 95% CI = 1.05−1.64; GG vs. GA/AA: OR = 1.56, 95% CI = 1.26−1.91). Stratification analysis showed the association between rs1048943 A > G and CRC risk was more obvious in studies with the population-based (PB) design or high quality score. The association between rs4646903 T > C and CRC risk did not reach statistical significance in the pooled analysis as well as stratification analysis. This meta-analysis demonstrated CYP1A1 rs1048943 A > G may increase the susceptibility to CRC instead of rs4646903 T > C. This conclusion suggested CYP1A1 may contribute to the pathogenesis of CRC.

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.

Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b-catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p

Objectives: Arsenic compounds have cytotoxic activities in gastric cancer cells, however, the underlying mechanism is unclear and the clinical potential need to be explored. This study was aimed to investigate the mechanism of arsenic on gastric cancer and find a novel regimen for the treatment of gastric cancer. Methods: Gastric cancer cell lines were treated with arsenics and/or chemotherapeutic drugs. MTT assay, FACS, Western blotting, q-RT-PCR and CHIP were used to detect proliferation, modulation of proteins and genes. Results: We previously showed that NFATc3 was a target of Arsenic sulfide and its inhibition blocks gastric cancer growth. Here we show that the NFATc3 expression is critically important for the growth and survival of gastric cancer cells because knockdown of NFATc3 resulted in DNA damage and cell cycle arrest. Arsenic sulfide can target NFATc3 in gastric cancer cells and cause cell double-strand DNA breaks (DSB). However, overexpression of NFATc3 can block the DNA damage. Abolishing NFATc3 expression, whether by shRNA-induced silencing or Arsenic sulfide treatment, directly upregulated recombination activating gene 1 (RAG1, an endonuclease which is essential for immunoglobulin V(D)J recombination), leading to fatal DSB. NFATc3 targets the promoter of RAG1 for transcriptional inhibition. Moreover, we find that Arsenic sulfide and topoisomerase inhibitors (Irinotecan and Epirubicin, Doxorubicin, Etoposide and SN38) synergistically inhibit gastric cancer. Arsenic sulfide, as well as Arsenic Trioxide, enhanced the cytotoxic effect of Irinotecan and they synergistically induced NFATc3 degradation, resulted in disability of DNA repair system, as reflected by the decrease in the phosphorylated ATM/CHK2/CHK1 protein level and the dramatic increase in the phosphorylated H2AX protein level. More inspiring, a patient with advanced gastric cancer with liver and lymph-node metastasis who failed in first-line treatment achieved PR with 2 months treatment of Irinotecan combined with Realgar-Indigo Naturalis Formula, the main component of which is Arsenic sulfide. The progression-free survival was 4 months with no additional adverse event. Conclusions: Our research links arsenic compounds to the regulation of DNA damage repair and RAG1 expression as a mechanism for the cytotoxic effect. The combination of arsenic with topoisomerase inhibitors may represent a novel regimen for the treatment of gastric cancer and warrants further studies. Citation Format: Ting Kang, Maolin Ge, Shumin Lu, Qing Wang, Shouhai Zhu, Chuanying Zhu, Leizhen Zheng, Han Liu, Siyu Chen. Combining arsenic and topoisomerase inhibitors synergistically inhibit gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6265.

MicroRNAs (miRNAs) may contribute to the initiation and progression of cancer. The role of circulating miRNAs as predictors of recurrence in esophageal adenocarcinoma (EAC) has not been extensively explored. Here we measured the expressions of 167 miRNAs in serum samples from a discovery cohort of 72 EAC patients (32 patients with recurrence and 40 patients without). A rank sum test was performed to identify differentially expressed miRNAs. Cox regression model was applied to estimate the effect of miRNA expression on recurrence-free survival. The eligible miRNAs were then validated in an independent cohort of 329 EAC patients (132 patients with recurrence and 197 patients without). miR-331-3p was identified and confirmed to be differentially expressed between EAC patients with and without recurrence and associated with recurrence-free survival. In both cohorts, the expression of miR-331-3p was consistently decreased in patients with recurrence compared to those without (P P = 0.040) and 0.55 (95% CI, 0.38–0.78, P = 0.001) in the discovery and validation cohorts, respectively. Therefore, serum miR-331–3p may be a useful biomarker for identifying EAC patients at high risk of recurrence.

Background The V325 study showed that docetaxel, cisplatin, and fluorouracil (DCF) prolonged overall survival (OS) of patients with advanced gastric cancer, but with a high incidence of dose-limiting toxicities. We investigated the efficacy and safety of a modified DCF (mDCF) regimen for Chinese patients with advanced gastric cancer. Methods Untreated advanced gastric cancer patients randomly received docetaxel and cisplatin at 60 mg/m2 (day 1) followed by fluorouracil at 600 mg/m2/day (days 1–5; mDCF regimen) or cisplatin at 75 mg/m2 (day 1) followed by fluorouracil at 600 mg/m2/day (days 1–5; CF) every 3 weeks. The primary end point was progression-free survival (PFS). The secondary end points were OS, overall response rate (ORR), time-to-treatment failure (TTF), and safety. Results In total, 243 patients were randomized to treatment (mDCF regimen 121; CF 122). Compared with CF, the mDCF regimen significantly improved PFS and OS: the median PFS was 7.2 and 4.9 months, respectively [hazard ratio (HR) 0.58, log-rank P = 0.0008], and the median OS was 10.2 and 8.5 months, respectively (HR = 0.71, P = 0.0319). Additionally, the mDCF regimen improved the parameters used as secondary objectives: the ORR was 48.7 % with the mDCF regimen versus 33.9 % with CF (P = 0.0244); the median TTF was 3.4 months with the mDCF regimen and 2.4 months with CF (HR = 0.67, P = 0.0027). Grade 3 and grade 4 treatment-related adverse events occurred in 77.3 % of patients who received the mDCF regimen versus 46.1 % of patients who received CF (P

Background Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Patients and methods We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Results Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p

Landmark analyses. Table S2. Distribution of risk scores and risk groups. (DOCX 61 kb)

The prognostic significance of HER2 expression in patients with gastric cancer remains controversial, partially due to the significant heterogeneity of the approaches and criteria used for HER2 assessment among different studies. We therefore conducted a meta-analysis enrolling only studies defining HER2 status by trastuzumab for gastric cancer (ToGA) criteria. Published studies investigating the association between HER2 expression and survival were identified. Only publications that defined HER2 expression using ToGA criteria were enrolled. Meta-analyses were performed by Revman 5.2. Pooled hazard ratio (HR) and its 95 % confidence interval (CI) were calculated to evaluate the risk of disease. A total of 11 studies were enrolled in meta-analyses. Pooled data of nine studies using univariate analysis showed that HER2 expression is not associated with overall survival (OS; pooled HR, 0.97; 95 % CI, 0.84–1.12; P = 0.63), which are maintained in six studies of multivariate analysis (pooled HR, 1.01; 95 % CI, 0.75–1.35; P = 0.95). The Q statistic test for nine studies of univariate analysis and for six studies of multivariate analysis showed no and low heterogeneity (I2 = 22 % and P = 0.25; I2 = 41 % and P = 0.13, respectively). Furthermore, pooled data of four studies without heterogeneity (I2 = 0 %, P = 0.74) showed that HER2 expression were not associated with relapse-free survival as well, with a pooled HR of 1.08 (95 % CI, 0.84–1.37; P = 0.55) in patients with HER2 expression. In conclusion, this meta-analysis indicated that HER2 expression based on ToGA criteria is not related to the survival in patients with gastric cancer.

Xeroderma pigmentosum complementation group C (XPC) gene plays a critical role in DNA damage recognition, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and cancer susceptibility. Numerous epidemiological studies have investigated the associations between XPC Lys939Gln and Ala499Val polymorphisms and lung cancer susceptibility, but the conclusions are inconclusive. We searched three electronic databases (MEDLINE, EMBASE and EBSCO) for eligible publications and performed a meta-analysis assessing the associations between XPC Lys939Gln and Ala499Val polymorphisms and lung cancer risk. We also analysed the genotype-mRNA expression correlation using the data of HapMap phase II release 23 with 270 individuals from 4 ethnicities for exploring biological plausibility of our findings. We included ten published studies of 3,882 cases and 5,219 controls for Lys939Gln, and five studies with 2,605 cases and 3,329 controls for Ala499Val. When all studies were pooled, we found a significantly increased overall lung cancer risk for Lys939Gln polymorphism (recessive model: OR = 1.14, 95 % CI = 1.01–1.29, P = 0.218 for heterogeneity). Stratification analysis also showed a higher lung cancer risk in Asian populations (recessive model: OR = 1.26, 95 % CI = 1.04–1.52, P = 0.263 for heterogeneity). Interestingly, we found significant correlation between Lys939Gln genotypes and XPC mRNA expression for Asian populations as well. However, we did not observe any association between Ala499Val polymorphism and overall lung cancer risk, nor in further stratification analysis. This meta-analysis suggests that XPC Lys939Gln polymorphism may contribute to lung cancer risk, which needs further validation in single larger studies.

Genome-wide association studies have reported a promising association of rs4072037 with gastric cancer (GC). This variant was associated with altered physiological function of MUC1 possibly by modulating promoter activity and alternative splicing of MUC1. However, the association results were inconclusive and estimate of the effect of this variant was not well evaluated. A meta-analysis by systematically reviewing relevant reports may facilitate to address these concerns. Association studies involving MUC1 rs4072037 polymorphism and GC risk were identified up to June 30, 2012. Odds ratio (OR) and 95 % confidence interval (CI) in additive model were estimated or extracted from each study. The pooled effect size was quantitatively synthesized using meta-analysis. Heterogeneity between studies was measured by the Q test and I 2 statistic, and publication bias was evaluated by a funnel plot and the Egger’s test. A total of 10 independent case–control studies including 6,580 GC cases and 10,324 controls were included in this meta-analysis. Eight of the ten studies were Asian ethnicity and two European. The G allele of MUC1 rs4072037 was significantly associated with a decreased risk of GC (OR = 0.72, 95 % CI 0.68–0.77; P = 7.82 × 10−25), as compared with A allele. Stratification for different ethnicity, tumor localization or type showed similar results. These findings represent important evidence for association of MUC1 rs4072037 variant with GC risk, and also provide a relatively reliable estimate of effect size. MUC1 is a strong candidate as a susceptibility gene of GC.

Purpose Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC. Patients and Methods Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C). Results We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare. Conclusion Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.

Background Previous studies have shown that human epidermal growth factor receptor 2 (HER2) may play an important role in the invasion and metastasis of pancreatic cancer, but the relationship between HER2 amplification level and prognosis of pancreatic cancer patients is still controversial. Therefore, we performed a meta-analysis to determine the prognostic significance of HER2 amplification based on fluorescence in situ hybridization (FISH) in patients with pancreatic cancer. Methods PubMed, EMBASE, and Web of Science (Jan 2001 to Jun 2015) were searched. Only articles that detect the HER2 amplification by FISH method were included. RevMan 5.3 and STATA version 12 were used to perform this meta-analysis. Pooled calculations were carried out on hazard ratio (HR) and 95 % confidence interval (CI) to assess the risk of disease. Results A total of six eligible studies were enrolled in meta-analysis. The univariate analysis results showed that HER2 amplification was not significantly associated with patients’ overall survival (pooled HR, 1.87, 95 % CI, 0.64–5.46, P = 0.25), which are maintained in one study of multivariate analysis (HR 0.51, 95 % CI, 0.12–2.14, P = 0.358). HER2 amplification also had no correlation with clinicopathological factors such as age, gender, lymph node metastasis, and tumor stage. Conclusions Our results showed that HER2 amplification based on FISH may not be a good prognostic factor for survival in patients with pancreatic cancer.

A variety of triple antiemetic regimens are being used to prevent cisplatin-based chemotherapy induced delayed emesis and nausea in cancer patients. We performed a network meta-analysis to compare the efficacies of the different regimens. Electronic searches of the PubMed, Cochrane Library and MEDLINE databases were performed to identify randomized controlled trials, and data were analyzed using JAGS, Stata 14.0 and R project. The primary outcome was a complete response (CR). The secondary outcomes were no vomiting (NV) and no nausea (NN). Among the 398 studies identified, 10 were eligible and included, providing data on nine regimens. In the CR analysis, the absolute rank of netupitant + palonosetron + dexamethasone (NEPA) was 0.8579. In the NV and NN analyses, NEPA's absolute ranks were 0.8631 and 0.7902, respectively. The compliance of patients treated with rolapitant + granisetron + dexamethasone (RGD) was the best due to a low incidence of adverse events, and good compliance was also observed with NEPA. It was difficult to achieve good compliance with aprepitant + granisetron + dexamethasone (AGD). Overall, NEPA was the best regimen, and aprepitant + ondansetron + dexamethasone (AOD) is also worthy of recommendation because of its low cost and good effect. For patients with severe constipation, hiccups, asthenia and/or delayed nausea, RGD is worthy of consideration.

Phospholipase C epsilon 1 (PLCE1) plays an important role in cell growth, differentiation and oncogenesis. An increasing number of individual studies have investigated the association between PLCE1 rs2274223 polymorphism and cancer risk, but the conclusions are inconclusive. To obtain a comprehensive conclusion, we performed a meta-analysis of 22 studies with 13188 cases and 14666 controls. The pooled results indicated that PLCE1 rs2274223 A > G polymorphism was associated with an increased risk of overall cancer (G vs. A: OR = 1.15, 95% CI = 1.06–1.25; GG vs. AA: OR = 1.30, 95% CI = 1.10–1.55; GA vs. AA: OR = 1.18, 95% CI = 1.08–1.30; GG/GA vs. AA: OR = 1.20, 95% CI = 1.08–1.32; GG vs. GA/AA: OR = 1.22, 95% CI = 1.04–1.42). The stratification analysis showed the polymorphism was significantly associated with an increased risk of esophageal squamous cell carcinoma (ESCC) other than gastric cancer (GC), especially among the subgroups of Asian, high quality score, sample size > 1000 and the studies consistent with Hardy-Weinberg equilibrium (HWE). This meta-analysis demonstrated that PLCE1 rs2274223 A > G polymorphism may be associated with increased susceptibility to cancer, especially for ESCC. However, due to the substantial heterogeneities across the studies, the conclusion might be not conclusive that need more studies to confirm.

Sulfotransferases (SULT) catalyze both the bioactivation and detoxification of a wide range of promutagens and procarcinogens. SULT1A1 appears to be an important phenol SULT because of its abundance and distribution in many tissues and wide substrate specificity. The SULT1A1 gene possesses a G--A polymorphism that results in an Arg to His amino acid substitution, and the His(213) allele has been shown to have low activity and low thermal stability. Because of its functional role and published data showing the influence of Arg213His polymorphism on the risk of some cancers, we hypothesized that the His(213) allele of the SULT1A1 gene may modify bladder cancer risk. To test this hypothesis, we determined the SULT1A1 Arg213His genotypes in 384 incident bladder cancer patients and 386 healthy frequency-matched controls. A comprehensive epidemiologic interview was conducted on all participants to collect personal information, such as demographics and smoking status. The Arg/His and His/His genotypes were more common in the controls than the cases (P=0.035), resulting in a His(213) allele frequency of 35.0% in controls and 28.8% in cases. When individuals with the His(213) allele genotypes (Arg/His+His/His) were combined and compared to individuals with the Arg/Arg genotype, we observed a statistically significant reduced risk of bladder cancer (OR=0.72; 95% CI 0.54-0.97). When we examined the data by gender, there was a statistically significant reduced risk of bladder cancer only in women (OR=0.42; 95% CI 0.23-0.78) and not in men (OR=0.84; 95% CI 0.60-1.19) with the His(213) genotypes. In addition, there was a reduced bladder cancer risk in never smokers (OR=0.59; 95% CI 0.36-0.98) with the His(213) allele genotypes, but not in former (OR=0.82; 95% CI 0.54-1.25) or current smokers (OR=0.68; 95% CI 0.29-1.58). The His(213) allele genotypes also appeared to provide some protective benefit for current and former smokers, as compared to those with the Arg/Arg genotype. In conclusion, this study provides epidemiologic evidence of a reduced bladder cancer risk associated with the SULT1A1 His(213) polymorphism. Further studies are warranted to elucidate the function of this SULT1A1 polymorphism with regard to organ specificity, gene-environment interactions, and the gender-related difference we observed.

Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.

The effect of blockade of NF-kappaB activity on human pancreatic cancer angiogenesis was determined in an orthotopic xenograft model. Highly metastatic L3.3 human pancreatic cancer cells, which expressed an elevated level of constitutive NF-kappaB activity, were transfected with a mutated IkappaBalpha (IkappaBalphaM). After implantation in the pancreas of nude mice, parental (L3.3) and control vector-transfected (L3.3-Neo) cells produced rapidly growing tumors and liver metastases, whereas IkappaBalphaM-transfected (L3.3-IkappaBalphaM) cells had decreased tumorigenicity and metastatic potential. NF-kappaB signaling blockade significantly inhibited the in vitro and in vivo expression of the major proangiogenic molecules vascular endothelial growth factor and interleukin-8 and decreased tumor vascular formation. These events were correlated with retarded tumor growth and suppression of metastasis. Collectively, these data suggest that suppression of tumorigenicity and metastasis by NF-kappaB blockade is due to impaired angiogenic potential of tumor cells.

4052 Background: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. Methods: We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria or hand and foot syndrome (HFS) in the first 4 weeks using Kaplan–Meier methods, Cox proportional hazard regression and logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model and risk scores were analyzed to predict overall survival (OS). Results: Presence of AEs in the first 4 weeks was associated with prolonged median OS (169 vs. 103 days, log-rank p=0.0039; adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.64-0.84, p=0.001), prolonged median progression-free survival (PFS, 87 vs. 62 days, log-rank p=0.0309; adjusted HR 0.69, 95%CI 0.53-0.91, p=0.007), and increased disease control rate (54.67% vs. 32.77%; adjusted odds ratio 2.67, p

571 Background: The clinical benefit and safety profile associated with raltitrexed in patients with advanced colorectal cancer (CRC) were established. However, safety information of raltitrexed in Chinese patients is rare. We aimed to assess the safety of raltitrexed monotherapy in Chinese patients with advanced CRC. Methods: This single-arm, open-label, multi-center, phase IV trial was conducted in 13 hospitals across China between March 2011 and July 2014. Patients with locally advanced or recurrent and metastatic colorectal cancer (mCRC) received raltitrexed (3mg/m2) as a 15-min infusion on day 1, every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was safety and the secondary objectives were disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: A total of 215 patients were enrolled, and the safety was assessed in 205 patients. 92 patients had 394 Adverse events (AEs) during the study. A majority (94.4%) of AEs was grade 1/2 and only 5.3% was grade 3/4. Most AEs were either resolved spontaneously or treated successfully with standard medical interventions. Severe AEs were reported by 5.8% (12/205) of patients. The most commonly reported AEs were increase of transaminases, leukopenia, nausea and vomiting. Serum transaminase elevation, an important safety concern associated with raltitrexed therapy, were transient, self-limiting and manageable. No deaths were reported during the study. The DCR in second-line and third-line therapy by raltitrexed reached 49.5% and 37.4%, respectively. The median PFS in second-line and third-line therapy was 1.43 months and 1.47 months, respectively. The median OS was 13.6 months and 8.9 months, respectively. Conclusions: Raltitrexed monotherapy is a safe, well-tolerated and convenient therapy option for Chinese patients. The treatment-associated toxicity is manageable and does not lead to discontinuation of treatment in oncology practice.